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    • br The differences between gamma

    2018-10-26


    The differences between gamma band activities during waking vs REM sleep are unknown. Why is this important? Because it is high frequency, especially beta/gamma band activity that drives our cognitive function during waking but also during REM sleep, two obviously different states. Our studies addressed the differential intracellular mechanisms assumed to subserve high frequency activity during waking vs REM sleep as a prelude to the selective pharmacological modulation of these states. In order to develop an effective treatment for insomnia, we would need to decrease waking drive, partially of course, without affecting REM sleep drive. We know that the two states are differentially regulated in the PPN, and the majority of this work was performed by the Datta lab. Injections of glutamate into the PPN were shown to increase both waking and REM sleep, but injections of NMDA increased only waking, while injections of kainic Stem Cell Compound Library (KA) increased only REM sleep [28–31]. Thus, the two states are independently activated by NMDA vs KA receptors. Moreover, the intracellular pathways mediating the two states appear to differ. For example, the CaMKII activation inhibitor, KN-93, microinjected into the PPN of freely moving rats resulted in decreased waking but not REM sleep [32]. Increased ERK1/2 signaling in the PPN is associated with maintenance of sleep via suppression of waking [33], and that activation of intracellular protein kinase A (PKA) in the PPN instead contributed to REM sleep recovery following REM sleep deprivation [34]. These authors showed that during REM sleep, pCREB activation in PPN cholinergic neurons was induced by REM sleep, and that PPN intracellular PKA activation and a transcriptional cascade involving pCREB occurred in cholinergic neurons [35]. These results suggest that waking is modulated by the CaMKII pathway while REM sleep is modulated by the cAMP-PKA pathway in the PPN. As mentioned above, in vivo recording studies have shown that PPN neurons manifest three major types of cellular activities in relation to waking and REM sleep in the form of “Wake/REM on”, “Wake-on”, and “REM on” cells [20–22]. This suggests that some PPN cells fire in relation to waking and REM sleep, only in relation to waking, and others only in relation to REM sleep, presumably through CaMKII and cAMP-PKA pathways vs only the cAMP-PKA pathway, respectively. We have breakthrough findings showing that in some PPN cells (50%), the N-type calcium channel blocker ω-conotoxin-GVIA (ω-CgTx) reduced gamma oscillation amplitude, while subsequent addition of the P/Q-type blocker ω-agatoxin-IVA (ω-Aga) blocked the remaining oscillations. Other PPN cells (20%) manifested gamma oscillations that were not significantly affected by the addition of ω-CgTx, however, ω-Aga blocked the remaining oscillations. In the rest of the cells (30%), ω-Aga had no effect on gamma oscillations, while ω-CgTx blocked them. Similar results were found during recordings of voltage-dependent calcium currents. These results confirm the presence of cells in the PPN that manifest gamma band oscillations through only N-type, only P/Q-type, Stem Cell Compound Library and both N- and P/Q-type calcium channels [36,37]. This new cell type classification suggests that some PPN neurons fire only during REM sleep (“REM-on”, N-type only), only during waking (“Wake-on”, P/Q-type only), or during both waking and REM sleep (“Wake/REM-on”, N-type+P/Q-type) [36,37]. Fig. 1 shows the responses to depolarizing ramps in each of these cell types, with responses being mediated by both N- and P/Q-type calcium channels (partial block by each channel blocker), by N-type only (complete block by ω-CgTx), and by P/Q-type only (complete block by ω-Aga). Fig. 2 shows the distribution and main intracellular control pathways modulating the two channel types, and presumed in vivo firing patterns.
    Two calcium channels N- and P/Q-type calcium channel subtypes both are linked to rapid release of synaptic vesicles [38,39], but knockout models manifest markedly different phenotypes [40]. P/Q-type (Cav2.1) knockout animals have deficient gamma band activity in the EEG, abnormal sleep-wake states, ataxia, are prone to seizures (low frequency synchrony), and die by 3 weeks of age [41,42]. On the other hand, N-type (Cav2.2) knockout animals show few sleep-wake abnormalities but exhibit decreased nociceptive responses, and are otherwise normal [40]. While the two types of receptors are modulated by G-protein coupled receptors, they require different G-protein subunits [43]. Intracellularly, protein kinase C (PKC) enhances N-type channel activity but has no effect on P/Q-type channel function [44], but CaMKII was shown to modulate P/Q-type channel function [45]. Again, the two calcium channel subtypes are modulated by different intracellular pathways, N-type by the cAMP/PK pathway, and P/Q-type via the CaMKII pathway. The implication from all of these results is that there is a “waking” pathway mediated by CaMKII and P/Q-type channels, and a “REM sleep” pathway mediated by cAMP/PK and N-type channels.