**Insights into Visual Cortex Plasticity: Interaction Between Genes and Sensory Experience**

José Fernando Maya-Vetencourt and Matteo Caleo

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/50721

## **1. Introduction**

278 Visual Cortex – Current Status and Perspectives

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[65] Ortuzar N, Argandoña EG, Bengoetxea H, Leis O, Bulnes S, Lafuente JV (2010) Effects of VEGF administration or neutralization on the BBB of developing rat brain. Acta

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[68] Storkebaum E, Lambrechts D, Carmeliet P (2004) VEGF: once regarded as a specific angiogenic factor, now implicated in neuroprotection. Bioessays. 26(9):943-954. [69] Kaya D, Gursoy-Ozdemir Y, Yemisci M, Tuncer N, Aktan S, Dalkara T (2005) VEGF protects brain against focal ischemia without increasing blood--brain permeability when administered intracerebroventricularly. J Cereb Blood Flow Metab. 25(9):1111-

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The central nervous system architecture is highly dynamic and continuously modified by sensory experience through processes of neuronal plasticity. Interactions with the external world, mediated by sensory input, update and modify the structural and functional architecture of the nervous system, particularly during short-term sensitive periods in early life (critical period (CP) for brain plasticity) during which experience drives the consolidation of synaptic circuitries (Katz & Shatz 1996; Berardi et al., 2000; Levelt & Hubener 2012). However, experience-dependent reorganization of neuronal circuitries continues in adult life, at least to some extent.

The visual cortex (VC) is a classical model to examine the influence of sensory experience on brain structure and function. Early electrophysiological studies demonstrated that occlusion of one eye (monocular deprivation, MD) during the CP leads to an ocular dominance (OD) shift of visual cortical neurons, i.e., a decrease in the number of cells responding to the deprived eye that is accompanied by an increment of cells driven by the open eye (Wiesel & Hubel 1963; Hubel & Wiesel 1970; Frenkel & Bear 2004). In addition, the deprived eye becomes amblyopic: its spatial acuity and contrast sensitivity are markedly impaired. At structural level, unilateral eyelid suture causes a reduction in the arborisation of geniculocortical terminals that serve the deprived eye, which parallels an increased spread of terminals serving the open eye (Antonini & Stryker 1993). Because MD does not cause amblyopia in adult life this is a typical example of a CP. These findings highlight the notion that sensory experience is critical for normal development of the nervous system.

The importance of sensory experience in development of the human brain is well exemplified by cases of strabismic or anisometric children that underwent no clinical treatment during early development. In either pathological condition proper visual experience is altered, causing a marked impairment of normal visual functions (amblyopia)

<sup>©</sup> Maya-Vetencourt and Caleo, licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2012 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

that is irreversible if not treated before 8 years of age (Holmes & Clarke 2006; Friedman et al., 2009; Maurer & Hensch 2012). A similar phenomenon is described by clinical observations of children born with congenital cataracts, a pathological condition in which the lens of the eye becomes milky and therefore no longer permits images to form on the retina (Lloyd et al., 2007; Milazzo et al., 2011). The recovery of normal visual functions after long-term sensory deprivation has long been a subject of study with the prospect of finding therapies for human amblyopia. Although amblyopia can be prevented by different strategies that restore the formation of proper retinal images or by eye patching in early life, such treatments are normally ineffective in adulthood. These observations indicate that proper sensory experience during early stages of development is necessary for normal visual perception and also point towards the enhancement of neuronal plasticity as a strategy for brain repair in adult life.

Insights into Visual Cortex Plasticity: Interaction Between Genes and Sensory Experience 281

also influenced by attentional mechanisms (Singer 1995). Sensory signals, for instance, promote marked modifications of neural circuitries only when animals attend to the sensory input and use this information for the control of behaviour (Singer 1990, 1995). Early studies performed in cats demonstrated that changes of visual cortical circuitries in response to experience during early life, are lessened when noradrenergic (Kasamatsu & Pettigrew 1979; Bear & Singer 1986), cholinergic (Gu & Singer 1993) and serotonergic (Gu & Singer 1995; Wang et al., 1997) projections to the cortex are inactivated. Moreover, there is evidence that these neuromodulatory systems mediate forms of plasticity in the adult visual system of cats (Pettigrew & Kasamatsu 1978; Kasamatsu et al., 1979; Kasamatsu et al., 1985; Imamura & Kasamatsu 1991; Mataga et al., 1992) and rodents (Maya-Vetencourt et al., 2008; Baroncelli et

Advances in the understanding of mechanisms by which neuromodulatory systems modulate experience-dependent plasticity derive from *in vitro* studies of synaptic plasticity. There is ample evidence that noradrenaline, acetylcholine and serotonin modulate two different forms of activity-dependent synaptic modifications: long-term potentiation (LTP) and long-term depression (LTD) (Kirkwood 2000). In the visual system, LTP and LTD can be induced by different patterns of electrical stimulation. Brief and strong episodes of high frequency stimulation promote LTP while prolonged low-frequency stimulation yields LTD. In the rodent VC, upon administration of noradrenaline and acetylcholine, weaker tetanic stimulation is required to induce LTP and shorter episodes of low frequency stimulation are needed to drive LTD (Brocher et al., 1992; Kirkwood et al., 1999). Likewise, serotonin facilitates the induction of both LTP and LTD in layer IV of the kitten VC (Kojic et al., 1997). Taken together, these findings are consistent with a role for neuromodulatory systems as enabling factors for visual cortical plasticity and indicate that activation of noradrenergic, cholinergic, and serotonergic receptors lowers the threshold of activity required for the induction of LTP and LTD. Intracellular mechanisms whereby neuromodulatory systems facilitate these forms of synaptic plasticity have been subject of extensive study. In the VC, the induction of LTP and LTD requires the activation of N-methyl-D-aspartate (NMDA) receptors together with a postsynaptic rise in intracellular calcium. The available evidence is consistent with a model in which the magnitude and duration of the calcium signal determines the magnitude of the synaptic modification (Bear 1996). Brief and large calcium influxes induce LTP, whereas smaller and prolonged calcium increases yield LTD. Of note, receptors of these three major neuromodulatory systems are able to activate the IP3 second messenger pathway, which can induce calcium release from intracellular stores and

Because the intracortical inhibitory/excitatory (I/E) ratio is critical for the induction of neuronal plasticity in the visual system (Jiang et al., 2005; Sale et al., 2010), the neuromodulators-mediated fine-tuning of the I/E balance may also play a critical role for the induction of experience-dependent plasticity. In line with this, the enhanced action of serotonin and/or acetylcholine decreases the intracortical I/E balance in the rodent visual

al., 2010; Maya-Vetencourt et al., 2011).

therefore modulate plasticity.

system (Amar et al., 2010; Moreau et al., 2010).

## **2. Sensory experience triggers the maturation of inhibitory circuitries that control the time-course of the CP**

Among the different factors that regulate the CP for VC plasticity, inhibitory processes seem to play a critical role. Visual experience seems to signal the time-course of the CP by promoting the transfer of the protein Otx2 from the retina to the VC, where Otx2 gradually promotes the maturation of parvalbumin-positive GABAergic interneurons (Sugiyama et al., 2008). An initial threshold of inhibition then triggers the CP in which neural networks are highly susceptible to sensory experience (Hensch et al., 1998; Fagiolini & Hensch 2000), while a second inhibitory threshold signals the end of this phase of enhanced plasticity (Huang et al., 1999). A direct demonstration that GABAergic inhibition is a crucial brake limiting VC plasticity derives from the recent observation that a pharmacological reduction of inhibitory transmission effectively restores OD plasticity in adulthood (Harauzov et al., 2010). This is consistent with the fact that experimental paradigms such as dark exposure (He et al., 2006), environmental enrichment (Baroncelli et al., 2010; Sale et al., 2010), food restriction (Spolidoro et al., 2011), long-term fluoxetine (FLX) administration (Maya-Vetencourt et al., 2008; Chen et al., 2011; Maya-Vetencourt et al., 2011), and exogenous IGF-I administration (Maya-Vetencourt et al., 2012), all promote plasticity late in life by reducing the intracortical inhibitory/excitatory (I/E) ratio. This has prompted the search for endogenous factors with the potential to enhance plasticity in adult life by modulating the intracortical I/E balance.

## **3. Long-distance projection systems regulate plasticity in the visual system**

The major modulatory systems in the brain (i.e., noradrenaline, dopamine, histamine, acetylcholine, serotonin) regulate complex functions of the central nervous system such as cognition, behaviour, and neuronal plasticity. Experience-dependent modifications of cortical circuitries are not determined solely by local correlations of electrical activity but are also influenced by attentional mechanisms (Singer 1995). Sensory signals, for instance, promote marked modifications of neural circuitries only when animals attend to the sensory input and use this information for the control of behaviour (Singer 1990, 1995). Early studies performed in cats demonstrated that changes of visual cortical circuitries in response to experience during early life, are lessened when noradrenergic (Kasamatsu & Pettigrew 1979; Bear & Singer 1986), cholinergic (Gu & Singer 1993) and serotonergic (Gu & Singer 1995; Wang et al., 1997) projections to the cortex are inactivated. Moreover, there is evidence that these neuromodulatory systems mediate forms of plasticity in the adult visual system of cats (Pettigrew & Kasamatsu 1978; Kasamatsu et al., 1979; Kasamatsu et al., 1985; Imamura & Kasamatsu 1991; Mataga et al., 1992) and rodents (Maya-Vetencourt et al., 2008; Baroncelli et al., 2010; Maya-Vetencourt et al., 2011).

280 Visual Cortex – Current Status and Perspectives

strategy for brain repair in adult life.

intracortical I/E balance.

**system** 

**control the time-course of the CP** 

that is irreversible if not treated before 8 years of age (Holmes & Clarke 2006; Friedman et al., 2009; Maurer & Hensch 2012). A similar phenomenon is described by clinical observations of children born with congenital cataracts, a pathological condition in which the lens of the eye becomes milky and therefore no longer permits images to form on the retina (Lloyd et al., 2007; Milazzo et al., 2011). The recovery of normal visual functions after long-term sensory deprivation has long been a subject of study with the prospect of finding therapies for human amblyopia. Although amblyopia can be prevented by different strategies that restore the formation of proper retinal images or by eye patching in early life, such treatments are normally ineffective in adulthood. These observations indicate that proper sensory experience during early stages of development is necessary for normal visual perception and also point towards the enhancement of neuronal plasticity as a

**2. Sensory experience triggers the maturation of inhibitory circuitries that** 

Among the different factors that regulate the CP for VC plasticity, inhibitory processes seem to play a critical role. Visual experience seems to signal the time-course of the CP by promoting the transfer of the protein Otx2 from the retina to the VC, where Otx2 gradually promotes the maturation of parvalbumin-positive GABAergic interneurons (Sugiyama et al., 2008). An initial threshold of inhibition then triggers the CP in which neural networks are highly susceptible to sensory experience (Hensch et al., 1998; Fagiolini & Hensch 2000), while a second inhibitory threshold signals the end of this phase of enhanced plasticity (Huang et al., 1999). A direct demonstration that GABAergic inhibition is a crucial brake limiting VC plasticity derives from the recent observation that a pharmacological reduction of inhibitory transmission effectively restores OD plasticity in adulthood (Harauzov et al., 2010). This is consistent with the fact that experimental paradigms such as dark exposure (He et al., 2006), environmental enrichment (Baroncelli et al., 2010; Sale et al., 2010), food restriction (Spolidoro et al., 2011), long-term fluoxetine (FLX) administration (Maya-Vetencourt et al., 2008; Chen et al., 2011; Maya-Vetencourt et al., 2011), and exogenous IGF-I administration (Maya-Vetencourt et al., 2012), all promote plasticity late in life by reducing the intracortical inhibitory/excitatory (I/E) ratio. This has prompted the search for endogenous factors with the potential to enhance plasticity in adult life by modulating the

**3. Long-distance projection systems regulate plasticity in the visual** 

The major modulatory systems in the brain (i.e., noradrenaline, dopamine, histamine, acetylcholine, serotonin) regulate complex functions of the central nervous system such as cognition, behaviour, and neuronal plasticity. Experience-dependent modifications of cortical circuitries are not determined solely by local correlations of electrical activity but are Advances in the understanding of mechanisms by which neuromodulatory systems modulate experience-dependent plasticity derive from *in vitro* studies of synaptic plasticity. There is ample evidence that noradrenaline, acetylcholine and serotonin modulate two different forms of activity-dependent synaptic modifications: long-term potentiation (LTP) and long-term depression (LTD) (Kirkwood 2000). In the visual system, LTP and LTD can be induced by different patterns of electrical stimulation. Brief and strong episodes of high frequency stimulation promote LTP while prolonged low-frequency stimulation yields LTD. In the rodent VC, upon administration of noradrenaline and acetylcholine, weaker tetanic stimulation is required to induce LTP and shorter episodes of low frequency stimulation are needed to drive LTD (Brocher et al., 1992; Kirkwood et al., 1999). Likewise, serotonin facilitates the induction of both LTP and LTD in layer IV of the kitten VC (Kojic et al., 1997). Taken together, these findings are consistent with a role for neuromodulatory systems as enabling factors for visual cortical plasticity and indicate that activation of noradrenergic, cholinergic, and serotonergic receptors lowers the threshold of activity required for the induction of LTP and LTD. Intracellular mechanisms whereby neuromodulatory systems facilitate these forms of synaptic plasticity have been subject of extensive study. In the VC, the induction of LTP and LTD requires the activation of N-methyl-D-aspartate (NMDA) receptors together with a postsynaptic rise in intracellular calcium. The available evidence is consistent with a model in which the magnitude and duration of the calcium signal determines the magnitude of the synaptic modification (Bear 1996). Brief and large calcium influxes induce LTP, whereas smaller and prolonged calcium increases yield LTD. Of note, receptors of these three major neuromodulatory systems are able to activate the IP3 second messenger pathway, which can induce calcium release from intracellular stores and therefore modulate plasticity.

Because the intracortical inhibitory/excitatory (I/E) ratio is critical for the induction of neuronal plasticity in the visual system (Jiang et al., 2005; Sale et al., 2010), the neuromodulators-mediated fine-tuning of the I/E balance may also play a critical role for the induction of experience-dependent plasticity. In line with this, the enhanced action of serotonin and/or acetylcholine decreases the intracortical I/E balance in the rodent visual system (Amar et al., 2010; Moreau et al., 2010).

## **4. Non-visual components of the environment alter visual system development**

Insights into Visual Cortex Plasticity: Interaction Between Genes and Sensory Experience 283

rodents, as in other mammals, callosal terminals are particularly concentrated in the area of primary VC mapping the central part of the visual field (Mizuno et al., 2007), thus contributing to binding together the two representations of the visual hemifields in the two hemispheres. A crucial role for callosal input activity in the functional maturation of the VC was indicated by experiments in which activity was unilaterally blocked in the striate cortex during the CP. Transient blockade of synaptic activity arrested maturation of visual acuity not only in the treated, but also in the contralateral hemisphere (Caleo et al., 2007). The CP for plasticity was also extended in both hemispheres (Caleo et al., 2007). These findings indicate that maturation of the blocked cortex is superimposable to that of the opposite side. Since the contralateral hemisphere maintains normal vision through the retinogeniculate pathway and only lacks callosal input, these data point towards a fundamental role for callosal linkages in regulating the process of cortical maturation. Similar conclusions have been drawn from experiments in knockout mice with reduced callosal connectivity; when tested as adults, these animals display a reduced visual acuity and a persistent OD plasticity (Pinto et al., 2009). The notion that inter-hemispheric callosal projections play a key role in the maturation of visual functions is exemplified by experimental observations in cats and humans. Early sections of the callosum in kittens, indeed, cause a reduction in the behavioural measure of visual acuity (Elberger 1984). Consistently, patients with hemianopia show impairments in figure detection tasks also in the intact hemifield, suggesting that these deficits may be caused by the loss of inter-hemispheric interactions

Other studies have indicated a role for the callosum in determining both normal binocularity and the shift of OD that follows a period of monocular eyelid suture in juvenile rats. In rodents, retinogeniculate afferent input to the cortex from the contralateral eye is much stronger than that from the ipsilateral eye. Indeed, over 95% of retinal fibers decussate at the chiasm. However, cells mapping the central part of the visual field are highly binocular, and experiments support the view that callosal afferents contribute to this binocularity by providing input from the ipsilateral eye. In particular, acute inactivation of transcallosal input activity in rats shifts OD towards the contralateral eye (Diao et al., 1983), due to a loss of ipsilateral eye responses (Restani et al., 2009). In a complementary experiment, binocularity was recorded before and after acute inactivation of thalamocortical input to isolate visual responses driven exclusively by callosal afferents in young rats (Cerri et al., 2010). After blockade of the ipsilateral thalamus, cortical neurons display a dramatic loss of contralateral eye driven responses, while ipsilateral eye driven responses are reduced to a less extent (Cerri et al., 2010). These experiments indicate that in rats, a substantial fraction of the influence of the ipsilateral eye on cortical responses arrives via callosal

Not only normal binocularity, but also the shift of OD that follows MD appears to depend on the function of callosal fibers. In particular, acute inactivation of transcallosal input activity restores binocularity after MD in juvenile rats (Restani et al., 2009). This recovery of binocularity following callosal silencing is due to an unexpected and selective increase in the strength of the deprived eye. Thus, acute removal of callosal influence following MD

connections from the opposite hemisphere, where it is the dominant eye.

