Optogenetically induced sleep spindle rhythms alter sleep architectures in mice

Abstract

Sleep spindles are rhythmic patterns of neuronal activity generated within the thalamocortical circuit. Although spindles have been hypothesized to protect sleep by reducing the influence of external stimuli, it remains to be confirmed experimentally whether there is a direct relationship between sleep spindles and the stability of sleep. We have addressed this issue by using in vivo photostimulation of the thalamic reticular nucleus of mice to generate spindle oscillations that are structurally and functionally similar to spontaneous sleep spindles. Such optogenetic generation of sleep spindles increased the duration of non-rapid eye movement (NREM) sleep. Furthermore, the density of sleep spindles was correlated with the amount of NREM sleep. These findings establish a causal relationship between sleep spindles and the stability of NREM sleep, strongly supporting a role for the thalamocortical circuit in sleep regulation.sleep rhythms | sleep protection S leep spindles are characteristic EEG rhythms observed during non-rapid eye movement (NREM) sleep. It is characterized by periodic waxing and waning and 7-to 15-Hz oscillations with durations ranging from 0.5 to 3 s (1-3), and is often used as an EEG marker of NREM sleep. Sleep spindles are hypothesized to originate from the thalamic reticular nucleus (TRN) (4, 5), where the rhythmic burst activity of TRN neurons could initiate spindle oscillations within the whole thalamocortical circuit. When it has been initiated, this oscillation is self-maintained by the reciprocal interactions among cortical, thalamocortical (TC), and TRN neurons during NREM sleep (4, 6, 7). Sleep spindles are of particular interest because they are known to be involved in several sleep-dependent physiological and cognitive processes, such as memory consolidation and neuronal plasticity (7-10). Moreover, a growing amount of evidence suggests that sleep spindles serve a sleep-protecting function by modulating the degree of sensory transmission through the thalamus (11). Patients with hypersomnia show increased spindle density (SD) compared with control (12), and KO mice whose sleep spindles are reduced as a result of impaired thalamocortical oscillations experience sleep disturbances during NREM sleep (13-16). Further, individuals with a higher spindle rate are more tolerant to noise that occurs during sleep (17). Despite considerable evidence hinting at the sleepprotecting function of sleep spindles, no experimental studies have yet demonstrated a direct causal relationship between sleep spindles and the stability of sleep. A recent study found that optogenetic stimulation of TRN induced burst firing in TC neurons, which were hypothesized to underlie the occurrence of neocortical sleep spindles (18). However, because sleep spindles also occur spontaneously, it was not clear whether sleep spindles were driven by optogenetic stimulation of the TRN.To experimentally examine the sleep-protecting function of sleep spindles, we used Channelrhodopsin2 (ChR2) transgenic (tg) mice to bilaterally ...

Driving Sleep Slow Oscillations by Auditory Closed-Loop Stimulation—A Self-Limiting Process

“…If applied time-locked to the ongoing SO up states during SWS, the presentation of clicks reliably induced further SOs with high amplitude, accompanied by surges of spindle activity in phase with the invoked SO up state. At the behavioral level the changes express themselves in an enhanced overnight retention of declarative memories, altogether corroborating the view that the induced SOs are functionally effective in the same way as endogenous SOs (Clemens et al, 2007;Chauvette et al, 2012;Cox et al, 2012;Phillips et al, 2012;Ruch et al, 2012;Wilhelm et al, 2013). In fact, the changes following both closed-loop stimulation protocols used here are highly specific, as indicated by comparisons with the effects of a Sham control condition, which were performed for the 2-Click protocol in a previous study (Ngo et al, 2013b) and for the Driving stimulation protocol here.…”

“…It reflects highly synchronized cortical activity, with down states representing widespread neuronal hyperpolarization and up states representing widespread depolarization and distinctly enhanced network excitability (Olcese et al, 2010;Timofeev, 2011). SOs originate from neocortical networks, preferentially involved in prior information encoding during wakefulness, possibly due to ongoing miniature excitatory postsynaptic potentials (Bazhenov et al, 2002;Huber et al, 2004). Functionally, they are thought to mediate a global renormalization of synapses potentiated during wakefulness (Tononi and Cirelli, 2014), though recent findings contradict this hypothesis (Chauvette et al, 2012;Seibt et al, 2012;Yang et al, 2014).…”

“…Note, inasmuch the algorithms for both 2-Click and Driving stimulation relied on constant time intervals (e.g., the individual delay between a detected SO-negative half-wave peak and click presentation) they do not account for the temporal jitter inherent to the SO rhythm and are, thus, not entirely precise as to the estimated peak of the SO up phase. Although such imprecision is expected to nonspecifically affect every click presentation in both protocols, it needs to be explored in future studies whether in-phase timing of stimuli might be optimized with different algorithms (Cox et al, 2014).…”

Manipulating sleep spindles – expanding views on sleep, memory, and disease

“…A 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 11 single, brief (20 ms) nRt activation intermittently resulted in cortical spindles during NREMS [63]. In transgenic mice expressing ChR2 under the Thy-1 promoter, photo-activation of the nRt at 8 Hz enhanced EEG power between 7-15 Hz [64]. In these animals, photostimulation increased NREMS duration, and the number of NREMS-REMS transitions correlated with the density of induced rhythmic activity.…”

The thalamic reticular nucleus: A functional hub for thalamocortical network dysfunction in schizophrenia and a target for drug discovery

“…The TRN is believed to act as the pacemaker for sleep spindles -slow frequency oscillations that occur particularly during the early stages of sleep (Fuentealba and Steriade, 2005;Halassa et al, 2011;Kim et al, 2012). Patients with schizophrenia exhibit disturbed sleep patterns, with increased sleep latency and more frequent night awakenings (Keshavan et al, 1995;Cohrs, 2008;Sarkar et al, 2010).…”