Impact and role of hypothalamic corticotropin releasing hormone neurons in withdrawal from chronic alcohol consumption in female and male mice

Abstract

Worldwide, alcohol use and abuse are a leading risk of mortality, causing 5.3% of all deaths. The endocrine stress response system, which is initiated by the peripheral release of corticotropin releasing hormone (CRH) from primarily glutamatergic neurons in the paraventricular nucleus of the hypothalamus (PVN), has been profoundly linked with alcohol use, abuse, and relapse. These PVN CRH releasing (PVNCRH) neurons are essential for peripheral and central stress responses, but little is known about how alcohol affects these neurons. First, we show that intermittent two-bottle choice alcohol consumption blunts endocrine mediated corticosterone response to stress during acute withdrawal in female mice. Conversely, using slice electrophysiology, we demonstrate that acute withdrawal engenders a hyperexcitable phenotype of PVNCRHneurons in females that is accompanied by increased glutamatergic transmission in both male and female mice. Only male mice show a concurrent increase in GABAergic synaptic transmission. We then tested whether chemogenetic inhibition of PVNCRHneurons would restore stress response behaviors in alcohol history female mice in the looming disc test, which mimics an approaching predator threat. Accordingly, inhibition of PVNCRHneurons reduced active escape in hM4Di alcohol history mice only. This study indicates that stress responsive PVNCRHneurons in females are particularly affected by a history of alcohol consumption. Interestingly, women have indicated an increase in heavy alcohol use to cope with stress, perhaps pointing to a potential underlying mechanism in alcohol mediated changes to PVNCRHneurons that alter stress response.