(Paramei & Sabel 2008).

In addition to MD, another classical paradigm used to assess the impact of experience in the functional maturation of the visual system is dark rearing (i.e., rearing animals in total darkness from birth). When dark-reared animals are brought back into the light, they turn out to be blind or, at least, display marked impairments of normal visual functions (Fagiolini et al., 1994). Total absence of visual experience delays the functional maturation of the striate cortex; an event that seems to be mediated by a down-regulation of BDNF expression (Castren et al., 1992), which results in a retarded maturation of GABAergic circuitries (Morales et al., 2002). The spatial resolution of visual cortical neurons is, in fact, reduced in dark-reared animals, this phenomenon being accompanied by longer latencies of responses to visual stimuli (Blakemore & Price 1987; Fagiolini et al., 1994). Moreover, visual cortical neurons have larger receptive field sizes and show alterations in the density of dendritic spines, which are shorter and fewer in dark-reared animals as compared to normally reared counterparts (Wallace & Bear 2004). Noteworthy, rearing animals in complete darkness extents the critical period far beyond its normal limits (Hensch 2005).

Although early studies of the visual system showed that sensory experience after eye opening is necessary for the functional maturation of the VC (Wiesel & Hubel 1963, 1963; Hubel & Wiesel 1970; LeVay et al., 1980), the notion that non-visual components of the environment can influence the structural and functional development of the visual system has been increasingly appreciated in the last few years. Experiments in dark-reared transgenic mice overexpressing BDNF, revealed a remarkable and unexpected finding: visual cortical neurons in these animals responded normally to visual stimuli, indicating that transgenic animals could see well despite the lack of visual experience during the CP (Gianfranceschi et al., 2003). This result was the first demonstration of a gene that could substitute for functional aspects caused by experience in the nervous system. These observations are in consonance with the fact that environmental enrichment, an experimental condition characterized by an increased exploratory behavior and sensory-motor stimulation, which increases BDNF signaling and enhances GABAergic inhibition during early stages of development, prevents the effects of dark rearing in the visual system (Bartoletti et al., 2004). Of note, environmental enrichment in normally reared animals accelerates the functional development of the VC, this phenomenon being accompanied by alterations in the expression of BDNF and GABA synthesizing enzymes well before eye opening (Cancedda et al., 2004). These findings further suggest that environmental influences on visual system development may be, at least in part, independent of visual experience.

## **5. Inter-hemispheric projections control visual cortical maturation and plasticity**

Recent studies in the rodent VC have demonstrated a key role for inter-hemispheric, transcallosal projections in processes of visual cortical development and plasticity. In rodents, as in other mammals, callosal terminals are particularly concentrated in the area of primary VC mapping the central part of the visual field (Mizuno et al., 2007), thus contributing to binding together the two representations of the visual hemifields in the two hemispheres. A crucial role for callosal input activity in the functional maturation of the VC was indicated by experiments in which activity was unilaterally blocked in the striate cortex during the CP. Transient blockade of synaptic activity arrested maturation of visual acuity not only in the treated, but also in the contralateral hemisphere (Caleo et al., 2007). The CP for plasticity was also extended in both hemispheres (Caleo et al., 2007). These findings indicate that maturation of the blocked cortex is superimposable to that of the opposite side. Since the contralateral hemisphere maintains normal vision through the retinogeniculate pathway and only lacks callosal input, these data point towards a fundamental role for callosal linkages in regulating the process of cortical maturation. Similar conclusions have been drawn from experiments in knockout mice with reduced callosal connectivity; when tested as adults, these animals display a reduced visual acuity and a persistent OD plasticity (Pinto et al., 2009). The notion that inter-hemispheric callosal projections play a key role in the maturation of visual functions is exemplified by experimental observations in cats and humans. Early sections of the callosum in kittens, indeed, cause a reduction in the behavioural measure of visual acuity (Elberger 1984). Consistently, patients with hemianopia show impairments in figure detection tasks also in the intact hemifield, suggesting that these deficits may be caused by the loss of inter-hemispheric interactions (Paramei & Sabel 2008).

282 Visual Cortex – Current Status and Perspectives

**development** 

**4. Non-visual components of the environment alter visual system** 

In addition to MD, another classical paradigm used to assess the impact of experience in the functional maturation of the visual system is dark rearing (i.e., rearing animals in total darkness from birth). When dark-reared animals are brought back into the light, they turn out to be blind or, at least, display marked impairments of normal visual functions (Fagiolini et al., 1994). Total absence of visual experience delays the functional maturation of the striate cortex; an event that seems to be mediated by a down-regulation of BDNF expression (Castren et al., 1992), which results in a retarded maturation of GABAergic circuitries (Morales et al., 2002). The spatial resolution of visual cortical neurons is, in fact, reduced in dark-reared animals, this phenomenon being accompanied by longer latencies of responses to visual stimuli (Blakemore & Price 1987; Fagiolini et al., 1994). Moreover, visual cortical neurons have larger receptive field sizes and show alterations in the density of dendritic spines, which are shorter and fewer in dark-reared animals as compared to normally reared counterparts (Wallace & Bear 2004). Noteworthy, rearing animals in complete darkness extents the critical period far beyond its normal limits (Hensch 2005).

Although early studies of the visual system showed that sensory experience after eye opening is necessary for the functional maturation of the VC (Wiesel & Hubel 1963, 1963; Hubel & Wiesel 1970; LeVay et al., 1980), the notion that non-visual components of the environment can influence the structural and functional development of the visual system has been increasingly appreciated in the last few years. Experiments in dark-reared transgenic mice overexpressing BDNF, revealed a remarkable and unexpected finding: visual cortical neurons in these animals responded normally to visual stimuli, indicating that transgenic animals could see well despite the lack of visual experience during the CP (Gianfranceschi et al., 2003). This result was the first demonstration of a gene that could substitute for functional aspects caused by experience in the nervous system. These observations are in consonance with the fact that environmental enrichment, an experimental condition characterized by an increased exploratory behavior and sensory-motor stimulation, which increases BDNF signaling and enhances GABAergic inhibition during early stages of development, prevents the effects of dark rearing in the visual system (Bartoletti et al., 2004). Of note, environmental enrichment in normally reared animals accelerates the functional development of the VC, this phenomenon being accompanied by alterations in the expression of BDNF and GABA synthesizing enzymes well before eye opening (Cancedda et al., 2004). These findings further suggest that environmental influences on visual system development

**5. Inter-hemispheric projections control visual cortical maturation and** 

Recent studies in the rodent VC have demonstrated a key role for inter-hemispheric, transcallosal projections in processes of visual cortical development and plasticity. In

may be, at least in part, independent of visual experience.

**plasticity** 

Other studies have indicated a role for the callosum in determining both normal binocularity and the shift of OD that follows a period of monocular eyelid suture in juvenile rats. In rodents, retinogeniculate afferent input to the cortex from the contralateral eye is much stronger than that from the ipsilateral eye. Indeed, over 95% of retinal fibers decussate at the chiasm. However, cells mapping the central part of the visual field are highly binocular, and experiments support the view that callosal afferents contribute to this binocularity by providing input from the ipsilateral eye. In particular, acute inactivation of transcallosal input activity in rats shifts OD towards the contralateral eye (Diao et al., 1983), due to a loss of ipsilateral eye responses (Restani et al., 2009). In a complementary experiment, binocularity was recorded before and after acute inactivation of thalamocortical input to isolate visual responses driven exclusively by callosal afferents in young rats (Cerri et al., 2010). After blockade of the ipsilateral thalamus, cortical neurons display a dramatic loss of contralateral eye driven responses, while ipsilateral eye driven responses are reduced to a less extent (Cerri et al., 2010). These experiments indicate that in rats, a substantial fraction of the influence of the ipsilateral eye on cortical responses arrives via callosal connections from the opposite hemisphere, where it is the dominant eye.

Not only normal binocularity, but also the shift of OD that follows MD appears to depend on the function of callosal fibers. In particular, acute inactivation of transcallosal input activity restores binocularity after MD in juvenile rats (Restani et al., 2009). This recovery of binocularity following callosal silencing is due to an unexpected and selective increase in the strength of the deprived eye. Thus, acute removal of callosal influence following MD

unmasks deprived eye inputs. These data highlight the notion that callosal afferents act primarily to inhibit closed eye inputs during visual deprivation (Restani et al., 2009).

Insights into Visual Cortex Plasticity: Interaction Between Genes and Sensory Experience 285

dendritic spine dynamics regulate the stability of synaptic plasticity. The relationship between Calcium influx and spine size actually determines the long-term synaptic stability and synaptic strength distribution, at least in synapses of hippocampal CA3-CA1 pyramidal

Plasticity is achieved by a complex interplay of environmental influences and physiological mechanisms that ultimately set in motion intracellular signal transduction pathways directly regulating gene expression. Processes of chromatin remodeling that modulate gene transcription are, in fact, conserved mechanisms by which the mammalian's nervous system accomplishes adaptive behavioral responses upon environmental demands. In rodents, for instance, maternal care seems to influence behavioral and endocrine responses to stress in the offspring by modifying chromatin susceptibility to transcription (Francis et al., 1999).

The reorganization of cortical circuitries during early development requires the activation of sensory transduction pathways, which eventually mediate the expression of genes that act as downstream effectors of plastic phenomena. Studies performed in cats and rodents during the CP indicate that electrical activity and experience-dependent expression of neurotrophins cooperate to set in motion different protein kinases: extracellular-signalregulated kinase (ERK1/2) (Di Cristo et al., 2001), cAMP-dependent protein kinase (PKA) (Beaver et al., 2001), and calclium/calmodulin-dependent protein kinase II (CaMKII) (Taha et al., 2002). The activation of these intracellular signal transduction pathways promotes the up-regulation of transcription factors that, in turn, mediate gene expression. A very well known activity-dependent mechanism is the activation of the transcription factor CREB, which triggers the expression of genes under control of the cAMP-response element (CRE) promoter, thus allowing phenomena of plasticity to occur (Pham et al., 1999). These findings are in consonance with the recent observation that visual experience during development promotes modifications of chromatin structure that are permissive for transcription, whereas a developmental down-regulation of histone post-translational modifications

regulates the closure of the CP in the mouse visual system (Putignano et al., 2007).

In line with this notion, previous studies have demonstrated that the process of plasticity reactivation in the adult visual system is a multifactorial event that comprises the action of different cellular and molecular mechanisms, working in parallel or in series, the sum of which results in the activation of intracellular signal transduction pathways regulating the expression of plasticity genes (Putignano et al., 2007; Maya-Vetencourt et al., 2008; Bavelier et al., 2010; Morishita et al., 2010; Silingardi et al., 2010; Maya-Vetencourt et al., 2011; Maya-Vetencourt et al., 2012). Experimental paradigms based upon the manipulation of environmental stimulation levels, genetic manipulations, and pharmacological treatments in rodents have revealed that a complex interplay between the enhanced action of longdistance projection systems (e.g., serotonergic and cholinergic transmission) and IGF-I signaling seems to modulate the intracortical inhibitory/excitatory balance in favour of excitation (Amar et al., 2010; Moreau et al., 2010; Maya-Vetencourt et al., 2012), which, in

neurons (O'Donnell et al., 2011).

**7. Epigenetics of visual cortex plasticity** 

## **6. Structural plasticity in the visual system**

Experience-dependent functional modifications in the visual system are accompanied by a structural remodeling of synaptic connectivity, in terms of growth and loss of dendritic spines. Dendritic spines in pyramidal neurons are markedly sensitive to experience as indicated by the observation that total lack of visual experience in early life induces modifications in spine morphology and density, both of which are partially reversible by light exposure (Wallace & Bear 2004). This is consistent with the observation that monocular deprivation in early life alters the motility, turnover, number and morphology of dendritic spines in the VC (Majewska & Sur 2003; Mataga et al., 2004; Hofer et al., 2009; Tropea et al., 2010).

Structural plasticity *in vivo* studies, using two-photon imaging, indicate that dendritic spine dynamics is high during early postnatal life but decreases thereafter, in parallel to the timecourse of CP plasticity over development (Fu & Zuo 2011). This suggests that, despite the absence of large-scale remodeling of dendrites, the reorganization of cortical connections in terms of growth and loss of dendritic spines may be the structural substrate for experiencedependent plasticity. Notably, chronic imaging experiments have recently demonstrated that changes in VC responsiveness after monocular deprivation during the CP correlate with structural modifications in terms of dendritic spines across the binocular VC; these two features being reversed when the deprived eye was reopened. After brief periods of MD, spine turnover increased significantly, with a larger percentage of spines being lost rather than gained, whereas after a 24-hours period of recovery (visual experience) the baseline number of dendritic spines was gained again (Yu et al., 2011). Interestingly, increasing the density and dynamics of spines by intracortical infusion of the bacterial toxin CNF1, restores a degree of plasticity in the mature cortex that is similar to that observed during early postnatal life (Cerri et al., 2011).

It is worth mentioning that new synapses formation may increase memory storage capacity of the brain and that new dendritic spines may serve as structural traces for earlier memories, enabling the brain for faster adaptations to similar future experiences (Hofer et al., 2009; Xu et al., 2009). Recent experiments carried out using the MD paradigm seem to confirm this notion. Modifications of dendritic spines caused by a first experience of unilateral eyelid suture persist even after restoration of binocular vision and may therefore be involved in the enhancement of plasticity observed after a second episode of visual deprivation (Hofer et al., 2009).

The imaging studies mentioned above raise the question of whether structural modifications of dendritic spines represent functional changes of synaptic transmission. Electrophysiological experiments in hippocampal slice cultures indicate that AMPA- and NMDA-type glutamate receptor currents of newborn spines resemble that of mature synaptic contacts (Zito et al., 2009). Interestingly, it has been recently demonstrated that dendritic spine dynamics regulate the stability of synaptic plasticity. The relationship between Calcium influx and spine size actually determines the long-term synaptic stability and synaptic strength distribution, at least in synapses of hippocampal CA3-CA1 pyramidal neurons (O'Donnell et al., 2011).

## **7. Epigenetics of visual cortex plasticity**

284 Visual Cortex – Current Status and Perspectives

postnatal life (Cerri et al., 2011).

deprivation (Hofer et al., 2009).

2010).

**6. Structural plasticity in the visual system** 

unmasks deprived eye inputs. These data highlight the notion that callosal afferents act

Experience-dependent functional modifications in the visual system are accompanied by a structural remodeling of synaptic connectivity, in terms of growth and loss of dendritic spines. Dendritic spines in pyramidal neurons are markedly sensitive to experience as indicated by the observation that total lack of visual experience in early life induces modifications in spine morphology and density, both of which are partially reversible by light exposure (Wallace & Bear 2004). This is consistent with the observation that monocular deprivation in early life alters the motility, turnover, number and morphology of dendritic spines in the VC (Majewska & Sur 2003; Mataga et al., 2004; Hofer et al., 2009; Tropea et al.,

Structural plasticity *in vivo* studies, using two-photon imaging, indicate that dendritic spine dynamics is high during early postnatal life but decreases thereafter, in parallel to the timecourse of CP plasticity over development (Fu & Zuo 2011). This suggests that, despite the absence of large-scale remodeling of dendrites, the reorganization of cortical connections in terms of growth and loss of dendritic spines may be the structural substrate for experiencedependent plasticity. Notably, chronic imaging experiments have recently demonstrated that changes in VC responsiveness after monocular deprivation during the CP correlate with structural modifications in terms of dendritic spines across the binocular VC; these two features being reversed when the deprived eye was reopened. After brief periods of MD, spine turnover increased significantly, with a larger percentage of spines being lost rather than gained, whereas after a 24-hours period of recovery (visual experience) the baseline number of dendritic spines was gained again (Yu et al., 2011). Interestingly, increasing the density and dynamics of spines by intracortical infusion of the bacterial toxin CNF1, restores a degree of plasticity in the mature cortex that is similar to that observed during early

It is worth mentioning that new synapses formation may increase memory storage capacity of the brain and that new dendritic spines may serve as structural traces for earlier memories, enabling the brain for faster adaptations to similar future experiences (Hofer et al., 2009; Xu et al., 2009). Recent experiments carried out using the MD paradigm seem to confirm this notion. Modifications of dendritic spines caused by a first experience of unilateral eyelid suture persist even after restoration of binocular vision and may therefore be involved in the enhancement of plasticity observed after a second episode of visual

The imaging studies mentioned above raise the question of whether structural modifications of dendritic spines represent functional changes of synaptic transmission. Electrophysiological experiments in hippocampal slice cultures indicate that AMPA- and NMDA-type glutamate receptor currents of newborn spines resemble that of mature synaptic contacts (Zito et al., 2009). Interestingly, it has been recently demonstrated that

primarily to inhibit closed eye inputs during visual deprivation (Restani et al., 2009).

Plasticity is achieved by a complex interplay of environmental influences and physiological mechanisms that ultimately set in motion intracellular signal transduction pathways directly regulating gene expression. Processes of chromatin remodeling that modulate gene transcription are, in fact, conserved mechanisms by which the mammalian's nervous system accomplishes adaptive behavioral responses upon environmental demands. In rodents, for instance, maternal care seems to influence behavioral and endocrine responses to stress in the offspring by modifying chromatin susceptibility to transcription (Francis et al., 1999).

The reorganization of cortical circuitries during early development requires the activation of sensory transduction pathways, which eventually mediate the expression of genes that act as downstream effectors of plastic phenomena. Studies performed in cats and rodents during the CP indicate that electrical activity and experience-dependent expression of neurotrophins cooperate to set in motion different protein kinases: extracellular-signalregulated kinase (ERK1/2) (Di Cristo et al., 2001), cAMP-dependent protein kinase (PKA) (Beaver et al., 2001), and calclium/calmodulin-dependent protein kinase II (CaMKII) (Taha et al., 2002). The activation of these intracellular signal transduction pathways promotes the up-regulation of transcription factors that, in turn, mediate gene expression. A very well known activity-dependent mechanism is the activation of the transcription factor CREB, which triggers the expression of genes under control of the cAMP-response element (CRE) promoter, thus allowing phenomena of plasticity to occur (Pham et al., 1999). These findings are in consonance with the recent observation that visual experience during development promotes modifications of chromatin structure that are permissive for transcription, whereas a developmental down-regulation of histone post-translational modifications regulates the closure of the CP in the mouse visual system (Putignano et al., 2007).

In line with this notion, previous studies have demonstrated that the process of plasticity reactivation in the adult visual system is a multifactorial event that comprises the action of different cellular and molecular mechanisms, working in parallel or in series, the sum of which results in the activation of intracellular signal transduction pathways regulating the expression of plasticity genes (Putignano et al., 2007; Maya-Vetencourt et al., 2008; Bavelier et al., 2010; Morishita et al., 2010; Silingardi et al., 2010; Maya-Vetencourt et al., 2011; Maya-Vetencourt et al., 2012). Experimental paradigms based upon the manipulation of environmental stimulation levels, genetic manipulations, and pharmacological treatments in rodents have revealed that a complex interplay between the enhanced action of longdistance projection systems (e.g., serotonergic and cholinergic transmission) and IGF-I signaling seems to modulate the intracortical inhibitory/excitatory balance in favour of excitation (Amar et al., 2010; Moreau et al., 2010; Maya-Vetencourt et al., 2012), which, in turn, set in motion cellular and molecular events that eventually mediate the expression of genes associated with functional modifications in the adult visual system. The reinstatement of adult VC plasticity caused by serotonergic transmission, for instance, is mediated by 5- HT1A receptors signaling and accompanied by a transitory increment of BDNF expression. This is paralleled by an enhanced histone acetylation status at the activity-dependently regulated BDNF promoter regions and by a decreased expression of histone deacetylase enzymes (HDACs) (Maya-Vetencourt et al., 2011). In keeping with this, long-term treatment with HDACs inhibitors (e.g., Trichostatin-A, Valproic Acid and Sodium Butyrate) not only reinstates OD plasticity in adulthood (Putignano et al., 2007; Maya-Vetencourt et al., 2011) but also promotes full recovery of visual functions in adult amblyopic animals (Silingardi et al., 2010).

Insights into Visual Cortex Plasticity: Interaction Between Genes and Sensory Experience 287

Phenomena of cross-modal plasticity have also been observed in the brain of deaf subjects. Functional magnetic resonance imaging studies have demonstrated that early deaf individuals use the primary auditory cortex alongside the visual system when they observe sign language (Lambertz et al., 2005). Although there is no hearing component to sign language, the auditory cortex is instead used to assist with visual and language processing. The effects of cochlear implants also provide another strategy to assess cross-modal plasticity in the deaf. Early deaf individuals, but not late-onset deaf subjects, actually display impairments in their ability to process language using a cochlear implant in adult life as the auditory cortex has been reshaped to deal with visual information and therefore it cannot deal

There is evidence for potent cross-modal plastic interactions even during normal development. A recent series of experiments have demonstrated that enhancement of somatosensory stimulation in terms of body massage, affects development of another sensory modality, the visual system (Guzzetta et al., 2009). It has been reported that an enriched environment accelerates the structural and functional development of the rodent VC (Cancedda et al., 2004) and that enriching the environment in terms of tactile stimulation (body massage with a soft toothbrush) in rat pups effectively mimics the effects of enrichment on visual system development (Guzzetta et al., 2009). The massage protocol in the offspring of rats accelerated the maturation of visual functions and increased circulating levels of insulin-like growth factor 1 (IGF-I), whereas antagonizing IGF-I signaling by systemic injections of an IGF-I receptor antagonist prevented the effects of massage (Guzzetta et al., 2009). In keeping with this, enriching the environment in terms of body massage in human preterm infants accelerates the maturation of the visual system as indicated by an enhanced development of spatial acuity and, as in the offspring of rats, this phenomenon is accompanied by high IGF-I levels (Guzzetta et al., 2009). Taken together, these findings indicate that processes of cross-modal plasticity may be involved in the effects caused by environmental enrichment in VC development and portray the wellcharacterized visual system as a model to investigate the functional integration of two or

**9. Achieving the recovery of sensory functions after long-term sensory** 

The recovery of normal visual functions after long-term sensory deprivation has long been a subject of study with the prospect of finding therapies for human amblyopia. In this context, perceptual learning has long been used to improve spatial acuity in adult amblyopic patients (Levi & Li 2009). Systematic training of patients with unilateral amblyopia (secondary to strabismus and anisometropia) in simple visual tasks revealed a 2-fold increase of contrast sensitivity and improved performance in letter-recognition tests (Polat et al., 2004). Likewise, Snellen acuities in anisometric amblyopes improved after intensive training in a Vernier acuity task. Moreover, video game playing appears to promote a significant rescue of visual functions in adult amblyopic patients. Playing video games for a short period of time using the amblyopic eye actually improves visual functions such as

as well with the new sensory input that the implant provides (Doucet et al., 2006).

more sensory modalities.

**deprivation** 

## **8. Cross-modal plasticity: Adaptive reorganization of neural networks**

Sensory deprivation in one modality during early stages of development can have marked effects on the development of the remaining modalities. This phenomenon is known as cross-modal plasticity and is particularly epitomized by cases of congenital blindness or deafness from birth. In such instances, processes of cross-modal plasticity strengthen other sensory systems to compensate for the lack of vision or hearing.

Although clinical studies of deaf and blind humans have clearly demonstrated increased functional capabilities and compensatory expansion in the remaining sensory modalities (Bavelier & Neville 2002), the neurological bases for these plastic phenomena remain poorly understood. It has been reported that congenitally blind subjects show better sound localization abilities as compared to sighted individuals (Roder et al., 1999) and display better two-point tactile discrimination skills as well (Bavelier & Neville 2002). Moreover, studies that combine Braille reading and functional brain imaging revealed that early blind individuals show a strong activation of the primary VC during the Braille reading task (Sadato et al., 1996). Remarkably, the inactivation of the VC by means of transcranial electrical stimulation in blind people during Braille reading not only distorts tactile perceptions of blind subjects but also induces errors in Braille reading. These findings indicate that the VC seems to be recruited to process somatosensory information after congenital blindness (Cohen et al., 1997). Recent experimental evidence also suggests that congenital blindness enables visual circuitries to contribute to language processing (Bedny et al., 2011).

The question of whether there is a CP for cross-modal plasticity has also been addressed by examining the activation of visual cortical areas by Braille reading in early and late-onset blind individuals (blindness after 14 years of age). It has been reported that VC responsiveness to somatosensory stimuli is higher in congenitally blind and early-onset subjects as compared to the late-onset blind group (Cohen et al., 1999). These data indicate that there is a CP for the visual system to be recruited to a role in the processing of somatosensory information, which does not extend beyond 14 years of age in humans.

Phenomena of cross-modal plasticity have also been observed in the brain of deaf subjects. Functional magnetic resonance imaging studies have demonstrated that early deaf individuals use the primary auditory cortex alongside the visual system when they observe sign language (Lambertz et al., 2005). Although there is no hearing component to sign language, the auditory cortex is instead used to assist with visual and language processing. The effects of cochlear implants also provide another strategy to assess cross-modal plasticity in the deaf. Early deaf individuals, but not late-onset deaf subjects, actually display impairments in their ability to process language using a cochlear implant in adult life as the auditory cortex has been reshaped to deal with visual information and therefore it cannot deal as well with the new sensory input that the implant provides (Doucet et al., 2006).

286 Visual Cortex – Current Status and Perspectives

al., 2010).

et al., 2011).

turn, set in motion cellular and molecular events that eventually mediate the expression of genes associated with functional modifications in the adult visual system. The reinstatement of adult VC plasticity caused by serotonergic transmission, for instance, is mediated by 5- HT1A receptors signaling and accompanied by a transitory increment of BDNF expression. This is paralleled by an enhanced histone acetylation status at the activity-dependently regulated BDNF promoter regions and by a decreased expression of histone deacetylase enzymes (HDACs) (Maya-Vetencourt et al., 2011). In keeping with this, long-term treatment with HDACs inhibitors (e.g., Trichostatin-A, Valproic Acid and Sodium Butyrate) not only reinstates OD plasticity in adulthood (Putignano et al., 2007; Maya-Vetencourt et al., 2011) but also promotes full recovery of visual functions in adult amblyopic animals (Silingardi et

**8. Cross-modal plasticity: Adaptive reorganization of neural networks** 

sensory systems to compensate for the lack of vision or hearing.

Sensory deprivation in one modality during early stages of development can have marked effects on the development of the remaining modalities. This phenomenon is known as cross-modal plasticity and is particularly epitomized by cases of congenital blindness or deafness from birth. In such instances, processes of cross-modal plasticity strengthen other

Although clinical studies of deaf and blind humans have clearly demonstrated increased functional capabilities and compensatory expansion in the remaining sensory modalities (Bavelier & Neville 2002), the neurological bases for these plastic phenomena remain poorly understood. It has been reported that congenitally blind subjects show better sound localization abilities as compared to sighted individuals (Roder et al., 1999) and display better two-point tactile discrimination skills as well (Bavelier & Neville 2002). Moreover, studies that combine Braille reading and functional brain imaging revealed that early blind individuals show a strong activation of the primary VC during the Braille reading task (Sadato et al., 1996). Remarkably, the inactivation of the VC by means of transcranial electrical stimulation in blind people during Braille reading not only distorts tactile perceptions of blind subjects but also induces errors in Braille reading. These findings indicate that the VC seems to be recruited to process somatosensory information after congenital blindness (Cohen et al., 1997). Recent experimental evidence also suggests that congenital blindness enables visual circuitries to contribute to language processing (Bedny

The question of whether there is a CP for cross-modal plasticity has also been addressed by examining the activation of visual cortical areas by Braille reading in early and late-onset blind individuals (blindness after 14 years of age). It has been reported that VC responsiveness to somatosensory stimuli is higher in congenitally blind and early-onset subjects as compared to the late-onset blind group (Cohen et al., 1999). These data indicate that there is a CP for the visual system to be recruited to a role in the processing of somatosensory information, which does not extend beyond 14 years of age in humans.

There is evidence for potent cross-modal plastic interactions even during normal development. A recent series of experiments have demonstrated that enhancement of somatosensory stimulation in terms of body massage, affects development of another sensory modality, the visual system (Guzzetta et al., 2009). It has been reported that an enriched environment accelerates the structural and functional development of the rodent VC (Cancedda et al., 2004) and that enriching the environment in terms of tactile stimulation (body massage with a soft toothbrush) in rat pups effectively mimics the effects of enrichment on visual system development (Guzzetta et al., 2009). The massage protocol in the offspring of rats accelerated the maturation of visual functions and increased circulating levels of insulin-like growth factor 1 (IGF-I), whereas antagonizing IGF-I signaling by systemic injections of an IGF-I receptor antagonist prevented the effects of massage (Guzzetta et al., 2009). In keeping with this, enriching the environment in terms of body massage in human preterm infants accelerates the maturation of the visual system as indicated by an enhanced development of spatial acuity and, as in the offspring of rats, this phenomenon is accompanied by high IGF-I levels (Guzzetta et al., 2009). Taken together, these findings indicate that processes of cross-modal plasticity may be involved in the effects caused by environmental enrichment in VC development and portray the wellcharacterized visual system as a model to investigate the functional integration of two or more sensory modalities.

## **9. Achieving the recovery of sensory functions after long-term sensory deprivation**

The recovery of normal visual functions after long-term sensory deprivation has long been a subject of study with the prospect of finding therapies for human amblyopia. In this context, perceptual learning has long been used to improve spatial acuity in adult amblyopic patients (Levi & Li 2009). Systematic training of patients with unilateral amblyopia (secondary to strabismus and anisometropia) in simple visual tasks revealed a 2-fold increase of contrast sensitivity and improved performance in letter-recognition tests (Polat et al., 2004). Likewise, Snellen acuities in anisometric amblyopes improved after intensive training in a Vernier acuity task. Moreover, video game playing appears to promote a significant rescue of visual functions in adult amblyopic patients. Playing video games for a short period of time using the amblyopic eye actually improves visual functions such as spatial acuity and stereopsis (Li et al., 2011). The improvement of performance seen in perceptual learning is proportional to the number of trials taken, although performance eventually reaches an asymptote with no further progress (Huang et al., 2008). Unfortunately, the extent to which acuity improvements occur is limited by the task specificity of perceptual learning (Crist et al., 1997). In most instances of perceptual learning, attention to the trained stimulus is necessary for improvements of vision to occur (Ahissar & Hochstein 1993). This observation is particularly important as it epitomizes the role of diffuse projection systems in the physiological state of arousal, which regulates mechanisms of attention and information processing that may contribute to functional changes of neural circuitries in the adult brain. Such notion points toward the possibility to pharmacologically enhance plasticity as a strategy for brain repair, which could facilitate restructuring of mature circuitries impaired by damage or disease.

Insights into Visual Cortex Plasticity: Interaction Between Genes and Sensory Experience 289

J.F.M.V. is supported by a research fellowship provided by the Scuola Normale Superiore,

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**Acknowledgement** 

*CNR Neuroscience Institute, Pisa, Italy* 

## **10. Conclusion**

The ability of the brain to change functionally in response to experience is most active during early stages of development but it decreases later in life when major alterations in neuronal network structures no longer take place in response to experience. For decades it has been believed that the plastic potential of the adult nervous system is insufficient to allow the recovery of lost sensory functions following long-term deprivation. Therefore, treatments for human amblyopia were generally not undertaken in older children and adults. However, novel experimental data obtained in animal models have demonstrated the effectiveness of different pharmacological treatments and experimental paradigms based upon manipulation of environmental input levels in restoring plasticity to the adult nervous system. In light of these findings, one can speculate that the beneficial effects exerted by these treatments could be exploited for clinical application. Since deterioration in functional plasticity contributes to the pathogenesis of several brain diseases, environmental enrichment (Baroncelli et al., 2010), food restriction (Spolidoro et al., 2011), brief dark exposure (He et al., 2006), long-term fluoxetine treatment (Maya-Vetencourt et al., 2008; Chen et al., 2011; Maya-Vetencourt et al., 2011) and exogenous IGF-I administration (Maya-Vetencourt et al., 2012), all of which reactivate adult brain plasticity, arise as potential therapeutic strategies for pathological conditions, such as human amblyopia, in which reorganization of neural circuitries would be beneficial in adult life. These therapeutic approaches bear some similarity to the interventions that have proved successful in promoting recovery from other pathological conditions such as stroke (Maurer & Hensch 2012). Fluoxetine treatment, indeed, enhances the effects of rehabilitation in the recovery from motor deficits after ischaemic stroke in humans (Chollet et al., 2011).

