**3. Connectivity of the amygdaloid complex**

The amygdaloid complex is a heterogeneous group of 13 nuclei and cortical areas located in the medial temporal lobe just rostral to the hippocampal formation [43]. The complex can Circuits Regulating Pleasure and Happiness in Schizophrenia: The Neurobiological Mechanism of Delusions http://dx.doi.org/10.5772/66412 117

superficial and deep corticoid amygdala. This means that almost the entire cerebral hemisphere is of quite recent origin. This is probably also true for the limbic cortical-subcorti-

cal-cortical connectivity we have previously suggested [2, 6]. Corticoid amygdaloid output reaches the hypothalamus and brainstem (to minor extent directly and) largely along nuclear amygdala (striatal amygdala) and bed nucleus of the stria terminalis (pallidal amygdala). This directly results from the regulation of vegetative and motor behaviour by the striatum instead of the pallium in lamprey [2]. However, the human frontal neocortex is reached through connectivity with the dorsal thalamus. This last connectivity must have developed later during the evolution of the mammalian forebrain. The amygdaloid equivalent of the habenula-projecting globus pallidus is probably localised within the bed nucleus of the stria terminalis.

**Figure 3.** Position of the limbic basal ganglia (extended amygdala and nucleus accumbens shell) relative to the

extrapyramidal striatum (caudate nucleus, putamen, nucleus accumbens core) and hippocampus.

The final picture of the position of the human limbic and extrapyramidal basal ganglia is

The amygdaloid complex is a heterogeneous group of 13 nuclei and cortical areas located in the medial temporal lobe just rostral to the hippocampal formation [43]. The complex can

given in **Figure 3**.

116 Schizophrenia Treatment - The New Facets

**3. Connectivity of the amygdaloid complex**

**Figure 4.** Overview of the connectivity of the rat amygdaloid complex [adapted from Ref. [45] with permission of the author].

neuroanatomically be divided into 'deep nuclei', 'superficial nuclei' and 'remaining nuclei' [43]. Both the cortical amygdalar nuclei and the basolateral amygdalar nuclear complex, which is located deep to it, have cortex-like cell types [44]. In contrast, the so-called extended amygdalar nuclei contain predominantly GABAergic spiny projection neurons, like the striatum [44]. In order to simplify, we usually divide the amygdala in a corticoid basolateral and a nuclear centromedial part (**Figure 3**). Each nucleus of the amygdala has a characteristic set of interconnections with other amygdalar nuclei and extrinsic brain regions (**Figure 4**) [43, 45]. Within the amygdalar nuclear complex, the primary flow is from corticoid to nuclear structures [46].

An unambiguous description of the structure and connectivity of the human amygdaloid amygdala is hampered by the existence of a predominance of contradictory, confusing, and unsubstantiated viewpoints both in recent and old scientific literature [47–49]. Moreover, the connections of the amygdaloid complex have been studied in mammalian animal species (mainly rats, cats and monkeys), which differ with respect to the extensiveness of their neocortex [48]. This large size of the neocortex causes dominance of projections from and to neocortical areas. Again looking into the connectivity of putative homologues of the amygdaloid complex in our early vertebrate ancestors may be of help. In amphibians, the amygdaloid complex is divided into three components: the vomeronasal amygdala, the olfactory/multimodal amygdala and the autonomic amygdala [4]. It should be realised that anuran species probably do not possess a true homologue of the human neocortex yet (see above). However, the anterior, lateral and medial areas of the anuran amygdaloid complex reveal connectivity which is roughly running ahead of the connectivity of the neocortex associated with amygdaloid complex [4, 50]. This includes output of the later deep corticoid and medial amygdaloid nucleus to the medial pallium, which is the later hippocampus.

Based on these start points, three or four components of amygdaloid connectivity can be distinguished: the accessory olfactory division, the main olfactory division, the autonomic division and the frontotemporal division [47, 48]. As possession of a true vomeronasal organ, which is originally the main source of input to the accessory olfactory division, by humans is still controversial, the first two may be added together in humans. The frontotemporal division is often primarily associated with strong bidirectional interactions with the prefrontal cortex and hippocampal formation [45, 46], but the amygdalo-hippocampal system can also be considered to be an output channel of the amygdaloid complex. The connectivity of the deep corticoid amygdaloid complex from and to the hippocampal complex is mediated through parahippocampal regions [51]. Via the fornix the hippocampus sends a GABAergic connection to the medial septum and a glutamatergic connection to the lateral septum [52, 53]. Reciprocally, cholinergic and to a far less extent GABAergic and glutamatergic fibres coming from the medial septum-diagonal band of Broca complex run through the fornix to the hippocampus [52, 53].

