Abstract
During non-REM sleep the EEG shows characteristics waves that are generated by the dynamic interactions between cortical and thalamic oscillators. In thalamic neurons, low-threshold T-type Ca2+ channels play a pivotal role in almost every type of neuronal oscillations, including slow (< 1 Hz) waves, sleep spindles and delta waves. The transient opening of T channels gives rise to the low threshold spikes (LTSs), and associated high frequency bursts of action potentials, that are characteristically present during sleep spindles and delta waves, whereas the persistent opening of a small fraction of T channels, (i.e., ITwindow) is responsible for the membrane potential bistability underlying sleep slow oscillations. Surprisingly thalamocortical (TC) neurons express a very high density of T channels that largely exceed the amount required to generate LTSs and therefore, to support certain, if not all, sleep oscillations. Here, to clarify the relationship between T current density and sleep oscillations, we systematically investigated the impact of the T conductance level on the intrinsic rhythmic activities generated in TC neurons, combining in vitro experiments and TC neuron simulation. Using bifurcation analysis, we provide insights into the dynamical processes taking place at the transition between slow and delta oscillations. Our results show that although stable delta oscillations can be evoked with minimal T conductance, the full range of slow oscillation patterns, including groups of delta oscillations separated by Up states (“grouped-delta slow waves”) requires a high density of T channels. Moreover, high levels of T conductance ensure the robustness of different types of slow oscillations.
Highlights
TC neurons of sensory, motor, and intralaminar thalamic nuclei recorded in the presence of trans-ACPD exhibit stereotypical firing patterns and oscillations when submitted to steady hyperpolarizing currents of increasing amplitudes, as we previously described (Hughes et al, 2002; Zhu et al, 2006; Crunelli et al, 2012, 2014): from stable UP states, at times showing tonic firing, to slow Up and Down state oscillations, “grouped-delta slow waves”, pure delta oscillations (1– 4 Hz) and stable silent DOWN states (Figure 2A)
In order to investigate how IT density affects the expression of these various oscillations, we compared in lateral geniculate nucleus (LGN) TC neurons the range of injected steady hyperpolarizing current required to observe the distinct patterns of oscillations in control conditions and when IT was partially blocked by the selective antagonist TTA-P2 (Dreyfus et al, 2010)
A close examination of the oscillatory regimes shows that for T conductance values where both “grouped-delta slow waves” and continuous delta developed (Figure 6B, gT 60 nS), the continuous delta disappeared upon introduction of the voltage-dependent potentiation (Figure 6B, gT 30 nS+gTP 30 nS). This suggests that compared to a simple increase in gT, this ATP-dependent T channel regulation can selectively enhance the occurrence of slow oscillations of TC neurons at the expenses of delta oscillations. Since their first development (Rose and Hindmarsh, 1989), TC neuron models have gained in precision and completeness (Destexhe et al, 1998), allowing detailed analysis of the dynamical processes that are intrinsic to these neurons (Destexhe and Sejnowski, 2003; Amarillo et al, 2015)
Summary
Sleep is characterized by the regular appearance of stereotyped sequences of EEG waves (Achermann and Borbely, 1997; Steriade, 2006; Crunelli et al, 2014) that are generated by the dynamic interaction between, and require the integrity of both cortical and thalamic oscillators (Steriade et al, 1993b; Crunelli and Hughes, 2010; David et al, 2013; Lemieux et al, 2014). Bifurcation Analysis of Thalamic Sleep Waves oscillations tightly depend on the expression of low-threshold T-type Ca2+ channels (T channels; Leresche et al, 1991; Williams et al, 1997a; Crunelli et al, 2014). While these channels are almost fully inactivated in the range of membrane potentials associated to the wake state (but see Lambert et al, 2014), during non-REM sleep the progressive reduction in the depolarizing tone exerted by modulatory afferents onto both cortical and thalamic neurons (McCormick, 1992) allows T channel de-inactivation. The interaction of the leak current with a small number of de-inactivated T channels opening with a low (but non-zero) probability in a narrow range of membrane potentials around −60 mV (i.e., ITwindow; Perez-Reyes, 2003; Dreyfus et al, 2010) is necessary for the generation of the membrane potential bistability that in TC neuron underlies the expression of the Up and Down state dynamics of sleep slow waves (Williams et al, 1997a; Toth et al, 1998; Hughes et al, 2002; Dreyfus et al, 2010)
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