Mechanisms Underlying Control of Wake-Promoting Dopamine Neurons by Norepinephrine and Alcohol

Abstract

Alcohol use disorder (AUD) and sleep disorders are commonly comorbid, where individuals with AUD frequently report insomnia, poor sleep quality and daytime sleepiness. The locus coeruleus (LC) promotes wakefulness via alpha-1 adrenergic receptor (α1AR) driven recruitment of dopamine (DA) neurons in the ventral periaqueductal gray (vPAGDA neurons). Understanding the effect of ethanol on the neuron-astrocyte interactions and norepinephrine (NE) release in the vPAG may better inform treatments for AUD sleep/wake dysfunction. Utilizing optical, electrical, and genetic approaches, we have identified a crucial role of vPAG astrocytic α1AR receptors in sustaining arousal through heightened excitability and activity of vPAGDA neurons mediated by local adenosine 2A (A2A) receptors. Furthermore, we found that chronic intermittent ethanol (CIE) exposure in mice increases sleep fragmentation, suggesting an increase in wakefulness. Additionally, acute and chronic ethanol in vivo increase baseline NE levels in the vPAG that persist through withdrawal and abstinence as measured with a fluorescence NE sensor (GRABNE2h) and fiber photometry. Acute ethanol ex vivo drives increases in vPAGDA neuron and vPAG astrocyte calcium activity via an α1AR and A2A independent mechanism. Thus, ethanol may be engaging the LC-vPAG arousal circuit via both a norepinephrine-dependent and an unidentified local direct mechanism to modulate wakefulness. In this dissertation I also present LIQ HD (Lick Instance Quantifier Home cage Device): an affordable, intuitive, and easy-to-build device that utilizes capacitive sensor technology to track two-bottle choice drinking behavior in up to 18 rodent home cages, or 36 single bottles, on a minute-to-minute timescale running off a single Arduino microcontroller.