## **Author details**

José Fernando Maya-Vetencourt \* *Scuola Normale Superiore, Pisa, Italy* 

<sup>\*</sup> Corresponding Author

Matteo Caleo *CNR Neuroscience Institute, Pisa, Italy* 

## **Acknowledgement**

J.F.M.V. is supported by a research fellowship provided by the Scuola Normale Superiore, Pisa, Italy.

### **11. References**

288 Visual Cortex – Current Status and Perspectives

mature circuitries impaired by damage or disease.

**10. Conclusion** 

**Author details** 

Corresponding Author

 \*

José Fernando Maya-Vetencourt \* *Scuola Normale Superiore, Pisa, Italy* 

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The ability of the brain to change functionally in response to experience is most active during early stages of development but it decreases later in life when major alterations in neuronal network structures no longer take place in response to experience. For decades it has been believed that the plastic potential of the adult nervous system is insufficient to allow the recovery of lost sensory functions following long-term deprivation. Therefore, treatments for human amblyopia were generally not undertaken in older children and adults. However, novel experimental data obtained in animal models have demonstrated the effectiveness of different pharmacological treatments and experimental paradigms based upon manipulation of environmental input levels in restoring plasticity to the adult nervous system. In light of these findings, one can speculate that the beneficial effects exerted by these treatments could be exploited for clinical application. Since deterioration in functional plasticity contributes to the pathogenesis of several brain diseases, environmental enrichment (Baroncelli et al., 2010), food restriction (Spolidoro et al., 2011), brief dark exposure (He et al., 2006), long-term fluoxetine treatment (Maya-Vetencourt et al., 2008; Chen et al., 2011; Maya-Vetencourt et al., 2011) and exogenous IGF-I administration (Maya-Vetencourt et al., 2012), all of which reactivate adult brain plasticity, arise as potential therapeutic strategies for pathological conditions, such as human amblyopia, in which reorganization of neural circuitries would be beneficial in adult life. These therapeutic approaches bear some similarity to the interventions that have proved successful in promoting recovery from other pathological conditions such as stroke (Maurer & Hensch 2012). Fluoxetine treatment, indeed, enhances the effects of rehabilitation in the recovery

from motor deficits after ischaemic stroke in humans (Chollet et al., 2011).


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**Chapter 14** 

© 2012 Sale et al., licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2012 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

In parallel to this seminal work based on a sensory deprivation approach, fundamental contributions to our knowledge of the effects of experience on the brain have been provided by the environmental enrichment (EE) paradigm, first introduced by the group of Rosenzweig and colleagues, in California. Originally defined as "a combination of complex

and reproduction in any medium, provided the original work is properly cited.

**Environmental Influences on** 

Additional information is available at the end of the chapter

neural plasticity in response to experience [7-12].

http://dx.doi.org/10.5772/48522

**1. Introduction** 

**Visual Cortex Development and Plasticity** 

The term "plasticity" refers to the ability of the nervous system to reorganize its connections functionally and structurally in response to changes in environmental experience, underlying the adaptive development and remodeling of neuronal circuitry. The primary visual cortex (V1) has been for decades the election model for studying experiencedependent plasticity in the brain. The pioneering experiments performed by Hubel and Wiesel showed how dramatically can early sensory deprivation affect the anatomy and physiology of the visual cortex. They reported that, early in development, reducing the visual input to one eye by means of lid suture, a treatment classically referred to as monocular deprivation (MD), disrupts the ocular dominance (OD) of V1 cells, with a loss of neurons driven by the deprived eye and a strong increment in the number of cells driven by the open eye, and reduces the number of binocular neurons [1]. Anatomically, the imbalance of activity between the two eyes results in the shrinkage of deprived eye ocular dominance columns, regions in V1 layer IV which receive thalamic inputs driven by the closed eye, and in the expansion of open eye ocular dominance columns [2-5], accompanied by a rapid remodeling of cortical horizontal connections [6]. Behaviorally, long-term MD is associated with a poor development of visual acuity (VA) and contrast sensitivity for the deprived eye and a loss of binocular vision. Strikingly, the same manipulation of visual experience appeared to be totally ineffective in the adult [4], leading to the characterization of a classic example or critical period, a time-window early in life in which the brain displays enhanced

Alessandro Sale, Nicoletta Berardi and Lamberto Maffei


## **Environmental Influences on Visual Cortex Development and Plasticity**

Alessandro Sale, Nicoletta Berardi and Lamberto Maffei

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/48522

## **1. Introduction**

294 Visual Cortex – Current Status and Perspectives

166.

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The term "plasticity" refers to the ability of the nervous system to reorganize its connections functionally and structurally in response to changes in environmental experience, underlying the adaptive development and remodeling of neuronal circuitry. The primary visual cortex (V1) has been for decades the election model for studying experiencedependent plasticity in the brain. The pioneering experiments performed by Hubel and Wiesel showed how dramatically can early sensory deprivation affect the anatomy and physiology of the visual cortex. They reported that, early in development, reducing the visual input to one eye by means of lid suture, a treatment classically referred to as monocular deprivation (MD), disrupts the ocular dominance (OD) of V1 cells, with a loss of neurons driven by the deprived eye and a strong increment in the number of cells driven by the open eye, and reduces the number of binocular neurons [1]. Anatomically, the imbalance of activity between the two eyes results in the shrinkage of deprived eye ocular dominance columns, regions in V1 layer IV which receive thalamic inputs driven by the closed eye, and in the expansion of open eye ocular dominance columns [2-5], accompanied by a rapid remodeling of cortical horizontal connections [6]. Behaviorally, long-term MD is associated with a poor development of visual acuity (VA) and contrast sensitivity for the deprived eye and a loss of binocular vision. Strikingly, the same manipulation of visual experience appeared to be totally ineffective in the adult [4], leading to the characterization of a classic example or critical period, a time-window early in life in which the brain displays enhanced neural plasticity in response to experience [7-12].

In parallel to this seminal work based on a sensory deprivation approach, fundamental contributions to our knowledge of the effects of experience on the brain have been provided by the environmental enrichment (EE) paradigm, first introduced by the group of Rosenzweig and colleagues, in California. Originally defined as "a combination of complex

© 2012 Sale et al., licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2012 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

inanimate and social stimulation" [13], EE consists in wide and attractive cages where the animals are reared in large social groups and in presence of a variety of objects (e.g. toys, tunnels, nesting material, stairs) that are frequently changed by the experimenter to stimulate explorative behavior, curiosity and attentional processes. A further, essential component of EE is the opportunity for the animals to attain sustained levels of voluntary physical exercise on one or more running wheels. EE definition is based on the comparison with alternative rearing conditions, such as the standard condition (SC), in which the animals are reared in small social groups and in very simple cages where no particular objects other than nesting material, food and water are present, or the so-called impoverished condition (IC), in which even social interactions are impossible because the animals are reared alone in individual cages, otherwise identical to those used for SC. With respect to their standard-reared or impoverished companions, enriched animals have the opportunity for enhanced social interaction, multi-sensorial stimulation and increased levels of physical activity, with the additional advantage that they are totally free to choose when and how much to experience the environmental richness, without the contingencies and risks typically associated with living in the wild [14].

Environmental Influences on Visual Cortex Development and Plasticity 297

running. Running levels are probably not increased in the enriched condition to the same levels occurring with standard cage running. Interestingly, running increases brain uptake of the insuline-like growth factor I (IGF-I) [33], and IGF-I has been shown to accelerate cell cycle in the embryonic cerebral cortex [34]. If present at the level of adult brain neurogenesis, this effect could explain the strong influence elicited by sustained levels of voluntary running on hippocampal cell proliferation. The ability of EE to interact with the programs of nerve cell renewal extends beyond the influence on neurogenesis, including the capability to reduce apoptotic cell death in the hippocampus under both natural conditions and following excitotoxic insults [35]. These results challenge the traditional view that the anatomical structure of the brain is immutable under non-pathological conditions, revealing an unexpected plasticity induced by environmental stimulation at the structural level.

One striking peculiarity of EE is its ability to improve learning and memory functions, and with a specific reduction of the cognitive decline associated with aging [36, 37]. This last effect is related to a robust facilitation of hippocampal LTP, a widely accepted synaptic plasticity model of learning and memory [38] and linked with general signs of "cellular health" in the hippocampus, such as increased levels of synaptophysin [39, 40], a glycoprotein found in membranes of neurotransmitter-containing presynaptic vesicles, a reduced load of lipofuscin deposits [41], which are good indicators of chronic oxidative stress [42], and the pronounced induction of hippocampal neurogenesis [41]. EE positively affects also emotional and stress reactivity, both in normal animals and in strains of mice considered pathologically anxious [43]. Interestingly, the effects of EE are not restricted to the cerebral cortex, as demonstrated by a recent work in which this paradigm has been used to investigate the effects of lifestyle change on metabolic parameters [44]. Enriched mice showed decreased leptin, reduced adipose mass, and increased food intake compared to standard-reared animals, demonstrating that the leptin-hypothalamic axis can be enhanced

At the molecular level, studies based on gene chip analysis have revealed that a large number of genes related to neuronal structure, synaptic transmission and plasticity, neuronal excitability and neuroprotection change their expression levels in response to EE [45]. One group of molecules particularly sensitive to experience are neurotrophins, a family of secreted factors critically involved in structural and functional plasticity during

An important line of research deals with the potential therapeutic effects of EE: indeed, it has been shown that enriching the housing environment delays the progression of, and facilitates recovery from, various nervous system dysfunctions, including neurodevelopmental disorders, neurodegenerative diseases, different types of brain injury and psychiatric disorders [47-54]. These studies have profound consequences for humans. The development of intervention protocols aimed at maintaining a healthy and active lifestyle has been effectively encouraged by the results of basic research on EE. For example, strong correlative and epidemiological evidence shows that living habits, including occupation, leisure activities and physical exercise, have a direct effect on the risk of cognitive decline, with an increasing number of results indicating that a higher level and

by environmental stimulation.

development and in adulthood [46].

In over fifty years of research in the field, a great number of studies have documented the positive impact of EE on the morphology, chemistry and physiology of the brain [14-17]. Initial experiments by Rosenzweig et al. [18] showed that after 30 days of exposition to an enriched living condition the cortex of enriched rats increased robustly in thickness and weight compared with that of standard reared animals. These changes occurred in the entire dorsal cortex, including frontal, parietal and occipital cortex. Since then, many studies have reported various anatomical changes associated with enriched living conditions, including nearly all structural components analyzed, such as increased dendritic arborization and length of dendritic spines [19-21], augmented synaptic size and number [22, 23] and increased postsynaptic thickening [24] and gliogenesis [25].

More recently, EE studies have regained special interest with the fall of the dogma regarding the postulated incapability of adult brain to generate new neurons. Although, in mammals, the majority of neurons are generated by the time of birth, some brain structures, with the paradigmatic examples of the granule cells of olfactory bulb and hippocampal dentate gyrus, maintain this potentiality for neurogenesis even after sexual maturity [26, 27], a property that has been demonstrated not only in rodents but also in monkeys [28] and, remarkably, in humans [29]. Numerous studies have shown that exposure to an enriched environment produces a significant increase in hippocampal neurogenesis [30]. A similar effect is induced by enhanced levels of physical exercise through running [31, 32], but the two conditions appear to act with distinct mechanisms: while voluntary exercise alone in a standard cage increases neurogenesis with an increment in both proliferation and survival of new-generated neurons, exposure to an enriched environment is only able to increase the number of surviving newborn cells, leaving the proportion of newly born cells unaffected. It has been suggested that to induce a shortening of the cell cycle or to elicit additional quiescent cells to enter the cell cycle (both effects resulting in increased amount of cell proliferation and neurogenesis) one specific type of very focused activity is needed, such as running. Running levels are probably not increased in the enriched condition to the same levels occurring with standard cage running. Interestingly, running increases brain uptake of the insuline-like growth factor I (IGF-I) [33], and IGF-I has been shown to accelerate cell cycle in the embryonic cerebral cortex [34]. If present at the level of adult brain neurogenesis, this effect could explain the strong influence elicited by sustained levels of voluntary running on hippocampal cell proliferation. The ability of EE to interact with the programs of nerve cell renewal extends beyond the influence on neurogenesis, including the capability to reduce apoptotic cell death in the hippocampus under both natural conditions and following excitotoxic insults [35]. These results challenge the traditional view that the anatomical structure of the brain is immutable under non-pathological conditions, revealing an unexpected plasticity induced by environmental stimulation at the structural level.

296 Visual Cortex – Current Status and Perspectives

risks typically associated with living in the wild [14].

increased postsynaptic thickening [24] and gliogenesis [25].

inanimate and social stimulation" [13], EE consists in wide and attractive cages where the animals are reared in large social groups and in presence of a variety of objects (e.g. toys, tunnels, nesting material, stairs) that are frequently changed by the experimenter to stimulate explorative behavior, curiosity and attentional processes. A further, essential component of EE is the opportunity for the animals to attain sustained levels of voluntary physical exercise on one or more running wheels. EE definition is based on the comparison with alternative rearing conditions, such as the standard condition (SC), in which the animals are reared in small social groups and in very simple cages where no particular objects other than nesting material, food and water are present, or the so-called impoverished condition (IC), in which even social interactions are impossible because the animals are reared alone in individual cages, otherwise identical to those used for SC. With respect to their standard-reared or impoverished companions, enriched animals have the opportunity for enhanced social interaction, multi-sensorial stimulation and increased levels of physical activity, with the additional advantage that they are totally free to choose when and how much to experience the environmental richness, without the contingencies and

In over fifty years of research in the field, a great number of studies have documented the positive impact of EE on the morphology, chemistry and physiology of the brain [14-17]. Initial experiments by Rosenzweig et al. [18] showed that after 30 days of exposition to an enriched living condition the cortex of enriched rats increased robustly in thickness and weight compared with that of standard reared animals. These changes occurred in the entire dorsal cortex, including frontal, parietal and occipital cortex. Since then, many studies have reported various anatomical changes associated with enriched living conditions, including nearly all structural components analyzed, such as increased dendritic arborization and length of dendritic spines [19-21], augmented synaptic size and number [22, 23] and

More recently, EE studies have regained special interest with the fall of the dogma regarding the postulated incapability of adult brain to generate new neurons. Although, in mammals, the majority of neurons are generated by the time of birth, some brain structures, with the paradigmatic examples of the granule cells of olfactory bulb and hippocampal dentate gyrus, maintain this potentiality for neurogenesis even after sexual maturity [26, 27], a property that has been demonstrated not only in rodents but also in monkeys [28] and, remarkably, in humans [29]. Numerous studies have shown that exposure to an enriched environment produces a significant increase in hippocampal neurogenesis [30]. A similar effect is induced by enhanced levels of physical exercise through running [31, 32], but the two conditions appear to act with distinct mechanisms: while voluntary exercise alone in a standard cage increases neurogenesis with an increment in both proliferation and survival of new-generated neurons, exposure to an enriched environment is only able to increase the number of surviving newborn cells, leaving the proportion of newly born cells unaffected. It has been suggested that to induce a shortening of the cell cycle or to elicit additional quiescent cells to enter the cell cycle (both effects resulting in increased amount of cell proliferation and neurogenesis) one specific type of very focused activity is needed, such as One striking peculiarity of EE is its ability to improve learning and memory functions, and with a specific reduction of the cognitive decline associated with aging [36, 37]. This last effect is related to a robust facilitation of hippocampal LTP, a widely accepted synaptic plasticity model of learning and memory [38] and linked with general signs of "cellular health" in the hippocampus, such as increased levels of synaptophysin [39, 40], a glycoprotein found in membranes of neurotransmitter-containing presynaptic vesicles, a reduced load of lipofuscin deposits [41], which are good indicators of chronic oxidative stress [42], and the pronounced induction of hippocampal neurogenesis [41]. EE positively affects also emotional and stress reactivity, both in normal animals and in strains of mice considered pathologically anxious [43]. Interestingly, the effects of EE are not restricted to the cerebral cortex, as demonstrated by a recent work in which this paradigm has been used to investigate the effects of lifestyle change on metabolic parameters [44]. Enriched mice showed decreased leptin, reduced adipose mass, and increased food intake compared to standard-reared animals, demonstrating that the leptin-hypothalamic axis can be enhanced by environmental stimulation.

At the molecular level, studies based on gene chip analysis have revealed that a large number of genes related to neuronal structure, synaptic transmission and plasticity, neuronal excitability and neuroprotection change their expression levels in response to EE [45]. One group of molecules particularly sensitive to experience are neurotrophins, a family of secreted factors critically involved in structural and functional plasticity during development and in adulthood [46].

An important line of research deals with the potential therapeutic effects of EE: indeed, it has been shown that enriching the housing environment delays the progression of, and facilitates recovery from, various nervous system dysfunctions, including neurodevelopmental disorders, neurodegenerative diseases, different types of brain injury and psychiatric disorders [47-54]. These studies have profound consequences for humans. The development of intervention protocols aimed at maintaining a healthy and active lifestyle has been effectively encouraged by the results of basic research on EE. For example, strong correlative and epidemiological evidence shows that living habits, including occupation, leisure activities and physical exercise, have a direct effect on the risk of cognitive decline, with an increasing number of results indicating that a higher level and variety of mental and physical activity is associated with lower cognitive decline and reduced risk for dementia (for a review, [55]).

Environmental Influences on Visual Cortex Development and Plasticity 299

stimulation from the white-matter [57]. Moreover, the functional effects of EE are preceded by a very early increase in the visual cortex of the expression of brain-derived neurotrophic factor (BDNF), a neurotrophin strongly involved in the maturation of brain circuitries. BDNF increase at P7 is accompanied by an enhanced expression of the GABA biosynthetic enzymes, GAD65 and 67, detectable both at P7 and P15. These findings led us to compare our results (see [14]) with those previously found in BDNF overexpressing mice. In these animals, BDNF expression in the visual cortex is higher than in wt mice starting from very early postnatal ages and this correlates with a precocious development of intracortical GABAergic inhibition, as shown by the faster developmental increase in inhibitory postsynaptic currents and GABA biosynthetic enzyme GAD65 in the perisomatic region of pyramidal cells [59]. This early development of GABAergic inhibition is accompanied by an accelerated maturation of visual acuity, likely due to the refinement of visual receptive fields under the direct control of inhibitory interneurons. Thus, EE effects on BDNF and GABA biosynthetic enzymes provide an explanation for EE action on visual cortical development and confirm the role of neurotrophins and of the intracortical GABAergic

Application of EE paradigms allowed us also to demonstrate a key role in visual development of another molecule, insuline-like growth factor-I (IGF-I). IGF-I expression is increased at P18 in the visual cortex of rats raised in EE compared to standard-reared animals, and exogenous IGF-I supply mimics, whereas blocking IGF-I action prevents, the EE effects on visual acuity maturation [60]. It is possible that BDNF and IGF-I signaling may eventually converge on the same pathways, as suggested by results showing that the CREB/CRE-mediated gene expression, which is regulated by both molecules [61, 62], is developmentally accelerated in the visual cortex of enriched animals, while chronic injections of control animals with rolipram, a pharmacological treatment increasing the phosphorylation of CREB, partially mimic the EE outcome on visual acuity maturation [57]. Another biochemical pathway shared by BDNF and IGF-I might be regulation of the inhibitory GABAergic system, since cortical interneurons respond to IGF-I infusion

The precociousness of EE effects on BDNF and GAD65/67 challenges the intuitive view by which the development of a particular sensory system should be strictly dependent on experience of the same sensory modality. Indeed, the increase in BDNF and GAD enzymes does not require vision at all, if one considers that it is clearly evident before eye opening and even before photoreceptor formation. This is confirmed by results obtained in enriched rats raised in darkness during development [63]. It is well known that rearing mammals in total darkness affects the maturation of visual cortical circuits, prolonging the duration of the critical period and impairing the process of visual acuity maturation until normal visual experience is re-established [64, 65]. We found that both effects of dark rearing were completely counteracted by EE [63]. Once again, the effect is very similar to that found in BDNF over-expressing mice, where a full rescue of the typical dark-rearing phenotype has

inhibition as determinants of visual functional development.

increasing GAD65 expression in their synaptic terminals [60].

been reported [66].

## **2. Environmental enrichment and visual system development**

## **2.1. Acceleration of visual system development by EE**

Most studies addressing the effects elicited by EE focused on the adult brain, leaving almost unexplored the question whether an enhanced environmental stimulation can also affect processes governing the development of the brain architecture. In Neuroscience and developmental Psychobiology, this is a fundamental issue dealing with the classic debate about the role of Nature and Nurture, or, in more biological terms, Genes and Environment, in the construction of brain structure and its functional output, the behavior.

The scarce interest attracted by early EE studies can be possibly attributed to the fact that pre-weaning enrichment is characterized by very little amounts of voluntary physical exercise, as the pups are too inert to engage in sustained motor activities. Since increased levels of physical activity are thought to be an essential component of the enrichment protocol [16], this can explain why the possibility to evoke neural and behavioral changes through pre-weaning enrichment have been considered quite limited. For instance, differently from adult animals, hippocampal neurogenesis was not found to be promoted by an intensive preweaning EE protocol consisting of increasing complex combinations of tactile, olfactory, visual, acoustic and vestibular stimuli to which pups were exposed from post-natal day 7 (P7) until P21 [56]. However, since early EE provides increased levels of polysensory stimulation occurring during a period of high anatomical and functional rearrangement of the cerebral cortex, it might be expected to elicit brain changes through experience-dependent plasticity processes.

Some years ago, we started in Pisa a series of studies in which we focused on visual system maturation in environmentally enriched rodents as a paradigmatic model to probe the impact of experience-dependent stimulation on central nervous system development. This approach has proved quite fruitful, allowing us to open a window on the dynamic building of the brain according to different levels of environmental stimulation.

One sensitive parameter which allows researchers to faithfully follow visual system maturation is the progressive increase of visual acuity that occurs during the first postnatal weeks (in rodents), months (in monkeys) or years (in humans). The time course of this process, which results in the ability to perceive fine spatial details in the visual world, turned out to be highly susceptible to the influence exerted by EE, with a one- (in the mouse) or two- (in the rat) week acceleration displayed by both mice and rats exposed to EE since birth [57, 58]. In the timescale of human visual development this is a strong effect, if one considers that is corresponds to an acceleration of about two years in the five-year period normally required for a child to reach adult-like visual acuity values. At the synaptic plasticity level, EE induces a faster closure of the time-window during which it is possible, early in development, to induce LTP in visual cortical slices through theta-frequency stimulation from the white-matter [57]. Moreover, the functional effects of EE are preceded by a very early increase in the visual cortex of the expression of brain-derived neurotrophic factor (BDNF), a neurotrophin strongly involved in the maturation of brain circuitries. BDNF increase at P7 is accompanied by an enhanced expression of the GABA biosynthetic enzymes, GAD65 and 67, detectable both at P7 and P15. These findings led us to compare our results (see [14]) with those previously found in BDNF overexpressing mice. In these animals, BDNF expression in the visual cortex is higher than in wt mice starting from very early postnatal ages and this correlates with a precocious development of intracortical GABAergic inhibition, as shown by the faster developmental increase in inhibitory postsynaptic currents and GABA biosynthetic enzyme GAD65 in the perisomatic region of pyramidal cells [59]. This early development of GABAergic inhibition is accompanied by an accelerated maturation of visual acuity, likely due to the refinement of visual receptive fields under the direct control of inhibitory interneurons. Thus, EE effects on BDNF and GABA biosynthetic enzymes provide an explanation for EE action on visual cortical development and confirm the role of neurotrophins and of the intracortical GABAergic inhibition as determinants of visual functional development.

298 Visual Cortex – Current Status and Perspectives

reduced risk for dementia (for a review, [55]).

experience-dependent plasticity processes.

variety of mental and physical activity is associated with lower cognitive decline and

Most studies addressing the effects elicited by EE focused on the adult brain, leaving almost unexplored the question whether an enhanced environmental stimulation can also affect processes governing the development of the brain architecture. In Neuroscience and developmental Psychobiology, this is a fundamental issue dealing with the classic debate about the role of Nature and Nurture, or, in more biological terms, Genes and Environment,

The scarce interest attracted by early EE studies can be possibly attributed to the fact that pre-weaning enrichment is characterized by very little amounts of voluntary physical exercise, as the pups are too inert to engage in sustained motor activities. Since increased levels of physical activity are thought to be an essential component of the enrichment protocol [16], this can explain why the possibility to evoke neural and behavioral changes through pre-weaning enrichment have been considered quite limited. For instance, differently from adult animals, hippocampal neurogenesis was not found to be promoted by an intensive preweaning EE protocol consisting of increasing complex combinations of tactile, olfactory, visual, acoustic and vestibular stimuli to which pups were exposed from post-natal day 7 (P7) until P21 [56]. However, since early EE provides increased levels of polysensory stimulation occurring during a period of high anatomical and functional rearrangement of the cerebral cortex, it might be expected to elicit brain changes through

Some years ago, we started in Pisa a series of studies in which we focused on visual system maturation in environmentally enriched rodents as a paradigmatic model to probe the impact of experience-dependent stimulation on central nervous system development. This approach has proved quite fruitful, allowing us to open a window on the dynamic building

One sensitive parameter which allows researchers to faithfully follow visual system maturation is the progressive increase of visual acuity that occurs during the first postnatal weeks (in rodents), months (in monkeys) or years (in humans). The time course of this process, which results in the ability to perceive fine spatial details in the visual world, turned out to be highly susceptible to the influence exerted by EE, with a one- (in the mouse) or two- (in the rat) week acceleration displayed by both mice and rats exposed to EE since birth [57, 58]. In the timescale of human visual development this is a strong effect, if one considers that is corresponds to an acceleration of about two years in the five-year period normally required for a child to reach adult-like visual acuity values. At the synaptic plasticity level, EE induces a faster closure of the time-window during which it is possible, early in development, to induce LTP in visual cortical slices through theta-frequency

of the brain according to different levels of environmental stimulation.

**2. Environmental enrichment and visual system development** 

in the construction of brain structure and its functional output, the behavior.

**2.1. Acceleration of visual system development by EE** 

Application of EE paradigms allowed us also to demonstrate a key role in visual development of another molecule, insuline-like growth factor-I (IGF-I). IGF-I expression is increased at P18 in the visual cortex of rats raised in EE compared to standard-reared animals, and exogenous IGF-I supply mimics, whereas blocking IGF-I action prevents, the EE effects on visual acuity maturation [60]. It is possible that BDNF and IGF-I signaling may eventually converge on the same pathways, as suggested by results showing that the CREB/CRE-mediated gene expression, which is regulated by both molecules [61, 62], is developmentally accelerated in the visual cortex of enriched animals, while chronic injections of control animals with rolipram, a pharmacological treatment increasing the phosphorylation of CREB, partially mimic the EE outcome on visual acuity maturation [57]. Another biochemical pathway shared by BDNF and IGF-I might be regulation of the inhibitory GABAergic system, since cortical interneurons respond to IGF-I infusion increasing GAD65 expression in their synaptic terminals [60].

The precociousness of EE effects on BDNF and GAD65/67 challenges the intuitive view by which the development of a particular sensory system should be strictly dependent on experience of the same sensory modality. Indeed, the increase in BDNF and GAD enzymes does not require vision at all, if one considers that it is clearly evident before eye opening and even before photoreceptor formation. This is confirmed by results obtained in enriched rats raised in darkness during development [63]. It is well known that rearing mammals in total darkness affects the maturation of visual cortical circuits, prolonging the duration of the critical period and impairing the process of visual acuity maturation until normal visual experience is re-established [64, 65]. We found that both effects of dark rearing were completely counteracted by EE [63]. Once again, the effect is very similar to that found in BDNF over-expressing mice, where a full rescue of the typical dark-rearing phenotype has been reported [66].

The impact of EE on visual system development turned out not to be restricted to the cerebral cortex, but was clearly present also at the level of the retina, a peripheral part of the central nervous system traditionally considered little or not plastic at all in response to changes of sensory inputs. This classic concept has been mostly based on results showing that retinal acuity, i.e. the spatial discrimination limit of the retinal output, determined with electroretinogram, is unresponsive to visual deprivation in cats, rats and humans [64, 67, 68]. However, when probed with EE, retinal development resulted to be robustly accelerated, both when taking into account retinal acuity development [58] and when analyzing the process of retinal ganglion cell dendrite segregation into ON and OFF sublaminae [69]. The molecular alphabet underlying these changes appears to be the same followed by the visual cortex: levels of retinal IGF-I and BDNF are precociously increased in the retinal ganglion cell layer of developing rats raised under enriched conditions, and separately blocking IGF-I or BDNF action prevents EE effects [58, 69]. Interestingly, the possibility to evoke retinal plasticity is not a prerogative of an enhanced environmental stimulation, as both the anatomical and physiological maturation of retinal circuits is also altered by a complete lack of visual experience in mice [70, 71].

Environmental Influences on Visual Cortex Development and Plasticity 301

an accelerated maturation of visual acuity, stimulated pups exhibited increased IGF-I levels at P18, and blocking the IGF-I action prevented its effects on visual system

**Figure 1. Massage therapy promotes visual acuity maturation in pre-term infants and rat pups.** In rat pups, massage was performed during the first twelve postnatal days, three times per day. Stimulated rats exhibited higher visual acuity values compared to non-stimulated controls at postnatal day (P) 25. In pre-term babies, massage therapy started on day 10 after birth and continued for a total of ten days. During tactile stimulation, the infants were placed prone and given moderate pressure stroking with the flats of the fingers of both hands. In addition, passive flexion/extension movements of the limbs were applied in sequence. Visual acuity in massaged infants was significantly higher than in controls at

Since the essence of EE embodies the concept of "optimization" of sensory-motor stimulation rather than its "alteration or reduction", this paradigm is an ideal candidate for application to humans. In parallel to the effects obtained in massaged rats, Guzzetta et al. [79] reported that enriching the environment in terms of body massage ('massage therapy') accelerates brain development in healthy pre-term infants (gestational age between 30 and 33 weeks). Massaged infants exhibited a faster developmental reduction in the latency of flash visual evoked potentials (VEPs) and an increase in behavioral visual acuity, which persisted above two

3 months. Asterisks indicate statistical significance. Data replotted from Guzzetta et al. [79].

development [79].

#### **2.2. Maternal enrichment effects**

The precociousness of the effects elicited by EE on brain development led us to hypothesize that they might be mediated by maternal behavior differences between enriched and non-enriched dams. What else, indeed, might cause a P7 increase of BDNF in pups spending the whole time in the nest, with no exploration of the enriched surroundings and no visual experience of it? Experience acquired between birth and weaning is essential in promoting and regulating neural development and behavioral traits of the newborn in both rodents and primates [72]. During this critical period of high developmental plasticity, maternal influence can be considered one of the most important sources of sensory experience for the developing subject [73-75], regulating physical growth and promoting the neural maturation of brain structures [72, 76, 77]. Our hypothesis of a critical involvement of maternal behavior in early EE effects has found experimental support in a detailed quantitative study of maternal care in different environmental conditions, which showed that enriched pups receive higher levels of maternal stimulation compared to standard-reared animals [78]. More specifically, enriched rats experience a continuous physical contact due to the presence of adult females in the nest and are also provided with increased levels of licking and grooming, a fundamental source of tactile stimulation. Thus, living in an EE setting provides the animals with an additional source of stimulation other than the social, cognitive and motor components: maternal touch. More recently [79], we were able to reproduce the EEdependent acceleration of visual development by providing standard-reared rat pups, during their first ten postnatal days of life, with a tactile stimulation (massage) mimicking maternal behavior, a procedure previously shown to compensate for the deleterious effects of long-lasting maternal deprivation (Figure 1) [80-82]. In addition to

an accelerated maturation of visual acuity, stimulated pups exhibited increased IGF-I levels at P18, and blocking the IGF-I action prevented its effects on visual system development [79].

300 Visual Cortex – Current Status and Perspectives

**2.2. Maternal enrichment effects** 

The impact of EE on visual system development turned out not to be restricted to the cerebral cortex, but was clearly present also at the level of the retina, a peripheral part of the central nervous system traditionally considered little or not plastic at all in response to changes of sensory inputs. This classic concept has been mostly based on results showing that retinal acuity, i.e. the spatial discrimination limit of the retinal output, determined with electroretinogram, is unresponsive to visual deprivation in cats, rats and humans [64, 67, 68]. However, when probed with EE, retinal development resulted to be robustly accelerated, both when taking into account retinal acuity development [58] and when analyzing the process of retinal ganglion cell dendrite segregation into ON and OFF sublaminae [69]. The molecular alphabet underlying these changes appears to be the same followed by the visual cortex: levels of retinal IGF-I and BDNF are precociously increased in the retinal ganglion cell layer of developing rats raised under enriched conditions, and separately blocking IGF-I or BDNF action prevents EE effects [58, 69]. Interestingly, the possibility to evoke retinal plasticity is not a prerogative of an enhanced environmental stimulation, as both the anatomical and physiological maturation of retinal circuits is also

The precociousness of the effects elicited by EE on brain development led us to hypothesize that they might be mediated by maternal behavior differences between enriched and non-enriched dams. What else, indeed, might cause a P7 increase of BDNF in pups spending the whole time in the nest, with no exploration of the enriched surroundings and no visual experience of it? Experience acquired between birth and weaning is essential in promoting and regulating neural development and behavioral traits of the newborn in both rodents and primates [72]. During this critical period of high developmental plasticity, maternal influence can be considered one of the most important sources of sensory experience for the developing subject [73-75], regulating physical growth and promoting the neural maturation of brain structures [72, 76, 77]. Our hypothesis of a critical involvement of maternal behavior in early EE effects has found experimental support in a detailed quantitative study of maternal care in different environmental conditions, which showed that enriched pups receive higher levels of maternal stimulation compared to standard-reared animals [78]. More specifically, enriched rats experience a continuous physical contact due to the presence of adult females in the nest and are also provided with increased levels of licking and grooming, a fundamental source of tactile stimulation. Thus, living in an EE setting provides the animals with an additional source of stimulation other than the social, cognitive and motor components: maternal touch. More recently [79], we were able to reproduce the EEdependent acceleration of visual development by providing standard-reared rat pups, during their first ten postnatal days of life, with a tactile stimulation (massage) mimicking maternal behavior, a procedure previously shown to compensate for the deleterious effects of long-lasting maternal deprivation (Figure 1) [80-82]. In addition to

altered by a complete lack of visual experience in mice [70, 71].

**Figure 1. Massage therapy promotes visual acuity maturation in pre-term infants and rat pups.** In rat pups, massage was performed during the first twelve postnatal days, three times per day. Stimulated rats exhibited higher visual acuity values compared to non-stimulated controls at postnatal day (P) 25. In pre-term babies, massage therapy started on day 10 after birth and continued for a total of ten days. During tactile stimulation, the infants were placed prone and given moderate pressure stroking with the flats of the fingers of both hands. In addition, passive flexion/extension movements of the limbs were applied in sequence. Visual acuity in massaged infants was significantly higher than in controls at 3 months. Asterisks indicate statistical significance. Data replotted from Guzzetta et al. [79].

Since the essence of EE embodies the concept of "optimization" of sensory-motor stimulation rather than its "alteration or reduction", this paradigm is an ideal candidate for application to humans. In parallel to the effects obtained in massaged rats, Guzzetta et al. [79] reported that enriching the environment in terms of body massage ('massage therapy') accelerates brain development in healthy pre-term infants (gestational age between 30 and 33 weeks). Massaged infants exhibited a faster developmental reduction in the latency of flash visual evoked potentials (VEPs) and an increase in behavioral visual acuity, which persisted above two

months after the end of the treatment. Moreover, a faster EEG maturation was evident in massaged babies, as shown by the more rapid shortening of the interbust intervals, a reliable index of the developmental stage of the brain electrical activity. Interestingly, massaged babies did not exhibit the change in EEG spectral power found in the comparison group [83], confirming that massage intervention affects the maturation of brain electrical activity and suggesting that if may favor a process more similar to that observed in utero in term infants. In good agreement with results obtained in the animal model, massaged infants displayed increased levels of plasma IGF-1 [79]. The results of these studies, which are one of the first attempts to rigorously investigate the effects of early EE on human brain, emphasize the role of mother Nurture as a driving force for brain development in humans.

Environmental Influences on Visual Cortex Development and Plasticity 303

**Figure 2. Prenatal enrichment modulates retinal development in the fetus.** The figure depicts a possible explicative model for the effects elicited by maternal enrichment during pregnancy on retinal development. Increased levels of physical exercise in gestating dams lead to higher amounts of circulating IGF-I in the maternal blood stream, stimulating the supply of nutrients transferred to the fetus through the placental barrier. The enhancement in glucose and placental lactogens received by the fetus stimulates the autonomous production of IGF-1 in fetal tissues, with an increased expression detectable in the ganglion cell layer of the retina. IGF, in turn, stimulates the maturation of retinal circuitries. The photographs depict two examples of one enriched (left) and one non-enriched (right) retinal sections immunostained for double-cortin, which labels migrating cells and is a good marker of the temporal and spatial distribution of neural progenitors during the early developmental stages of the

The decay of plasticity levels in the adult visual system is not absolute, of course, but is dependent on the kind of stimuli and neural processes under investigation. A striking example of use-dependent plasticity in the adult visual cortex has been described in the work of Bear and colleagues which showed that repeated exposure to grating stimuli of a single orientation results in a long-lasting increase of VEP amplitudes in response to the test

rat retina. Modified from Sale et al. [87].

Maternal influence on the offspring development not only takes the form of maternal care given to pups during the first postnatal weeks, but it also includes the complex supply of nutrients, hormones and respiratory gases provided by the mother to the fetus during pregnancy, through placental exchanges [84]. The extent to which different environmental conditions experienced by the mother during pregnancy affect fetal development is still debated. For many years, the best documented effects were only those elicited by prenatal stress protocols, which have a well established role in growth retardation and structural malformations of the offspring [85, 86]. We found that the ability of EE to modulate growth factors critical for central nervous system development is present also during prenatal life (Figure 2).

Indeed, enriching female rats for the entire length of gestation results in faster dynamics of neural progenitor migration and spontaneous apoptosis in the retinal ganglion cell layer, an effect mediated also in this case by IGF-I [87]. We proposed a model in which sustained physical exercise during pregnancy increases IGF-I in the mother, promoting placental transfer of nutrients to the fetus; this would in turn lead to increased amounts of IGF-I autonomously produced by the fetus, resulting in the accelerated development detectable at retinal level (Figure 2). The influence exerted by maternal enrichment during pregnancy on the fetus is not restricted to the visual system. The hippocampus of pups born from enriched mothers, indeed, displays increased expression of BDNF [88] and increased proliferation of progenitor cells in the granule layer [89], resulting in improved cognitive functions when the animals reach adult ages [90].

## **3. Impact of EE on adult visual system plasticity**

## **3.1. Amblyopia recovery in enriched animals**

When visual functions mature up to their adult-like levels, the critical period for plasticity in the visual cortex closes and the possibility to induce further functional and structural changes by manipulating sensory experience abruptly wanes. This poses enduring brakes to the potential for recovery from defective development and for functional rehabilitation. Overcoming the obstacles which limit plasticity in the adult brain is a fundamental goal of both basic and clinical research in Neuroscience [91].

(Figure 2).

the animals reach adult ages [90].

**3. Impact of EE on adult visual system plasticity** 

**3.1. Amblyopia recovery in enriched animals** 

both basic and clinical research in Neuroscience [91].

months after the end of the treatment. Moreover, a faster EEG maturation was evident in massaged babies, as shown by the more rapid shortening of the interbust intervals, a reliable index of the developmental stage of the brain electrical activity. Interestingly, massaged babies did not exhibit the change in EEG spectral power found in the comparison group [83], confirming that massage intervention affects the maturation of brain electrical activity and suggesting that if may favor a process more similar to that observed in utero in term infants. In good agreement with results obtained in the animal model, massaged infants displayed increased levels of plasma IGF-1 [79]. The results of these studies, which are one of the first attempts to rigorously investigate the effects of early EE on human brain, emphasize the role of

Maternal influence on the offspring development not only takes the form of maternal care given to pups during the first postnatal weeks, but it also includes the complex supply of nutrients, hormones and respiratory gases provided by the mother to the fetus during pregnancy, through placental exchanges [84]. The extent to which different environmental conditions experienced by the mother during pregnancy affect fetal development is still debated. For many years, the best documented effects were only those elicited by prenatal stress protocols, which have a well established role in growth retardation and structural malformations of the offspring [85, 86]. We found that the ability of EE to modulate growth factors critical for central nervous system development is present also during prenatal life

Indeed, enriching female rats for the entire length of gestation results in faster dynamics of neural progenitor migration and spontaneous apoptosis in the retinal ganglion cell layer, an effect mediated also in this case by IGF-I [87]. We proposed a model in which sustained physical exercise during pregnancy increases IGF-I in the mother, promoting placental transfer of nutrients to the fetus; this would in turn lead to increased amounts of IGF-I autonomously produced by the fetus, resulting in the accelerated development detectable at retinal level (Figure 2). The influence exerted by maternal enrichment during pregnancy on the fetus is not restricted to the visual system. The hippocampus of pups born from enriched mothers, indeed, displays increased expression of BDNF [88] and increased proliferation of progenitor cells in the granule layer [89], resulting in improved cognitive functions when

When visual functions mature up to their adult-like levels, the critical period for plasticity in the visual cortex closes and the possibility to induce further functional and structural changes by manipulating sensory experience abruptly wanes. This poses enduring brakes to the potential for recovery from defective development and for functional rehabilitation. Overcoming the obstacles which limit plasticity in the adult brain is a fundamental goal of

mother Nurture as a driving force for brain development in humans.

**Figure 2. Prenatal enrichment modulates retinal development in the fetus.** The figure depicts a possible explicative model for the effects elicited by maternal enrichment during pregnancy on retinal development. Increased levels of physical exercise in gestating dams lead to higher amounts of circulating IGF-I in the maternal blood stream, stimulating the supply of nutrients transferred to the fetus through the placental barrier. The enhancement in glucose and placental lactogens received by the fetus stimulates the autonomous production of IGF-1 in fetal tissues, with an increased expression detectable in the ganglion cell layer of the retina. IGF, in turn, stimulates the maturation of retinal circuitries. The photographs depict two examples of one enriched (left) and one non-enriched (right) retinal sections immunostained for double-cortin, which labels migrating cells and is a good marker of the temporal and spatial distribution of neural progenitors during the early developmental stages of the rat retina. Modified from Sale et al. [87].

The decay of plasticity levels in the adult visual system is not absolute, of course, but is dependent on the kind of stimuli and neural processes under investigation. A striking example of use-dependent plasticity in the adult visual cortex has been described in the work of Bear and colleagues which showed that repeated exposure to grating stimuli of a single orientation results in a long-lasting increase of VEP amplitudes in response to the test stimulus [92]. Another well defined phenomenon is the shift in orientation or spatial frequency selectivity displayed by neurons in the cat primary visual cortex after a period of adaptation consisting in the presentation of a stimulus at non-preferred orientations or spatial frequencies [93, 94]. Despite these and other [95] remarkable examples of adult V1 plasticity, however, the possibility of recovery from the consequences of an altered visual experience extending beyond the end of critical periods is extremely limited. One paradigmatic example of an enduring loss of visual abilities which is still orphan of treatment is amblyopia (lazy eye), a severe condition with an estimated prevalence of 1-5% in the total world population [96]. Amblyopia is caused by a marked functional imbalance between the two eyes occurring early in development and due to an unequal refractive power in the two eyes (anisometropia), an abnormal alignment of ocular axes (strabismus) or visual clouding caused, for instance, by congenital cataract [97]. If the cause of visual impairment is not rapidly removed, amblyopic subjects develop a dramatic degradation of visual acuity and contrast sensitivity in the anisometropic, strabismic or cataract affected eye and experience a broad range of other perceptual deficits, including stereopsis defects [96, 98, 99]. These deficits are attributed to the alteration in ocular dominance and binocularity of neurons in the developing visual cortex caused by the imbalance between the inputs form the two eyes.

Environmental Influences on Visual Cortex Development and Plasticity 305

driving amblyopia rescue in enriched animals. This was one of the first demonstrations that reducing the inhibition-excitation balance reinstates plasticity in the adult brain [103], as subsequently confirmed by another study in which a pharmacological reduction of inhibition through intracortical infusion of either MPA (an inhibitor of GABA synthesis) or picrotoxin (a GABAA antagonist) was reported to reactivate plasticity in response to

**Figure 3.** Developmental increase of brain GABAergic inhibition levels is paralleled by a progressive reduction of experience-dependent plasticity. Plasticity is high during early development (green block) and very low in the adult brain (yellow block). Anomalous increases in the strength of inhibitory neural circuits may lead to overinhibition linked to permanent deficits in synaptic plasticity and neural development, like in the Down syndrome. Reducing GABAergic inhibition with environmental enrichment, fluoxetine or pharmacological treatments (blockers of GABA synthesis or GABA receptor antagonists) can increase plasticity in the adult brain, enabling plasticity in V1 and favoring recovery from amblyopia. The capability of EE to reduce GABAergic inhibition makes this paradigm eligible for therapeutic applications also in the treatment of developmental intellectual disabilities. Plasticity levels

have been normalized to the normal adult values (red curve). Modified from Sale et al. [113].

In amblyopia, one case of particularly relevant clinical interest is that of those patients who loose their better eye due to an accident or ocular illnesses, thus becoming severely visually impaired. It has been reported that the visual acuity of the amblyopic eye can display partial spontaneous recovery following loss of vision in the fellow eye [105-109], but the occurrence of this fortunate response is unpredictable and which factors promote improvement under

MD in adult rats [104] (Figure 3).

While it is generally accepted that recovery of visual functions is possible only if normal visual experience is re-established early in development, recent studies in rodents have shown new therapeutic possibilities for the treatment of adult subjects [100]. In animal models like rats and mice, amblyopia can be easily induced by imposing a long-term occlusion of vision through one eye by an enduring MD procedure starting at the peak of plasticity early in development and protracted until adulthood. In the effort to challenge the critical period dogma, we showed that adult amblyopic rats transferred to an EE setting for three weeks undergo a full recovery of visual functions [101]. Immediately before starting the EE procedure, all rats were subjected to reverse suture, which consists in the re-opening of the long-term deprived (amblyopic) eye and the concomitant closure of the eyelids in the fellow eye, a procedure that, analogously to the so-called patching therapy in humans [102], is aimed at penalizing the preferred eye and forcing the brain to use visual inputs carried by the amblyopic eye. Reverse suture is very effective in promoting recovery form amblyopia if performed during the critical period but it is ineffective in adult subjects. On the contrary, reverse suture in animals exposed to EE was found to promote a complete rescue of ocular dominance and visual acuity, with beneficial effects detectable at both the electrophysiological and behavioral level and outlasting the end of the treatment for at least ten days. Recovery of plasticity in enriched animals was accompanied by a three-fold reduction in GABA-release detected in the visual cortex contralateral to the previously deprived eye by means of in vivo brain microdialysis, without any significant change in the release of glutamate. Moreover, the beneficial effects elicited by EE were totally counteracted by intracortical infusion of the benzodiazepine Diazepam, revealing a key role for decreased GABAergic transmission in driving amblyopia rescue in enriched animals. This was one of the first demonstrations that reducing the inhibition-excitation balance reinstates plasticity in the adult brain [103], as subsequently confirmed by another study in which a pharmacological reduction of inhibition through intracortical infusion of either MPA (an inhibitor of GABA synthesis) or picrotoxin (a GABAA antagonist) was reported to reactivate plasticity in response to MD in adult rats [104] (Figure 3).

304 Visual Cortex – Current Status and Perspectives

the two eyes.

stimulus [92]. Another well defined phenomenon is the shift in orientation or spatial frequency selectivity displayed by neurons in the cat primary visual cortex after a period of adaptation consisting in the presentation of a stimulus at non-preferred orientations or spatial frequencies [93, 94]. Despite these and other [95] remarkable examples of adult V1 plasticity, however, the possibility of recovery from the consequences of an altered visual experience extending beyond the end of critical periods is extremely limited. One paradigmatic example of an enduring loss of visual abilities which is still orphan of treatment is amblyopia (lazy eye), a severe condition with an estimated prevalence of 1-5% in the total world population [96]. Amblyopia is caused by a marked functional imbalance between the two eyes occurring early in development and due to an unequal refractive power in the two eyes (anisometropia), an abnormal alignment of ocular axes (strabismus) or visual clouding caused, for instance, by congenital cataract [97]. If the cause of visual impairment is not rapidly removed, amblyopic subjects develop a dramatic degradation of visual acuity and contrast sensitivity in the anisometropic, strabismic or cataract affected eye and experience a broad range of other perceptual deficits, including stereopsis defects [96, 98, 99]. These deficits are attributed to the alteration in ocular dominance and binocularity of neurons in the developing visual cortex caused by the imbalance between the inputs form

While it is generally accepted that recovery of visual functions is possible only if normal visual experience is re-established early in development, recent studies in rodents have shown new therapeutic possibilities for the treatment of adult subjects [100]. In animal models like rats and mice, amblyopia can be easily induced by imposing a long-term occlusion of vision through one eye by an enduring MD procedure starting at the peak of plasticity early in development and protracted until adulthood. In the effort to challenge the critical period dogma, we showed that adult amblyopic rats transferred to an EE setting for three weeks undergo a full recovery of visual functions [101]. Immediately before starting the EE procedure, all rats were subjected to reverse suture, which consists in the re-opening of the long-term deprived (amblyopic) eye and the concomitant closure of the eyelids in the fellow eye, a procedure that, analogously to the so-called patching therapy in humans [102], is aimed at penalizing the preferred eye and forcing the brain to use visual inputs carried by the amblyopic eye. Reverse suture is very effective in promoting recovery form amblyopia if performed during the critical period but it is ineffective in adult subjects. On the contrary, reverse suture in animals exposed to EE was found to promote a complete rescue of ocular dominance and visual acuity, with beneficial effects detectable at both the electrophysiological and behavioral level and outlasting the end of the treatment for at least ten days. Recovery of plasticity in enriched animals was accompanied by a three-fold reduction in GABA-release detected in the visual cortex contralateral to the previously deprived eye by means of in vivo brain microdialysis, without any significant change in the release of glutamate. Moreover, the beneficial effects elicited by EE were totally counteracted by intracortical infusion of the benzodiazepine Diazepam, revealing a key role for decreased GABAergic transmission in

**Figure 3.** Developmental increase of brain GABAergic inhibition levels is paralleled by a progressive reduction of experience-dependent plasticity. Plasticity is high during early development (green block) and very low in the adult brain (yellow block). Anomalous increases in the strength of inhibitory neural circuits may lead to overinhibition linked to permanent deficits in synaptic plasticity and neural development, like in the Down syndrome. Reducing GABAergic inhibition with environmental enrichment, fluoxetine or pharmacological treatments (blockers of GABA synthesis or GABA receptor antagonists) can increase plasticity in the adult brain, enabling plasticity in V1 and favoring recovery from amblyopia. The capability of EE to reduce GABAergic inhibition makes this paradigm eligible for therapeutic applications also in the treatment of developmental intellectual disabilities. Plasticity levels have been normalized to the normal adult values (red curve). Modified from Sale et al. [113].

