**4. Discussion**

Overall, the current knowledge in neuroscience conducts us through a multiscale world. The understanding of whatever peculiarity the human behavior exhibits requires us to travel throughout our brain's different levels of organization. In particular, this is the case with sleep neuroscience.

Here, we speculate the dopaminergic influence on neuron states associated to sleep and sleep alterations in PD. Our ideas, however, should be considered by keeping in mind the broad cascade of events that underlies the wake-sleep cycle.

Environmental as well as genetic factors trigger networks of intra and inter cellular signals, which promote the specific characteristics associated to wake or sleep states. For instance, due to the light impinging on the retina, signals from circadian oscillators reach specific hypothalamic regions. Such areas regulate the action of distinct brain systems associated to the different responses that an organism presents throughout the sleep-wake cycle. In this sense, the hypothalamus regulates wake-sleep switches through its suprachiasmatic, subparaventricular and dorsomedial nuclei; together with the basal forebrain, it controls ascending arousal systems, through its ventrolateral preopitic, lateral and tuberomammilary nuclei. The hypothalamus also regulates brainstem nuclei, as dorsal raphe and locus ceruleus, which control the cyclic transition between the rapid eye movement (REM) and non-REM (NREM) sleep phases. On the other hand, projections from such brainstem and diencephalon ascending arousal systems reach cortical and thalamic areas, known to be involved in the origin and maintenance of different brain rhythms that specifically underlie some sleep states (Pace-Schott & Hobson, 2002; Hobson & Pace-Schott, 2002).

Brain rhythms reflect the spike mode occurring in groups of neurons. And, as revealed by polysonographic recordings, the wake state as well as the NREM and REM sleep phases, are defined, each one, by characteristic field potential oscillations (Pace-Schott & Hobson, 2002;

Fig. 6. Decrease in receptor D4 activation, under mesothalamic dopaminergic hyperactivity,

Overall, the current knowledge in neuroscience conducts us through a multiscale world. The understanding of whatever peculiarity the human behavior exhibits requires us to travel throughout our brain's different levels of organization. In particular, this is the case

Here, we speculate the dopaminergic influence on neuron states associated to sleep and sleep alterations in PD. Our ideas, however, should be considered by keeping in mind the

Environmental as well as genetic factors trigger networks of intra and inter cellular signals, which promote the specific characteristics associated to wake or sleep states. For instance, due to the light impinging on the retina, signals from circadian oscillators reach specific hypothalamic regions. Such areas regulate the action of distinct brain systems associated to the different responses that an organism presents throughout the sleep-wake cycle. In this sense, the hypothalamus regulates wake-sleep switches through its suprachiasmatic, subparaventricular and dorsomedial nuclei; together with the basal forebrain, it controls ascending arousal systems, through its ventrolateral preopitic, lateral and tuberomammilary nuclei. The hypothalamus also regulates brainstem nuclei, as dorsal raphe and locus ceruleus, which control the cyclic transition between the rapid eye movement (REM) and non-REM (NREM) sleep phases. On the other hand, projections from such brainstem and diencephalon ascending arousal systems reach cortical and thalamic areas, known to be involved in the origin and maintenance of different brain rhythms that specifically underlie

Brain rhythms reflect the spike mode occurring in groups of neurons. And, as revealed by polysonographic recordings, the wake state as well as the NREM and REM sleep phases, are defined, each one, by characteristic field potential oscillations (Pace-Schott & Hobson, 2002;

some sleep states (Pace-Schott & Hobson, 2002; Hobson & Pace-Schott, 2002).

originates the burst state in both TRNx and TRNy.

broad cascade of events that underlies the wake-sleep cycle.

**4. Discussion** 

with sleep neuroscience.

Hobson & Pace-Schott, 2002). Accordingly, each behavioral state presents distinct cognitive activities and conscious experiences. Throughout the night, there is a cyclic occurrence of NREM and REM sleep phases, where the NREM stage is composed by the slow wave sleep (SWS) - that includes the sleep stages 3 and 4, besides the lighter sleep stages 1 and 2. In particular, the SWS is characterized by rhythms known as slow oscillations, spindles and sharp wave-ripples (Pace-Schott & Hobson, 2002; Hobson & Pace-Schott, 2002; Hobson, 2009; Diekelmann & Born, 2010).

Thalamocortical systems are highly involved in the achievement of oscillations associated to the SWS, in special, slow oscillations and spindles (Steriade et al., 1993; Steriade, 2006). Whereas slow oscillations originate at the cortex and propagate to the thalamus, the spindles have their origins in the thalamus and propagate to the cortex mediated by the TRN pacemaker (Steriade et al., 1993; Llinás & Steriade, 2006; Steriade, 2006). In both cases, however, the origin of the oscillatory pattern is associated to some strong inhibition leading to a consequent burst mode of spiking. More, according to (Steriade et al., 1993), different types of rhythms may appear depending on the magnitude of such inhibitory event.

