Mediodorsal thalamic nucleus mediates resistance to ethanol through Cav3.1 T-type Ca 2+ regulation of neural activity
Charles-Francois V Latchoumane, Joon-Hyuk Lee, Seong-Wook Kim, Jinhyun Kim, Hee-Sup Shin
bioRxiv September 27, 2023 preprint DOI: 10.1101/2023.09.25.558585 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal experimental study (knockout and knock-down mouse study) |
|---|---|
| Population | Ca v 3.1 T-type calcium channel knockout and MD-specific knock-down mice, compared with wild-type mice, during natural sleep and ethanol-induced unconsciousness |
| Intervention | Ethanol |
| Key findings | Knockout and MD-specific knock-down mice showed enhanced resistance to ethanol-induced unconsciousness. Wild-type MD neurons reduced firing and increased bursting during ethanol-induced unconsciousness, whereas Ca v 3.1 knockout neurons sustained wakefulness-level firing without bursts. The authors suggest that maintaining MD neural firing at a wakeful level is sufficient to induce resistance to ethanol-induced hypnosis in wild-type mice. |
Abstract
ABSTRACT: Thalamocortical activity is known to orchestrate sensory gating and consciousness switching. The precise thalamic regions involved, or the firing patterns related to the unconsciousness remain unclear. Interestingly, the highly-expressed thalamic T-type calcium currents have been considered as a candidate for the ionic mechanism for the generation of thalamo-cortically-driven change in conscious state. Here, we tested the hypothesis that Ca v 3.1 T-type channels in the mediodorsal thalamic nucleus (MD) might control neuronal firing during unconsciousness using Ca v 3.1 T-type channel knock-out (KO) and knock-down (KD) mice under natural sleep and ethanol-induced unconsciousness. During natural sleep, the MD neurons in KO mice showed general characteristics of sustained firing across sleep stages. We found that KO and MD-specific KD mice showed enhanced resistance to ethanol. During ethanol-induced unconscious state, wild-type (WT) MD neurons showed a significant reduction in neuronal firing from baseline with increased burst firing, whereas Ca v 3.1 KO neurons showed well sustained neural firing, within the level of wakefulness, and no burst firing. Further, 20 Hz optogenetic and electrical activation of MD neurons mimicked the ethanol resistance behavior in WT mice. These results suggest that maintaining MD neural firing at a wakeful level is sufficient to induce resistance to ethanol-induced hypnosis in WT mice. This work has important implications for the design of treatments for consciousness disorders using thalamic stimulation of deeper nuclei including the targeting of the mediodorsal thalamic nucleus. GRAPHICAL ABSTRACT: