0074 Pharmacologic And Optogenetic Dissection Of Sleep Homeostatic Circuits In The Basal Forebrain. (27th April 2018)

• Record Type: Journal Article
• Authors: Bouaouda, H; Shukla, C; McKenna, J T; McNally, J M; Winston, S; Kalinchuk, A V; Thankachan, S; Strecker, R E; Deisseroth, K; Brown, R E; Basheer, R
• Is Part Of: Sleep. Volume 41(2018)Supplement 1
• Page Start: A30
• Page End: A30
• Publication Date: 2018-04-27
• Subjects: Sleep -- Physiological aspects -- Periodicals; Sleep disorders -- Periodicals; Sommeil -- Aspect physiologique -- Périodiques; Sommeil, Troubles du -- Périodiques; Sleep disorders; Sleep -- Physiological aspects; Sleep -- physiological aspects; Sleep Wake Disorders; Psychophysiology; Electronic journals; Periodicals; 616.8498
• DOI: 10.1093/sleep/zsy061.073
• Languages: English
• ISSNs: 0161-8105

Abstract

Abstract: Introduction: Selective optogenetic stimulation of basal forebrain (BF) neuronal subtypes, Cholinergic (ChAT+), vesicular glutamate transporter2-expressing glutamatergic (vGluT2+) and parvalbumin-expressing GABAergic (PV+), causes arousal. However, it is unclear if they are equally effective in eliciting a homeostatic sleep response (HSR). The importance of interactions between these cell-types in the HSR has not previously been investigated. Thus, we used optogenetics and reverse microdialysis of pharmacological agents to investigate these questions. Methods: C57BL/6 (WT) mice were sleep deprived (6h) with and without reverse microdialysis of cholinergic antagonists into BF. The amount of recovery sleep and delta activity (0.5–4.5Hz) were used as the markers of HSR. In ChAT-Cre, vGluT2-Cre, PV-Cre transgenic mice transduced with AAV-ChR2-EYFP in BF, we examined the effect of 6h laser (473nm) illuminations (5s/min, 10 Hz for ChAT+ and vGluT2+, 40Hz for PV+) on HSR, during the 2h poststimulation period and compared it with time matched sham stimulation (BL, TTLpulse without laser). In ChAT-Cre mice we performed optodialysis of cholinergic antagonists during 6h optical stimulation and examined the post stimulation HSR. Results: In WT mice (n=4) microdialysis of cholinergic antagonists did not prevent HSR, as evaluated by an increase in sleep time (36%) and delta power (8.14%, p<0.001). Optogenetic stimulation of ChAT+ neurons (N=3), led to an increase in sleep (BL 52.6 ± 0.56 vs poststim 57 ± 2.88) and delta by 24% during the 2h poststimulation compared to BL, that was not blocked by cholinergic antagonist. In contrast, GABA/PV+ neuronal stimulation did not cause HSR. Optogenetic stimulation of vGluT2+ neurons in 1 mouse, showed a tendency towards HSR. Conclusion: Preliminary results suggest that ChAT+ and vGluT2+, but not PV+ neurons, are involved in mediating HSR. Furthermore, local effects of acetylcholine on non-ChAT+ neurons are not required for HSR. These results, together with previous cholinergic lesion studies, suggest a model whereby direct or indirect excitation of ChAT+ neurons (via vGluT2+ neurons) is key to trigger HSR. Support (If Any): VA I01BX001404, I01BX001356, I01BX002774, IK2BX002130, NIH R21NS079866, R01MH039683, P01HL095491, R01MH099180, R03-MH107650. JTM received partial salary from Merck MISP, no COI with this work.