The four divisions of the amygdaloid system have more conjoined than separated functional significance. All regulate in combination with each other several components of instinctive, emotional behaviour. The accessory olfactory component is perhaps somewhat more involved in social behaviour related to reproduction and the autonomic part somewhat more with the regulation of visceral aspects of the emotional response. However, the abundancy of the interactions between separate amygdaloid areas and the extensive mixed connectivity with other brain structures [43–45] make that separate pathways cannot be clearly distinguished. An important part of this amygdaloid output is delivered, either directly or via hippocampus indirectly, to hypothalamic structures regulating reward-gaining and misery-fleeing behaviour [6, 54, 55]. These hypothalamic areas are also reached via the non-centromedial parts of the extended amygdala (including the bed nucleus of the stria terminalis) [49, 56]. However, a major role is played by the deep corticoid complex (mainly basolateral nuclei) in bidirectional interaction with prefrontal cortical areas, the hippocampal complex, as well as sensory cortical areas [44, 46, 57–59]. An essential characteristic of this bidirectional amygdaloid connectivity is the capability to learn from experiences through associative learning, complex response conditioning, episodic memorisation and so on [46]. The best description of the function of the amygdaloid complex is to analyse the complex input concerning the actual daily life situation within the individual's biotope (nature, flora, fauna, social circumstances) and to select the sensory input which deserves more attention in order to improve the current chances (misery fleeing and reward seeking). The amygdala also receives information about the environment from the sensory thalamus and sensory cortices. The input is compared with memorised information and modulated by programmes concerning implicit and explicit behavioural output. This includes direct inhibition of the amygdala-dependent emotional response when this is expected to be more profitable. This last function is primarily attributed to ventromedial areas of the prefrontal cortex [6, 60, 61]. Traditionally, the amygdala is supposed to induce an emotional response mainly by giving output to the hypothalamus and brainstem via the centromedial nucleus after this validation process has been completed [46]. We want to suggest that the significant part of output is additionally given via the hippocampus and fornix to medial and lateral septal areas [52, 53]. After comparison with memorised experiences in the hippocampus and processing within the septal area, this information may reach the medial habenula (MHb). The septum, particularly the medial septum and the adjacent nucleus of the diagonal band of Broca, is the main input to the MHb [5, 62, 63]. Although the MHb has been far less extensively studied than the lateral habenula (LHb), experimental data support hyperactivity of the MHb to be associated with depression, anxiety and fear [63]. The MHb projects through the inner area of the fasciculus retroflexus to the interpeduncular nucleus within the midbrain [5, 62, 64, 65]. The interpeduncular nucleus is a singular, unpaired structure located at the ventral midline of the midbrain [62, 66]. The major efferent pathways originating in the interpeduncular nucleus project to the dorsal tegmental nucleus [66], the ventral tegmental area [62] and the raphe nuclei [62, 64]. However, the interpeduncular nucleus is well known for its widespread projections both ascending and descending [62, 66]. Hence, the above pathway from the corticoid amygdala, via hippocampus, septal nuclei, medial habenula and interpeduncular nucleus to ventral tegmental area and raphe nuclei, may represent a primary regulation mechanism to increase or decrease the intensity of the emotional misery-fleeing response.

the anterior, lateral and medial areas of the anuran amygdaloid complex reveal connectivity which is roughly running ahead of the connectivity of the neocortex associated with amygdaloid complex [4, 50]. This includes output of the later deep corticoid and medial amygdaloid

