Physiological consequences of alcohol exposure on CRF 1 neurons in the nucleus tractus solitarius

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Abstract Alcohol use disorder (AUD) is a highly prevalent chronically relapsing disorder characterized by increased alcohol (EtOH) intake, inability to control consumption, and a negative emotional state during withdrawal. These behaviors are mediated by cellular and circuit adaptations, which can lead to changes in neuronal structure and function. One key neuroadaptation involves activation of the corticotropin releasing factor (CRF) system, a peptide released widely throughout the brain in response to stress. CRF signaling through the CRF1 receptor (CRF1) is associated with increased stress reactivity, anxiety-like behavior, and excessive drinking. Indeed, polymorphisms in Crhr1 (the gene encoding CRF1) are associated with binge drinking, emotionality, and risk for developing an AUD. A majority of the research concerning AUDs and CRF1 has focused on the prefrontal cortex and amygdala, while other areas such as the brainstem are much less well-studied. Located in the caudal medulla, the nucleus tractus solitarius (NTS) is an autonomic center containing an abundance of CRF1 receptors. While chronic EtOH drinking has been shown to increase activity of NTS neurons, little is known about the role of specific NTS subpopulations, most notably CRF1 neurons, in this effect. In this proposal, we will use male and female CRF1:cre: tdTomato rats and established models of voluntary EtOH intake combined with a cellular electrophysiological approach. In Aim 1, I will determine the effects of acute EtOH on excitability and synaptic transmission in CRF1NTS neurons from male and female CRF1:cre: tdTomato rats. In Aim 2, I will examine the changes in excitability and synaptic transmission in CRF1NTS neurons in male and female CRF1:cre: tdTomato rats following chronic voluntary EtOH drinking. In Aim 3, I will examine the effect of chemogenetic manipulation of CRF1NTS neurons on voluntary EtOH drinking in male and female CRF1:cre: tdTomato rats. Together, these experiments will reveal how CRF1NTS neurons are differentially impacted by acute and chronic EtOH exposure and how CRF1NTS neurons contribute to alcohol drinking. Collectively, the results of these studies will advance our understanding of the sex-specific consequences of alcohol exposure on defined subpopulations in the brainstem and how those subpopulations contribute to behaviors associated with AUD.