Characterizing alcohol and stress induced changes in dorsomedial frontal cortex function

About This Grant

PROJECT SUMMARY The ability to adaptively and appropriately respond to changes in the environment is a crucial behavior. It is cognitive flexibility that enables this adaptive responding. An inability to adaptively shift behavior (cognitive inflexibility) despite negative outcomes is observed in various psychiatric disorders and is a key diagnostic criterion of alcohol use disorder (AUD). The long-term objective of this work is to elucidate how chronic alcohol and stress promote AUD through cognitive inflexibility. In humans, AUD is accompanied by aberrant frontal cortex function alongside deficits in cognitive flexibility. A significant body of work, including that from our lab, has demonstrated impaired cognitive flexibility in animal models following chronic alcohol which can be exacerbated by stress exposure. However, the frontal cortical neuroadaptations that mediate these alcohol and stress induced cognitive impairments remain unresolved. This is a critical gap given that stress is a key risk factor in perseverative relapse for individuals with AUD. My central hypothesis is that functional network changes across the dorsomedial frontal cortex underlie cognitive flexibility impairments following repeated alcohol and stress exposure. Moreover, I hypothesize that changes in modulatory norepinephrine inputs to this region are critical contributors to these flexibility deficits. To test these hypotheses, I will investigate the mechanisms underlying the negative impact of chronic alcohol and stress on cognitive flexibility using a novel attentional set shifting task. In Aim 1 I will use in vivo calcium imaging to investigate alcohol- and stress- associated changes in dorsomedial frontal cortex dynamics underlying behavioral impairment. In Aim 2, I will determine whether chronic alcohol and stress functionally disrupts noradrenergic regulation of the dorsomedial frontal cortex using in situ hybridization readouts and pharmacological interventions to recover cognition. These proposed studies will provide ample training in cutting-edge techniques and facilitate my professional development in the alcohol research field. At the same time, this work will advance our understanding of the impact of long-term alcohol and stress exposure on cortical function and identify potential mechanisms for therapeutic interventions.