In amblyopia, one case of particularly relevant clinical interest is that of those patients who loose their better eye due to an accident or ocular illnesses, thus becoming severely visually impaired. It has been reported that the visual acuity of the amblyopic eye can display partial spontaneous recovery following loss of vision in the fellow eye [105-109], but the occurrence of this fortunate response is unpredictable and which factors promote improvement under similar circumstances remains totally unknown. We recently addressed the possibility to rescue visual acuity in long-term deprived adult rats exposed to EE immediately after silencing of retino-thalamic projections of the fellow (non amblyopic) eye due to optic nerve dissection [110]. While no spontaneous rescue of visual abilities was detected in animals reared under standard environmental conditions, a full recovery of visual acuity was achieved in monocular rats exposed to EE, an effect accompanied by lower numbers of GAD67+ cells and increased BDNF in the visual cortex. Thus, an enhanced environmental stimulation can promote visual cortex plasticity and functional recovery even in a condition in which competition between the two eyes is completely suppressed. However, this effect fits also well with a competition-based model, because stronger inputs from the fellow eye could mask activity in the weaker connections from the amblyopic eye until they are selectively silenced by optic nerve dissection.

Environmental Influences on Visual Cortex Development and Plasticity 307

encourage the implementation of new environmental strategies devoted to promote stimulation of the amblyopic eye in adult patients as a way to increase their chance of visual

The possibility to reinstate plasticity in the adult visual cortex by using a non-invasive procedure such as EE is appealing. A growing body of evidence in humans shows that experimental paradigms akin to EE, such as playing videogames or practicing visual perceptual learning (PL), are effective in promoting recovery from amblyopia in adulthood [115-118].

**Figure 4. Impact of motor, social and sensory components on recovery from amblyopia in adult rats.**  Adult amblyopic rats were subjected for three weeks to either motor enrichment (consisting of a standard cage equipped with a running wheel connected to an automatic device recording the number of wheel turns), visual enrichment (consisting of a standard cage positioned at the centre of a rotating fluorescent drum where specific visual patterns were drawn), social stimulation (consisting of a slightly bigger standard cage where numerous rats where housed together), or visual perceptual learning (see Figure 5 for more details). A complete rescue of visual acuity in the amblyopic eye was achieved by rats performing physical exercise on a running wheel, in animals exposed to visual enrichment and in animals engaged in visual perceptual learning. This effect was also accompanied by a reduced inhibition/excitation balance in the visual cortex. In contrast, no recovery occurred in socially enriched rats or in animals practicing a purely associative visual task. Asterisk indicates statistical significance.

functional improvements.

Data replotted from Baroncelli et al. [114].

**3.2. Visual perceptual learning and amblyopia** 

Since it is currently thought that the inhibition-excitation balance is also impaired during development in amblyopic human subjects and that excessive inhibition levels are involved in the degradation of their spatial vision abilities [111, 112], EE appears as a very promising strategy to counteract visual impairments in amblyopia. Application to clinics of these results obtained in animal models requires the ability to transfer the EE paradigm in the much more complicated and variegated dimension of human life. A fruitful approach might be that of investigating the role of various independent EE components (e.g. social, sensory, motor) in reproducing the beneficial effects elicited by the entire enriched experience, and then designing therapeutic approaches based on the most promising and effective variables.

Recently, we followed this route by separately assessing the efficacy of physical exercise, increased levels of social interaction and enhanced visual stimulation for their potential in promoting recovery from amblyopia in adult rats [114]. Our results show a full recovery of ocular dominance and visual acuity either in both animals experiencing high levels of voluntary motor activity in a running wheel and in rats exposed to a protocol of visual enrichment inside a rotating fluorescent drum specifically designed to maximize stimulation of V1 cortical neurons (Figure 4). The strong involvement of visual experience in the recovery process was further indicated by the demonstration that amblyopic animals placed under classic EE conditions, but completely deprived from visual stimulation, failed to recover normal visual functions, and that using EE in no-reverse sutured animals in which the long-term deprived eye was maintained closed, prevented the animals to differentiate their visual function abilities from untreated controls. In contrast to motor and visual enrichment, enhancing social stimulation alone was not able to induce restoration of normal visual acuity and ocular dominance (Figure 4). Recovery from amblyopia was faithfully associated with a reduction of GABAergic intracortical inhibition, as revealed by decreased GABA release in synaptosome analysis. Thus, potentiation of single components typically present in EE is able to reproduce the effect of visual function recovery from amblyopia previously reported in classically-enriched animals [101, 114]. These findings should encourage the implementation of new environmental strategies devoted to promote stimulation of the amblyopic eye in adult patients as a way to increase their chance of visual functional improvements.

## **3.2. Visual perceptual learning and amblyopia**

306 Visual Cortex – Current Status and Perspectives

selectively silenced by optic nerve dissection.

effective variables.

similar circumstances remains totally unknown. We recently addressed the possibility to rescue visual acuity in long-term deprived adult rats exposed to EE immediately after silencing of retino-thalamic projections of the fellow (non amblyopic) eye due to optic nerve dissection [110]. While no spontaneous rescue of visual abilities was detected in animals reared under standard environmental conditions, a full recovery of visual acuity was achieved in monocular rats exposed to EE, an effect accompanied by lower numbers of GAD67+ cells and increased BDNF in the visual cortex. Thus, an enhanced environmental stimulation can promote visual cortex plasticity and functional recovery even in a condition in which competition between the two eyes is completely suppressed. However, this effect fits also well with a competition-based model, because stronger inputs from the fellow eye could mask activity in the weaker connections from the amblyopic eye until they are

Since it is currently thought that the inhibition-excitation balance is also impaired during development in amblyopic human subjects and that excessive inhibition levels are involved in the degradation of their spatial vision abilities [111, 112], EE appears as a very promising strategy to counteract visual impairments in amblyopia. Application to clinics of these results obtained in animal models requires the ability to transfer the EE paradigm in the much more complicated and variegated dimension of human life. A fruitful approach might be that of investigating the role of various independent EE components (e.g. social, sensory, motor) in reproducing the beneficial effects elicited by the entire enriched experience, and then designing therapeutic approaches based on the most promising and

Recently, we followed this route by separately assessing the efficacy of physical exercise, increased levels of social interaction and enhanced visual stimulation for their potential in promoting recovery from amblyopia in adult rats [114]. Our results show a full recovery of ocular dominance and visual acuity either in both animals experiencing high levels of voluntary motor activity in a running wheel and in rats exposed to a protocol of visual enrichment inside a rotating fluorescent drum specifically designed to maximize stimulation of V1 cortical neurons (Figure 4). The strong involvement of visual experience in the recovery process was further indicated by the demonstration that amblyopic animals placed under classic EE conditions, but completely deprived from visual stimulation, failed to recover normal visual functions, and that using EE in no-reverse sutured animals in which the long-term deprived eye was maintained closed, prevented the animals to differentiate their visual function abilities from untreated controls. In contrast to motor and visual enrichment, enhancing social stimulation alone was not able to induce restoration of normal visual acuity and ocular dominance (Figure 4). Recovery from amblyopia was faithfully associated with a reduction of GABAergic intracortical inhibition, as revealed by decreased GABA release in synaptosome analysis. Thus, potentiation of single components typically present in EE is able to reproduce the effect of visual function recovery from amblyopia previously reported in classically-enriched animals [101, 114]. These findings should The possibility to reinstate plasticity in the adult visual cortex by using a non-invasive procedure such as EE is appealing. A growing body of evidence in humans shows that experimental paradigms akin to EE, such as playing videogames or practicing visual perceptual learning (PL), are effective in promoting recovery from amblyopia in adulthood [115-118].

**Figure 4. Impact of motor, social and sensory components on recovery from amblyopia in adult rats.**  Adult amblyopic rats were subjected for three weeks to either motor enrichment (consisting of a standard cage equipped with a running wheel connected to an automatic device recording the number of wheel turns), visual enrichment (consisting of a standard cage positioned at the centre of a rotating fluorescent drum where specific visual patterns were drawn), social stimulation (consisting of a slightly bigger standard cage where numerous rats where housed together), or visual perceptual learning (see Figure 5 for more details). A complete rescue of visual acuity in the amblyopic eye was achieved by rats performing physical exercise on a running wheel, in animals exposed to visual enrichment and in animals engaged in visual perceptual learning. This effect was also accompanied by a reduced inhibition/excitation balance in the visual cortex. In contrast, no recovery occurred in socially enriched rats or in animals practicing a purely associative visual task. Asterisk indicates statistical significance. Data replotted from Baroncelli et al. [114].

The cellular and molecular mechanisms underlying PL effects are still scarcely known. We reported that visual PL induces long-term potentiation (LTP) of intracortical synaptic responses in rat V1 [119], in agreement with Cooke and Bear [120]. To elicit visual PL, we first trained a group of adult animals to practice in a forced-choice visual discrimination task that requires them to distinguish between two vertical gratings differing only for their spatial frequency; then, we made the two stimuli progressively more similar to each other, until the animal performance reached a steady plateau (Figure 5A). This task requires activation of V1 circuitries, as indicated by the strong selectivity of PL for the orientation of gratings employed during training (Figure 5B). Control animals only learned the association task, i.e. they were only required to discriminate between a grating and a homogeneous grey panel, matching the overall swim time and number of training days in the water maze with those of PL rats (Figure 5A). Within 1 h from the last discrimination trial, LTP from layer II-III of V1 slices appeared occluded in PL animals compared to controls, both when testing its inducibility in vertical connections (stimulating electrode placed in layer IV) and when stimulating at the level of horizontal connections (stimulating electrode placed in layer II/III) (Figure 5A). Moreover, a significant shift toward increased amplitude of fEPSPs was found in the input/output curves of trained animals compared to controls. Thus, the data fulfill two of the most commonly accepted criteria used to relate LTP with learning, i.e.occlusion and mimicry, demonstrating that the improvements displayed by PL rats in discriminating visual gratings of progressively closer spatial frequencies can be explained in terms of long-term increments of synaptic efficacy in V1, the same cortical area at work during perception. This is consistent with the critical role for LTP in mediating learning processes previously reported in other brain areas such as the amygdala, the hippocampus and the motor cortex [122-124]. An impact on V1 LTP appears to be a common prerogative of visual PL and EE. Indeed, enriched rats also show an enhancement of thalamocortical LTP triggered by theta-burst stimulation (TBS) of the dorsal lateral geniculate nucleus of the thalamus [125], leading to an enhancement in VEP responses to visual stimulation across a wide range of contrasts.

Environmental Influences on Visual Cortex Development and Plasticity 309

**Figure 5. Visual perceptual learning induces long-term potentiation in the primary visual cortex. A)** A modified version of the visual water box task [57, 121] was used to induce visual perceptual learning in a group of adult rats that were first trained to distinguish a low 0.117 cycles per degree (c/deg) spatial frequency (SF) grating (reference grating) from a 0.712 c/deg SF grating (test grating) (right panel) and then learned to distinguish the two gratings when they became more and more similar to each other. A group of control animals was trained to distinguish the reference grating from a homogeneous grey (left panel). After training, LTP from layer II-III of V1 slices was occluded in PL animals compared to controls, at the level of both vertical (blue arrow) and horizontal (red arrow) connections. Sample traces from PL and control slices 5 min before (thin line) and 25 min after (thick line) induction of LTP are shown. **B)** Visual perceptual learning is specific for stimulus orientation. The graphs show daily discrimination threshold values obtained in PL animals trained in discriminating first horizontal gratings and then tested with vertical. After the orientation change, the animals displayed a marked

impairment in their discrimination abilities. Data replotted from Sale et al. [119].

Since potentiation of synaptic transmission might help the recovery process of visual responses for the long-term deprived eye, practice with visual PL through the amblyopic eye is expected to favor a functional rescue in amblyopic animals. In agreement with evidence on human subjects, a marked recovery of visual functions was evident in amblyopic rats subjected to visual PL, while no recovery occurred in two control groups in which the treatment did not induce LTP in V1, i.e. in rats that only learned the associative visual task and in animals that were trained only until the first step of the discrimination procedure between the test and the reference grating, without proceeding further with a progression of finer discrimination trials [114] (Figure 5A). Recovery of visual abilities in PL animals was accompanied by a robust decrease of the inhibition-excitation balance, which could pave the way for future therapeutic attempts in humans based on a manipulation of the GABAergic tone. In line with this, repetitive transcranial magnetic stimulation, a treatment increasing cortical excitability, transiently improves contrast sensitivity in adult amblyopes [126].

wide range of contrasts.

The cellular and molecular mechanisms underlying PL effects are still scarcely known. We reported that visual PL induces long-term potentiation (LTP) of intracortical synaptic responses in rat V1 [119], in agreement with Cooke and Bear [120]. To elicit visual PL, we first trained a group of adult animals to practice in a forced-choice visual discrimination task that requires them to distinguish between two vertical gratings differing only for their spatial frequency; then, we made the two stimuli progressively more similar to each other, until the animal performance reached a steady plateau (Figure 5A). This task requires activation of V1 circuitries, as indicated by the strong selectivity of PL for the orientation of gratings employed during training (Figure 5B). Control animals only learned the association task, i.e. they were only required to discriminate between a grating and a homogeneous grey panel, matching the overall swim time and number of training days in the water maze with those of PL rats (Figure 5A). Within 1 h from the last discrimination trial, LTP from layer II-III of V1 slices appeared occluded in PL animals compared to controls, both when testing its inducibility in vertical connections (stimulating electrode placed in layer IV) and when stimulating at the level of horizontal connections (stimulating electrode placed in layer II/III) (Figure 5A). Moreover, a significant shift toward increased amplitude of fEPSPs was found in the input/output curves of trained animals compared to controls. Thus, the data fulfill two of the most commonly accepted criteria used to relate LTP with learning, i.e.occlusion and mimicry, demonstrating that the improvements displayed by PL rats in discriminating visual gratings of progressively closer spatial frequencies can be explained in terms of long-term increments of synaptic efficacy in V1, the same cortical area at work during perception. This is consistent with the critical role for LTP in mediating learning processes previously reported in other brain areas such as the amygdala, the hippocampus and the motor cortex [122-124]. An impact on V1 LTP appears to be a common prerogative of visual PL and EE. Indeed, enriched rats also show an enhancement of thalamocortical LTP triggered by theta-burst stimulation (TBS) of the dorsal lateral geniculate nucleus of the thalamus [125], leading to an enhancement in VEP responses to visual stimulation across a

Since potentiation of synaptic transmission might help the recovery process of visual responses for the long-term deprived eye, practice with visual PL through the amblyopic eye is expected to favor a functional rescue in amblyopic animals. In agreement with evidence on human subjects, a marked recovery of visual functions was evident in amblyopic rats subjected to visual PL, while no recovery occurred in two control groups in which the treatment did not induce LTP in V1, i.e. in rats that only learned the associative visual task and in animals that were trained only until the first step of the discrimination procedure between the test and the reference grating, without proceeding further with a progression of finer discrimination trials [114] (Figure 5A). Recovery of visual abilities in PL animals was accompanied by a robust decrease of the inhibition-excitation balance, which could pave the way for future therapeutic attempts in humans based on a manipulation of the GABAergic tone. In line with this, repetitive transcranial magnetic stimulation, a treatment increasing

cortical excitability, transiently improves contrast sensitivity in adult amblyopes [126].

