**3.2.4 Variations in the dopaminergic activity and the oscillatory state**

In our last series of simulations, we deepen our investigations on the changes in the spiking mode. Now, we repeat the strategy undertaken in Subsection 3.2.1, where a stimulus *X* is presented to the asymmetrical network before a stronger one, *Y.* Through the extended mathematical model we propose in Section 2, here we look for situations where changes in the dopaminergic action lead to the burst mode in neurons of the thalamic complex. In this set of simulations, we examine only extreme cases of dopaminergic alterations. Such option was because all previous experiments indicated these extreme situations as the more plausible to initiate the ionic events that underlie the burst mode occurrence. Table 6 summarizes our results.

Fig. 3. Decreases in the receptor D4 activation, under mesothalamic dopaminergic hypoactivity, turned the tonic state into the burst one in Tx.

Mesothalamic Dopaminergic Activity: Implications in Sleep Alterations in Parkinson's Disease 521

Fig. 5. The distinct spiking modes of Tx and Ty. When SN spikes every 100ms and *ĝd4* = 0.9,

Also with the SN neuron set to spike each 100ms, we started a 800ms-experiment with the parameter *ĝd4* = 0.9. This time, however, we turned *ĝd4* to 1.0 after 350ms. It is plausible to interpret such alteration in the *ĝd4* value as a consequence of some increase in the dopaminergic level, due to an exogenous factor. In this case, both *Tx* and *Ty* start to oscillate. The last situation presented in Table 6 refers to the extreme case of mesothalamic hyperactivity. During a 800ms-experiment, the interval between spikes in the SN was set to 5ms. In addition, at the beginning we imposed a high activation in receptor D4 with *ĝd4* = 1.1. This dopaminergic context inhibited the TRN neurons, which suffer even a hyperpolarization. It was, however, the imposed decrease of *ĝd4* to 0.8, after 350ms, that starts the burst mode in both *TRN* neurons. In this case, the lowering in the dopaminergic receptor activity enables the *TRNs* membrane potential to reach a threshold value that

triggered LTS in such neurons. Figure 6 illustrates such situation.

Tx presents the burst mode of spiking.

In the case of mesothalamic hypoactivity, where the SN neuron spikes every 150ms, the constant activation of D4 as *ĝd4* = 0.9 made the *Ty* neuron to spike through bursts – not Tx one. This occurs because the Ty activation is greater than the *Tx* one by an amount enough to trigger the LTS - after the hyperpolarization due to the high activity in the TRN. In Figure 4, we can observe the *Tx* and *Ty* behaviors. The receptor D4 activations imposed by *ĝd4* = 1.0 or *ĝd4* = 1.1 did not allow the TRN neurons to spike highly enough to start the necessary hyperpolarization that activates the calcium currents.

Another case of mesothalamic hypoactivity we simulate by fixing the SN frequency in one spike each 100ms. Compared to the previous experiment, the SN is slightly more active. This time, it is the *Tx* neuron that presents an oscillatory pattern, when *ĝd4* = 0.9. In this case, the inhibition from TRNx was not strong enough to hyperpolarize *Ty*. However, the less stimulated *Tx* neuron suffered the necessary inhibition that activated calcium currents, thus facilitating the consolidation of the burst mode of spiking. Figure 5 illustrates the distinct spiking modes of *Tx* and *Ty*.


Table 6. Distinct dopaminergic activities in presence of different stimuli.

Fig. 4. Behaviors of Tx and Ty. Mesothalamic dopaminergic hypoactivity enables the oscillatory behavior of Ty. SN spikes every 150ms and *ĝd4* = 0.9.

In the case of mesothalamic hypoactivity, where the SN neuron spikes every 150ms, the constant activation of D4 as *ĝd4* = 0.9 made the *Ty* neuron to spike through bursts – not Tx one. This occurs because the Ty activation is greater than the *Tx* one by an amount enough to trigger the LTS - after the hyperpolarization due to the high activity in the TRN. In Figure 4, we can observe the *Tx* and *Ty* behaviors. The receptor D4 activations imposed by *ĝd4* = 1.0 or *ĝd4* = 1.1 did not allow the TRN neurons to spike highly enough to start the necessary

Another case of mesothalamic hypoactivity we simulate by fixing the SN frequency in one spike each 100ms. Compared to the previous experiment, the SN is slightly more active. This time, it is the *Tx* neuron that presents an oscillatory pattern, when *ĝd4* = 0.9. In this case, the inhibition from TRNx was not strong enough to hyperpolarize *Ty*. However, the less stimulated *Tx* neuron suffered the necessary inhibition that activated calcium currents, thus facilitating the consolidation of the burst mode of spiking. Figure 5 illustrates the distinct

150 0.9 Ty Bursting

100 0.8 all Tonic

5 1.1 to 0.8 TRNx and TRNy Bursting

Fig. 4. Behaviors of Tx and Ty. Mesothalamic dopaminergic hypoactivity enables the

oscillatory behavior of Ty. SN spikes every 150ms and *ĝd4* = 0.9.

(*ĝd4*) Neurons Spike Mode

1.0 all Tonic 1.1 all Tonic

0.9 Tx Bursting 0.9 to 1.0 Tx and Ty Bursting

Activity of Dopamine Receptor D4\*

Table 6. Distinct dopaminergic activities in presence of different stimuli.

hyperpolarization that activates the calcium currents.

spiking modes of *Tx* and *Ty*.

Interval between Spikes in SN (ms)

Fig. 5. The distinct spiking modes of Tx and Ty. When SN spikes every 100ms and *ĝd4* = 0.9, Tx presents the burst mode of spiking.

Also with the SN neuron set to spike each 100ms, we started a 800ms-experiment with the parameter *ĝd4* = 0.9. This time, however, we turned *ĝd4* to 1.0 after 350ms. It is plausible to interpret such alteration in the *ĝd4* value as a consequence of some increase in the dopaminergic level, due to an exogenous factor. In this case, both *Tx* and *Ty* start to oscillate. The last situation presented in Table 6 refers to the extreme case of mesothalamic hyperactivity. During a 800ms-experiment, the interval between spikes in the SN was set to 5ms. In addition, at the beginning we imposed a high activation in receptor D4 with *ĝd4* = 1.1. This dopaminergic context inhibited the TRN neurons, which suffer even a hyperpolarization. It was, however, the imposed decrease of *ĝd4* to 0.8, after 350ms, that starts the burst mode in both *TRN* neurons. In this case, the lowering in the dopaminergic receptor activity enables the *TRNs* membrane potential to reach a threshold value that triggered LTS in such neurons. Figure 6 illustrates such situation.

Mesothalamic Dopaminergic Activity: Implications in Sleep Alterations in Parkinson's Disease 523

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,

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

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,

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

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

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

dopamine hyperactivity, enables the burst mode in the TRN.

types of rhythms may appear depending on the magnitude of such inhibitory event.

2009; Diekelmann & Born, 2010).

2002).

alterations.

Fig. 6. Decrease in receptor D4 activation, under mesothalamic dopaminergic hyperactivity, originates the burst state in both TRNx and TRNy.
