Hypothalamic feedforward inhibition of thalamocortical network controls arousal and consciousness

Abstract

During non-rapid eye movement (NREM) sleep, synchronous synaptic activity within the thalamocortical network generates predominantly low frequency oscillations (< 4 Hz) that are modulated by inhibitory inputs from the thalamic reticular nucleus (TRN). Whether TRN cells integrate sleep-wake signals from sub-cortical circuits remains unclear. Here, we identified a monosynaptic LHGABA-TRNGABA transmission that exerts a strong inhibitory control over TRN neurons. We showed that optogenetic activation of this circuit recapitulated state-dependent changes of TRN neuron activity in behaving mice and induced rapid arousal during NREM, but not REM sleep. During deep anesthesia, activation of this circuit induced sustained cortical arousal. In contrast, optogenetic silencing of LHGABA-TRNGABA increased the duration of NREM sleep and amplitude of delta (1–4 Hz) oscillations. Collectively, these results demonstrate that TRN cells integrate subcortical arousal inputs selectively during NREM sleep and may participate in sleep intensity.

Orexin-driven GAD65 network of the lateral hypothalamus sets physical activity in mice

“…These findings establish the GAD65 LH cells as key players in intra-LH information processing. Together with recent findings on roles of defined LH neurons in eating and arousal (7,36,38), our results substantiate specific LH circuits as orchestrators of key voluntary actions.…”

A Novel Population of Wake-Promoting GABAergic Neurons in the Ventral Lateral Hypothalamus

“…ChR2-eYFP+ fibers were densely clustered around histidine decarboxylase (HDC)-containing neurons in the TMN and, to a lesser extent, serotonergic (5-HT) neurons in the dorsal raphe (DR) and tyrosine hydroxylase (TH)-containing neurons in the VPAG and LC (Figure [S1]). Notably, axonal labelling was relatively sparse in the sleep-promoting parafacial zone (PZ) [17, 18] and completely absent throughout the thalamic reticular nucleus (RTN) [19] (Figure 1G–I), the latter of which receives inputs from both from the dorsally adjacent zona incerta and the rostrally and laterally adjacent basal forebrain [20]. …”

A Genetically Defined Circuit for Arousal from Sleep during Hypercapnia

“…The third virus which we used in our optogenetic experiments is the optogenetic neural silencer AAV-CAG-FLEX-ArchT-GFP that co-expresses ArchT and GFP in a Cre dependent manner. This viral vector was procured from the University of North Carolina (UNC) vector core and has been used previously by many groups for silencing neurons and of their terminals (Herrera et al, 2016;Kim et al, 2015;Stefanik and Kalivas, 2013). In order to test the Cre dependent expression of the silencer AAV-CAG-FLEX-ArchT-GFP, we injected this in to PBel of mice that were heterozygous both for the CGRP-CreER and TD Tomato alleles (n=3).…”

“…We adjusted the laser such that the light power exiting the fiber-optic cable was 8–10 mW, and this was checked before and after the experiment. Using an online light transmission calculator for brain tissue (www.stanford.edu/group/dlab/cgi-bin/graph/chart.php), we estimated the light power at the PBel to be less than10 mW/mm 2 and a similar range has been used by most researchers for neuronal silencing at the terminal fields (Herrera et al, 2016;Kim et al, 2015;Stefanik and Kalivas, 2013). Note that this is probably a high estimate because some light is probably lost at the interface between the fiber-optic cable and the implanted optic-fiber.…”