Indeed, the cholinergic and noradrenergic neuromodulatory systems are known to regulate the neurophysiologic aspects underlying the brain rhythms in the NREM and REM sleep phases (Diekelmann & Born, 2010). However, the experiments revealing the existence of the mesothalamic dopaminergic pathway (Freeman et al., 2001) made it possible to hypothesize on the dopaminergic influence on neuron states associated to sleep (Pace-Schott & Hobson, 2002).

In this work, we propose that the mesothalamic dopamine action in the thalamocortical circuit is able of generating oscillatory patterns that are typical in sleep states, both in thalamic and TRN neurons, depending on the level of dopaminergic activity. In particular, we consider that the dopaminergic alteration in PD is an essential factor underlying the sleep problems observed in such disease. In this case, both the dopaminergic hypoactivity due to the SN neurons degeneration -, and the increases in the dopaminergic activity due to the appliance of dopamine-related drugs, would contribute to the appearance of sleep alterations.

Basically, our computational simulations explore two ways by which mesothalamic dopamine may affect the thalamocortical dynamics: the SN activity and the dopamine receptor D4 activation. Overall, we conclude that an extreme dopaminergic mesothalamic hypoactivity favors the appearance of the burst mode in thalamic neurons. Conversely, a high degree of dopaminergic mesothalamic hyperactivity propitiates such an oscillatory rhythm in the TRN neurons. In addition, our simulations hint that, when the SN activity is markedly diminished, a slight factor inducing an increase in the receptor D4 activation triggers the bursting pattern in thalamic neurons. On the other hand, the application of some agent that lowers the D4 activation, under a situation of extreme mesothalamic dopamine hyperactivity, enables the burst mode in the TRN.

In the context of PD, such results point anomalous somnolence as a consequence of the lack of dopamine, due to the SN degeneration. More, neural sleep states may appear as a consequence of drugs administration to increase the dopamine action, when the SN activity is highly disrupted. Another situation we consider important to emphasize refers to the dopaminergic hyperactivity case. Due to the lifelong need of medication for equilibrating the nigral dopaminergic level, PD patients usually present symptoms related to excess of dopamine (March, 2005). We illustrate such situation by increasing the dopaminergic activity. We then observe that a slight diminishing in the receptor D4 activation induces the

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## **5. Acknowledgments**

This work is kindly dedicated to the memory of Magdalena C. L. Madureira. The author thanks the Brazilian agency CNPq (PCI/LNCC, grants 560108/2010-9, 474218/2008) for the financial support.

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**24** 

*USA* 

**Pathophysiology of Non-Dopaminergic** 

**Implications for Mood Dysfunction** 

*Department of Psychology, Binghamton University, Binghamton, NY* 

Nirmal Bhide and Christopher Bishop

**Monoamine Systems in Parkinson's Disease:** 

Parkinson's disease (PD) is a neurodegenerative disorder affecting millions worldwide and is one of the most common diseases affecting the aging population (Delau et al., 2006). Clinical hallmarks of PD feature severe motor deficits characterized by bradykinesia, tremor, rigidity and postural instability. Though less recognized, PD symptoms also include psychiatric complications such as depression, anxiety and psychosis that deleteriously influence quality of life. While the origin of motor deficits is the progressive degeneration of nigrostriatal dopamine (DA) neurons, other monoamine neurons within the serotonin (5-HT) and norepinephrine (NE) system also degenerate, likely contributing to mood dysfunction. In this chapter the pathophysiology of non-dopaminergic monoamine systems, their contribution to

In PD, the cardinal cell death of the dopaminergic substantia nigra pars compacta (SNpc) neurons is accompanied by deficits in other monoamine neurotransmitter systems. Of these, NE appears most most consistently affected. Numerous studies, both neuroanatomical and biochemical, have documented severe loss of NE neurons, originating from the locus coeruleus (LC), concomitant with or even preceding the loss of DA neurons (Mann and Yates, 1983; Marien et al., 2004; Schapira et al., 2006). The precise anatomical relationship between the LC and the SNpc and the striatum remains to be elucidated; however, evidence exists for a functional relationship between these brain regions (Fornai et al., 2007). Most notable, loss of NE may exacerbate damage to the DA nigrostriatal system, as NE is postulated to play a neuroprotective and neuromodulator role in the progression of PD (Rommelfanger and Weinshenker, 2007). The following sections will focus on the pathophysiology of NE, its relative contribution to the development of psychiatric symptoms of PD, and the treatment of

As early as 1917, noradrenergic neurons originating from the LC were reported to be severely deteriorated in patients suffering from PD (Tretiakoff et al., 1917; Fornai et al.,

PD-related mood dysfunction, and therapeutics targeting them will be discussed.

**1. Introduction** 

**2. Norepinephrine system** 

these symptoms using noradrenergic drugs.

**2.1 CNS pathophysiology of NE system in PD 2.1.1 Neuroanatomical evidence in PD patients** 