### **3.3. Serotonin: A master regulator of adult neural plasticity**

The capability of EE to reinstate juvenile-like plasticity in the adult brain is not limited to its effects on amblyopia. Indeed, the visual cortex of enriched rats displays a remarkable reactivation of ocular dominance plasticity in response to MD [127, 128]. The ocular dominance shift of cortical neurons is detectable using both VEPs and single-unit recordings. While, also in this case, recovery of plasticity is paralleled by a marked reduction of the inhibitory tone and an increase in the number of BDNF-expressing neurons in the visual cortex, a crucial role for the neurotransmitter serotonin in triggering the plastic changes elicited by exposure to EE has been identified. Indeed, EE elicits a twofold enhancement of serotoninergic transmission in the visual cortex and infusion of a serotonin synthesis inhibitor not only blocks plasticity in response to MD but also completely counteracts the effects produced by EE on GABAergic inhibition and BDNF [127]. This led us to put forward a model in which serotonin, probably enhanced by a more sustained attention and arousal level promoted by living in the enriched condition, is the first trigger in the chain of plastic changes set in motion by EE, eliciting the decrease of GABA-mediated intracortical inhibition and, in parallel or in series, the enhancement of BDNF levels (Figure 6).

Environmental Influences on Visual Cortex Development and Plasticity 311

complete recovery of visual functions from amblyopia. As found for enriched rats, these functional effects are associated with a marked reduction of GABAergic inhibition and are completely prevented by cortical Diazepam administration [129]. The reduction of inhibition triggered by fluoxetine provides a permissive environment for structural changes, such as the addition of new synapse-bearing branch spine tips [130]. In light of these promising results, fluoxetine appears to behave as a powerful enviromimetic [131], a drug that can be successfully exploited, alone or in combination with EE, to reproduce or to strengthen the

**4. Life-long beneficial outcome of EE: from developmental disorders to** 

As underscored by the effects on amblyopia, the non invasive nature of EE makes this paradigm eligible for application in the domain of brain dysfunctions. The beneficial impact of EE does not only apply to the case of diseases deriving form alterations of sensory

One paradigmatic example is that of Down syndrome, the most common genetic cause of mental retardation [76] caused by triplication of chromosome 21. People with Down syndrome have a marked cognitive impairment [132, 133], and a number of attention and visual deficits [134-136] together with various disturbances in learning and memory abilities [132, 133]. The most widely animal study of Down syndrome is the Ts65Dn mouse, which carries triplication of a segment of Chr16, syntenic with human Chr21 [137, 138]. This model recapitulates the main hallmarks of the syndrome phenotype, including craniofacial abnormalities, impaired learning abilities and attention and visual function deficits (e.g., [139-141]. Moreover, in vivo cellular analyses, which are of course prevented in humans but easily conducted in the animal model, have allowed a substantial advancement in our knowledge concerning the mechanisms underlying neural impairments in Ts65Dn mice. In particular, a critical role for excessive levels of brain inhibition emerges, with an ensuing failure of long-term synaptic plasticity in the hippocampus [142-145]. This is in agreement with results obtained in post-mortem tissue from people with Down syndrome, which displays an impaired balance between excitatory and inhibitory systems (see [146]. The central role of overinhibition in Down syndrome pathogenesis is confirmed by the demonstration that administration of noncompetitive antagonists of GABA-A receptors reverses spatial learning disabilities and LTP deficits in Ts65Dn mice [146]. Since EE is effective in reducing GABAergic inhibition, we have tested its potential for therapeutic application in the Ts65Dn model of the syndrome. Our findings show that EE promotes recovery from cognitive impairment and synaptic plasticity failure and induces a full rescue of visual acuity, ocular dominance and visual neuronal response latencies in Ts65Dn mice compared to their littermates reared in standard conditions, an effect accompanied by normalization of GABA release in

experience, but it also extends to genetically programmed states of brain disability.

hippocampal and visual cortex synaptosomes [147].

positive effects elicited by the environment on brain health and plasticity.

**the aging brain** 

**Figure 6. A critical role for serotonin in restoring ocular dominance plasticity in the adult visual cortex.** Enhancing serotonergic transmission through exposure to environmental enrichment or administration of a chronic treatment with fluoxetine reinstates ocular dominance plasticity in adult rats. We propose a model in which serotonin drives a reduction of GABAergic inhibition and an increase in BDNF levels in the visual cortex. The graph on the right depicts the time course of the critical period for plasticity in response to monocular deprivation in rodents, and the reopening of plasticity achievable, though to a slightly reduced extent, at multiple distinct ages in adulthood (red arrows). Ocular dominance plasticity is normalized to the critical period peak's level.

The central role of serotonin in promoting adult visual cortex plasticity has been further demonstrated in animals chronically treated with fluoxetine, a selective serotonin reuptake inhibitor (SSRI) widely prescribed in the treatment of depression and various psychiatric disorders. The authors showed that fluoxetine delivered in the drinking water induces a full reinstatement of ocular dominance plasticity in response to MD (Figures 3 and 6) and a complete recovery of visual functions from amblyopia. As found for enriched rats, these functional effects are associated with a marked reduction of GABAergic inhibition and are completely prevented by cortical Diazepam administration [129]. The reduction of inhibition triggered by fluoxetine provides a permissive environment for structural changes, such as the addition of new synapse-bearing branch spine tips [130]. In light of these promising results, fluoxetine appears to behave as a powerful enviromimetic [131], a drug that can be successfully exploited, alone or in combination with EE, to reproduce or to strengthen the positive effects elicited by the environment on brain health and plasticity.

310 Visual Cortex – Current Status and Perspectives

**3.3. Serotonin: A master regulator of adult neural plasticity** 

parallel or in series, the enhancement of BDNF levels (Figure 6).

The capability of EE to reinstate juvenile-like plasticity in the adult brain is not limited to its effects on amblyopia. Indeed, the visual cortex of enriched rats displays a remarkable reactivation of ocular dominance plasticity in response to MD [127, 128]. The ocular dominance shift of cortical neurons is detectable using both VEPs and single-unit recordings. While, also in this case, recovery of plasticity is paralleled by a marked reduction of the inhibitory tone and an increase in the number of BDNF-expressing neurons in the visual cortex, a crucial role for the neurotransmitter serotonin in triggering the plastic changes elicited by exposure to EE has been identified. Indeed, EE elicits a twofold enhancement of serotoninergic transmission in the visual cortex and infusion of a serotonin synthesis inhibitor not only blocks plasticity in response to MD but also completely counteracts the effects produced by EE on GABAergic inhibition and BDNF [127]. This led us to put forward a model in which serotonin, probably enhanced by a more sustained attention and arousal level promoted by living in the enriched condition, is the first trigger in the chain of plastic changes set in motion by EE, eliciting the decrease of GABA-mediated intracortical inhibition and, in

**Figure 6. A critical role for serotonin in restoring ocular dominance plasticity in the adult visual cortex.** Enhancing serotonergic transmission through exposure to environmental enrichment or administration of a chronic treatment with fluoxetine reinstates ocular dominance plasticity in adult rats. We propose a model in which serotonin drives a reduction of GABAergic inhibition and an increase in BDNF levels in the visual cortex. The graph on the right depicts the time course of the critical period for plasticity in response to monocular deprivation in rodents, and the reopening of plasticity achievable, though to a slightly reduced extent, at multiple distinct ages in adulthood (red arrows).

The central role of serotonin in promoting adult visual cortex plasticity has been further demonstrated in animals chronically treated with fluoxetine, a selective serotonin reuptake inhibitor (SSRI) widely prescribed in the treatment of depression and various psychiatric disorders. The authors showed that fluoxetine delivered in the drinking water induces a full reinstatement of ocular dominance plasticity in response to MD (Figures 3 and 6) and a

Ocular dominance plasticity is normalized to the critical period peak's level.

## **4. Life-long beneficial outcome of EE: from developmental disorders to the aging brain**

As underscored by the effects on amblyopia, the non invasive nature of EE makes this paradigm eligible for application in the domain of brain dysfunctions. The beneficial impact of EE does not only apply to the case of diseases deriving form alterations of sensory experience, but it also extends to genetically programmed states of brain disability.

One paradigmatic example is that of Down syndrome, the most common genetic cause of mental retardation [76] caused by triplication of chromosome 21. People with Down syndrome have a marked cognitive impairment [132, 133], and a number of attention and visual deficits [134-136] together with various disturbances in learning and memory abilities [132, 133]. The most widely animal study of Down syndrome is the Ts65Dn mouse, which carries triplication of a segment of Chr16, syntenic with human Chr21 [137, 138]. This model recapitulates the main hallmarks of the syndrome phenotype, including craniofacial abnormalities, impaired learning abilities and attention and visual function deficits (e.g., [139-141]. Moreover, in vivo cellular analyses, which are of course prevented in humans but easily conducted in the animal model, have allowed a substantial advancement in our knowledge concerning the mechanisms underlying neural impairments in Ts65Dn mice. In particular, a critical role for excessive levels of brain inhibition emerges, with an ensuing failure of long-term synaptic plasticity in the hippocampus [142-145]. This is in agreement with results obtained in post-mortem tissue from people with Down syndrome, which displays an impaired balance between excitatory and inhibitory systems (see [146]. The central role of overinhibition in Down syndrome pathogenesis is confirmed by the demonstration that administration of noncompetitive antagonists of GABA-A receptors reverses spatial learning disabilities and LTP deficits in Ts65Dn mice [146]. Since EE is effective in reducing GABAergic inhibition, we have tested its potential for therapeutic application in the Ts65Dn model of the syndrome. Our findings show that EE promotes recovery from cognitive impairment and synaptic plasticity failure and induces a full rescue of visual acuity, ocular dominance and visual neuronal response latencies in Ts65Dn mice compared to their littermates reared in standard conditions, an effect accompanied by normalization of GABA release in hippocampal and visual cortex synaptosomes [147].

On the opposite end of lifetime, severe functional deterioration can also occur during the aging process, across multiple systems including cognitive and sensory-motor domains. These deficits can, at least in part, be attributed to a progressive decay of neural plasticity in the elderly [148]. Interestingly, an enhanced environmental stimulation is able to restore ocular dominance plasticity not only in young adults [127], but also in the aging visual cortex, though to a slightly lower extent [149]. Plasticity in response to one week of MD is detectable at both the level of subthreshold modifications of postsynaptic potentials (by means of VEPs) and that of spike properties of cortical neurons (by means of single-unit recordings). In agreement to our previous results in younger animals, the number of GAD67+ cells was decreased while density of extracellular matrix PNNs increased in the visual cortex of aged enriched rats compared to age-matched standard-reared animals, demonstrating that the brain retains its capacity to undergo plastic changes elicited by a rich environmental experience without substantial changes in the underlying molecular machinery. This effect on neural plasticity offers an attractive explanation for the well known positive effects elicited by EE in the aging brain (e.g. [40, 148, 150]. Accordingly, intervention protocols aimed at promoting an active lifestyle in aging people should be encouraged.

Environmental Influences on Visual Cortex Development and Plasticity 313

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## **5. Concluding remarks and future research lines**

The data reviewed in this chapter have shown that EE is a powerful tool to modulate the development of the central nervous system and to boost plasticity in the adult cerebral cortex. The great success of this approach should not be hailed as a miracle, as it stands on the reliable EE ability to impact at multiple molecular substrate levels in the brain, including stimulation of maturational processes by enhanced activation of growth factors, reopening of plasticity windows through reduced intracortical inhibition and upregulation of plastic structural and functional changes by neurotrophin increments, which could in turn promote the expression of genes specifically involved in brain plasticity. We believe that the combination of a proper pharmacotherapy with non invasive strategies of environmental stimulation aimed at enhancing the spontaneous reparative potential held by the brain might emerge as the election curative approach for several neurological diseases.

## **Author details**

Alessandro Sale\* , Nicoletta Berardi and Lamberto Maffei *Institute of Neuroscience, National Research Council (CNR), Pisa, Italy Department of Psychology, Florence University, Florence, Italy* 

Lamberto Maffei *Laboratory of Neurobiology, Scuola Normale Superiore, Pisa, Italy* 

<sup>\*</sup> Corresponding Author

#### **6. References**

312 Visual Cortex – Current Status and Perspectives

encouraged.

several neurological diseases.

**Author details** 

Alessandro Sale\*

Lamberto Maffei

Corresponding Author

 \*

**5. Concluding remarks and future research lines** 

, Nicoletta Berardi and Lamberto Maffei *Institute of Neuroscience, National Research Council (CNR), Pisa, Italy* 

*Department of Psychology, Florence University, Florence, Italy* 

*Laboratory of Neurobiology, Scuola Normale Superiore, Pisa, Italy* 

On the opposite end of lifetime, severe functional deterioration can also occur during the aging process, across multiple systems including cognitive and sensory-motor domains. These deficits can, at least in part, be attributed to a progressive decay of neural plasticity in the elderly [148]. Interestingly, an enhanced environmental stimulation is able to restore ocular dominance plasticity not only in young adults [127], but also in the aging visual cortex, though to a slightly lower extent [149]. Plasticity in response to one week of MD is detectable at both the level of subthreshold modifications of postsynaptic potentials (by means of VEPs) and that of spike properties of cortical neurons (by means of single-unit recordings). In agreement to our previous results in younger animals, the number of GAD67+ cells was decreased while density of extracellular matrix PNNs increased in the visual cortex of aged enriched rats compared to age-matched standard-reared animals, demonstrating that the brain retains its capacity to undergo plastic changes elicited by a rich environmental experience without substantial changes in the underlying molecular machinery. This effect on neural plasticity offers an attractive explanation for the well known positive effects elicited by EE in the aging brain (e.g. [40, 148, 150]. Accordingly, intervention protocols aimed at promoting an active lifestyle in aging people should be

The data reviewed in this chapter have shown that EE is a powerful tool to modulate the development of the central nervous system and to boost plasticity in the adult cerebral cortex. The great success of this approach should not be hailed as a miracle, as it stands on the reliable EE ability to impact at multiple molecular substrate levels in the brain, including stimulation of maturational processes by enhanced activation of growth factors, reopening of plasticity windows through reduced intracortical inhibition and upregulation of plastic structural and functional changes by neurotrophin increments, which could in turn promote the expression of genes specifically involved in brain plasticity. We believe that the combination of a proper pharmacotherapy with non invasive strategies of environmental stimulation aimed at enhancing the spontaneous reparative potential held by the brain might emerge as the election curative approach for


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**Chapter 15** 

© 2012 Molotchnikoff et al., licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2012 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

and reproduction in any medium, provided the original work is properly cited.

**Adaptation and Neuronal Network** 

Additional information is available at the end of the chapter

Lyes Bachatene, Vishal Bharmauria and Stéphane Molotchnikoff

Complex mechanisms from retina to different visual areas allow us to read these lines. The visual system is inevitable for the way we interact with our surroundings as majority of our impressions, memories, feelings are bound to the visual perception. Millions of cortical neurons are implicated and programmed specifically to frame this incredible interface (perception) for us to interact with the world. Neurons in the visual cortex respond essentially to the variations in luminance occurring within their receptive fields, where each neuron fires maximally by acting as a filter for stimulus features such as orientation, motion,

The seminal work of Hubel and Wiesel on the visual cortex of cat [1, 2, 6-8], has been instrumental in establishing the anatomical and physiological aspects of the visual cortex. Many studies by various investigators on the visual cortex of different animals, thereafter, have been phenomenal in understanding the brain in general and the vision in particular; yet, neuronal mechanisms involved in processing of stimuli still elude our complete understanding of cortical functioning. These findings have been crucial in unravelling the organization of the visual cortex. The visual cortex reorganises itself in the postnatal development, within a specific period called 'the critical period' [9], which is a period characterised with pronounced brain plasticity. In recent years, the focus of the research has been to comprehend the 'reorganization' of neuronal framework, especially after the so called 'critical period' [10-12] in response to various conditions and its ability to adapt accordingly. This amazing tendency of brain to change its neuronal connections and properties is termed 'plasticity' [13]. Two common approaches to study the reorganization of visual cortex are frequently applied: deprivation and induced adaptation. Deprivation refers to the removal of sensory inputs, whereas induced adaptation refers to the forceful application of a sensory input. Consequently, neurons communicate dynamically with each

direction and velocity, with an appropriate combination of these properties [1-5].

**in Visual Cortex** 

http://dx.doi.org/10.5772/46011

**1. Introduction** 

