The modulation of NREM sleep by corticotropin-releasing hormone through the thalamic reticular nucleus

The thalamic reticular nucleus (TRN) is an essential pacemaker within the thalamocortical circuitry that gives rise to non-rapid eye movement (NREM) sleep-related oscillations, such as sleep spindles. Spindle density fluctuations in the infraslow scale define NREM sleep microarchitecture, with alternating substates of continuity and fragility. The restorative benefits of NREM sleep and memory consolidation can be impaired by frequent microarousals (MAs) that occur during periods of sleep fragility that induce sleep fragmentation. Stress, anxiety, and several psychiatric conditions are associated with fragmented sleep by MAs and subsequent impairments in cognitive processing and memory. Corticotropin-releasing hormone (CRH) is the main stress- and anxiety-related peptide that was also linked to modulation of sleep regulation. CRH receptor 1 (CRHR1) has been reported to be highly expressed in TRN neurons for more than two decades, yet the potential modulation of NREM sleep by CRH acting on TRN has not been investigated.

Considering the strong associations between the stress- and anxiety-related CRH and sleep fragmentation, I explored the contribution of CRH modulation to TRN and related sleep rhythms, particularly sleep spindles, and its cellular mechanisms in mice. I found that the spindle pacemaking parvalbumin (PV) positive TRN subpopulation highly expresses CRHR1 mRNA, indicating a potential substrate for CRH modulation of sleep spindles. Tracing experiments revealed that the sensory TRN receives heterogeneous neuromodulatory CRH afferents from subnuclei of the geniculate nucleus of the thalamus and limbic-related structures. During NREM sleep, the endogenous CRH release pattern in TRN fluctuated in the infraslow scale, anti-correlating with sigma power (proxy of sleep spindles), with high CRH release coinciding with periods of sleep fragility. Optogenetically increasing CRH release in the TRN during NREM sleep increased the number of MAs and decreased sigma power, fragmenting NREM sleep. In contrast, optogenetic inhibition of CRH-releasing terminals in the TRN decreased the number of MAs and increased delta power, consolidating NREM sleep. In patch-clamp recordings, CRHR1 activation in TRN decreased cyclical bursting of TRN neurons, indicating a cellular mechanism that could explain the decrease induced by CRH in the spindle-related power band. Knocking down CRHR1 in TRN PV+ neurons abolished the effect of CRH on the firing pattern of TRN neurons and on sleep fragmentation, involving CRHR1 causally in the CRH modulation of NREM sleep.

With the results in this thesis, I describe novel CRH circuits acting on the TRN to modulate arousal (MAs) during NREM sleep. I also explore associations with trait anxiety and find differences in both endogenous CRH release and divergent responses to optogenetically increased CRH release. These results are relevant for our understanding of the neuromodulation of NREM sleep. They shed light on stress- and anxie