**1. Introduction**

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Movement, sleep and cognition: three connected realms enriching to the human life. Three harmed realms limiting parkinsonian patients.

A degenerative process in dopaminergic neurons from the substantia nigra (SN) midbrain nucleus is the basic origin underlying a set of symptoms developed in patients with Parkinson's Disease (PD) (Andrade & Ferraz, 2003). The devastating motor difficulties usually do not appear isolated. Indeed, PD consists of distinct kinds of manifestations involving motor and mental rigidity as well as sleep alterations (Dubois & Pillon, 1996; Rye et al., 2000; De Cock et al., 2008; Arnulf & Leu-Semenescu, 2009).

Even though impairments in other brain nuclei also contribute to the symptoms present in PD **(**Braak et al., 2000**)**, it is surprising how so distinct brain systems suffer influence of the degenerative alterations in the SN. This phenomenon may be regarded as a simple consequence of the connections between the SN and diverse brain areas. As a matter of fact, it also highlights that distinct behavioral aspects are achieved through the sharing of brain resources. Here, we examine - through a neurocomputational model - relationships between alterations in the mesothalamic dopaminergic activity (MDA) and sleep impairments in PD.

With origins in the SN, the mesothalamic pathway (MP) reaches the thalamic complex, in particular the thalamic reticular nucleus (TRN). Investigations on such dopaminergic pathway, evidenced by Freeman and colleagues (Freeman et al., 2001), have been contributing to a more global comprehension of cognitive processes in the brain. Based on experimental results (Florán et al., 2004), the mathematical model proposed in (Madureira et al., 2010) indicates a way by which the mesothalamic dopamine inhibits neurons in the TRN. And computational simulations of this model suggest that alterations in the MDA lead to inattention symptoms as observed in PD and Attention Deficit Hyperactivity Disorder (ADHD).

Thalamic neurons are able to spike under tonic and burst states (Steriade et al., 1993; Llinás & Steriade, 2006). Whenever in the tonic state, these neurons respond linearly to input stimuli. By this way, they propagate information reliably from perceptual systems to the cerebral cortex, where a more refined processing takes place. This mode of activity is crucial to the thalamocortical filtering of perceptual stimuli that allows attention focusing (Madureira et al., 2007, 2010; Carvalho, 1994).

Mesothalamic Dopaminergic Activity: Implications in Sleep Alterations in Parkinson's Disease 509

In (Madureira et al., 2010), we proposed a mathematical model indicating how the mesothalamic dopamine influences the thalamocortical loop, through the TRN, and thus modulates the attentional focus formation. In particular, we investigated relationships between alterations in this dopaminergic pathway and attention deficits in PD and

Here, we extend this model to address how dopamine influences the emergence of distinct spiking modes in thalamic neurons. Since the thalamic modes of spiking are specifically related to sleep and wake neuron states, our modeling enables us to discuss if and how dopaminergic alterations in PD are related to the sleep problems observed in the disease. Throughout the sleep-wake cycle, complex chemical and electrical networks of events occur in the thalamocortical neural circuit. They give rise to distinct patterns of neural behavior that underlies the different brain rhythms specifically associated to different sleep phases and also to the wake state (Pace-Schott & Hobson, 2002; Hobson & Pace-Schott, 2002;

The variety of brain rhythms extensively studied by the neuroscience of sleep (Steriade et al., 2003; De Gennaro & Ferrara, 2003; Llinás & Steriade, 2006; Steriade, 2006; Pace-Schott & Hobson, 2002; Hobson & Pace-Schott, 2002; Hobson, 2009; Diekelmann & Born, 2010) reflects the behavior of neural groups. Indeed, such brain rhythms, e.g. spindles, slow oscillation and theta activity, are measurements of field potential oscillations captured by EEGs experiments – not by single cell recordings. Therefore, they provide information from a scale

Our model, on the other hand, addresses the dynamics of ionic and synaptic currents. It thus deals with information at the same level of single cell recordings, in particular, variations in

Under this approach, it is reasonable to examine sleep issues by mathematically modeling neurons in the thalamocortical loop, and computationally simulating the action of

As an outcome of our neurocomputational model, we conjecture that the inhibitory action of mesothalamic dopamine in the thalamic reticular nucleus (TRN) (Florán et al., 2004) affects the spiking mode of thalamocortical neurons. This is possible whenever the dopaminergic action leads to a period of neuron hyperpolarization that activates the calcium conductance, thus changing the way by which the neuron behaves (Carvalho, 1994). Next,