Based on these start points, three or four components of amygdaloid connectivity can be distinguished: the accessory olfactory division, the main olfactory division, the autonomic division and the frontotemporal division [47, 48]. As possession of a true vomeronasal organ, which is originally the main source of input to the accessory olfactory division, by humans is still controversial, the first two may be added together in humans. The frontotemporal division is often primarily associated with strong bidirectional interactions with the prefrontal cortex and hippocampal formation [45, 46], but the amygdalo-hippocampal system can also be considered to be an output channel of the amygdaloid complex. The connectivity of the deep corticoid amygdaloid complex from and to the hippocampal complex is mediated through parahippocampal regions [51]. Via the fornix the hippocampus sends a GABAergic connection to the medial septum and a glutamatergic connection to the lateral septum [52, 53]. Reciprocally, cholinergic and to a far less extent GABAergic and glutamatergic fibres coming from the medial septum-diagonal band of Broca complex run through the fornix to the hip-

The four divisions of the amygdaloid system have more conjoined than separated functional significance. All regulate in combination with each other several components of instinctive, emotional behaviour. The accessory olfactory component is perhaps somewhat more involved in social behaviour related to reproduction and the autonomic part somewhat more with the regulation of visceral aspects of the emotional response. However, the abundancy of the interactions between separate amygdaloid areas and the extensive mixed connectivity with other brain structures [43–45] make that separate pathways cannot be clearly distinguished. An important part of this amygdaloid output is delivered, either directly or via hippocampus indirectly, to hypothalamic structures regulating reward-gaining and misery-fleeing behaviour [6, 54, 55]. These hypothalamic areas are also reached via the non-centromedial parts of the extended amygdala (including the bed nucleus of the stria terminalis) [49, 56]. However, a major role is played by the deep corticoid complex (mainly basolateral nuclei) in bidirectional interaction with prefrontal cortical areas, the hippocampal complex, as well as sensory cortical areas [44, 46, 57–59]. An essential characteristic of this bidirectional amygdaloid connectivity is the capability to learn from experiences through associative learning, complex response conditioning, episodic memorisation and so on [46]. The best description of the function of the amygdaloid complex is to analyse the complex input concerning the actual daily life situation within the individual's biotope (nature, flora, fauna, social circumstances) and to select the sensory input which deserves more attention in order to improve the current chances (misery fleeing and reward seeking). The amygdala also receives information about the environment from the sensory thalamus and sensory cortices. The input is compared with memorised information and modulated by programmes concerning implicit and explicit behavioural output. This includes direct inhibition of the amygdala-dependent emotional response when this is expected to be more profitable. This last function is primarily attributed to ventromedial areas of the prefrontal cortex [6, 60, 61]. Traditionally, the amygdala is supposed to

nucleus to the medial pallium, which is the later hippocampus.

pocampus [52, 53].

118 Schizophrenia Treatment - The New Facets

**Figure 5.** Scheme showing the connectivity of limbic (cortical) system to the midbrain through the habenular complex. BSTh, habenula-projecting part of the bed nucleus of the stria terminalis; DR, dorsal raphe nucleus; DTg, dorsal tegmental nucleus; IPN, interpeduncular nucleus; LHb, lateral habenula; MHb, medial habenula; PHC, parahippocampal cortex; RMTg, rostromedial tegmental nucleus; sCg, subgenual cingulate gyrus; and VTA, ventral tegmental area.

In addition, the amygdala affects the activity of the ventral tegmental area through a pathway including the lateral habenula. We want to suggest that anteromedial division of the bed nucleus of the stria terminalis contains the human limbic equivalent of the lamprey habenula-projecting globus pallidus (GPh). This area receives input from GABAergic projection neurons originating within the central amygdaloid nucleus [40] and gives output to medial and caudal regions of the lateral habenula [41, 42]. When this limbic GPh is functioning similar to lamprey GPh, the amygdala can inhibit reward-seeking behaviour by stimulating the pathway, which runs from corticoid amygdala, through central amygdala, anteromedial bed nucleus of the stria terminalis, lateral habenula and rostromedial tegmental nucleus to ventral tegmental area (**Figure 5**).

In conclusion, the amygdaloid complex plays an essential role in fear and anger control, perception and attention to relevant sensory input (including, e.g. facial expression in order to allow adequate social functioning), by validating this input with respect to their significance for reward-seeking and misery-fleeing behaviour. The activity of this emotional response is regulated through a pathway including the habenula, in which two routes can be distinguished: one including the hippocampus, septal nuclei and medial habenula and the other including central amygdala, bed nucleus of the stria terminalis and lateral habenula.