We model a thalamocortical circuit with a dopaminergic projection from SN to the TRN, according to Figure 1. We can note the excitatory and inhibitory connections in the modeled neural network. Thalamocortical and corticothalamic projections are excitatory, mediated by glutamate. Both areas send glutamatergic excitatory collateral axons to the TRN. Conversely, efferent projections from the TRN to thalamus are GABAergic inhibitory

With relation to the dopaminergic action, the architecture of the network incorporates results gathered together from Freeman et al. (2001) and Florán et al. (2004), which reveal the inhibitory dopaminergic projection from SN to the TRN, or the mesothalamic dopaminergic pathway. The explanation we suggest for the dopaminergic action in TRN is

**2. The model** 

Diekelmann & Born, 2010).

above the cellular one.

**2.1 The neural network** 

(Guillery & Harting, 2003).

the membrane electric potential.

neuromodulators throughout this brain area.

we present the model and develop such ideas more deeply.

ADHD.

Conversely, under the burst state thalamic neurons are no more reliable channels through which neural representations from sensorial inputs reach the cerebral cortex. As a matter of fact, this mode of activity underlies the thalamic behavior during sleep (Steriade et al., 1993; Pace-Schott & Hobson, 2002). In this case, the environmental stimuli are not perceived consciously as it occurs throughout wakefulness (Carvalho, 1994). The thalamic burst mode also permeates epileptic episodes during which environmental information is not processed reliably (Jeanmonod et al., 1996; Llinás et al., 1999). The dynamics of the ionic channels under the burst mode are different from the ones underlying the thalamic tonic state. That is why, under the burst mode, thalamic neurons spike quite autonomously, in such a way that their pattern of activity does not represent the input information.

Since the inattention symptoms addressed in (Madureira et al., 2010) concerned awakened people, the model considered the behavior of thalamic neurons under the tonic state. In the present work, we go further with the matter and scrutinize relationships between the MDA and the oscillatory state of neurons in the thalamic complex. Doing so, it becomes possible to widen the investigation to examine a possible MDA contribution to sleep alterations in PD and, to look at attention focusing aspects under a little more detailed point of view.

Clinical evidences indicating a variety of sleep alterations in PD suggest that this class of symptoms should not be considered as a secondary one: on the contrary, sleep problems certainly pertain to the core symptoms that define PD (De Cock et al., 2008; Arnulf & Leu-Semenescu, 2009). Such sleep alterations involve daytime sleepiness, inappropriate intrusion of REM sleep episodes throughout the day, and nocturne movement. In other words, parkinsonism disrupts the control of the sleep-wake cycle (Jancovic, 2002; Arnulf & Leu-Semenescu, 2009).

The question thus that naturally arises concerns the dopaminergic role in the sleep-wake cycle control. Given the clinical evidence from sleep impairments in PD, a disease whose basic neural origins is the dopaminergic neurons degeneration, we tend to conclude that dopamine does participate in the sleep regulation. Is it the case?

Up to recently, the above mentioned clinical observations have been quite disregarded. If, through PD, the dopaminergic participation in the control of the sleep cycle may be inferred (Rye, 2004), there is, on the other hand, a number of neuroscientific studies showing that the variation in the dopaminergic level throughout the sleep-wake cycle is too small to be taken into account (Jancovic, 2002).

A series of experiments undertaken by (Dzirasa et al., 2006), however, illuminated this controversy. They were capable of demonstrating that sleep-wake states are also controlled by dopamine. This seminal work shows the importance of the dopaminergic influence in the sleep regulation – even under small variations. In addition, they emphasize the relationship between dopaminergic alterations and sleep impairments in PD.

Here, we address – through a neurocomputational approach – the interference of SN neurons, particularly the degenerated ones, in the thalamocortical spiking modes. Our goal consists in investigating if the PD dopaminergic disruption alters the typical spiking patterns associated to sleep and wake states, thus compromising the normal sleep-wake cycle in PD.

We now outline the contents of this chapter. In Section 2 we introduce our hypothesis of dopaminergic influence on the control of the sleep-wake cycle, and describe the model. In Section 3, we explain how the computational simulations of the model are designed, and present the computational results. Finally, we conclude by discussing the consequences of our results in terms of sleep alterations in PD, in the context of the neuroscience of sleep.
