The Role of Extrasynaptic GABAAR Signaling in the Gustatory Cortex on Taste-Dependent Impulsive Behavior

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Project Summary Impulsivity, generally defined as acting without thinking, is a preexisting personality trait in most people. It can be advantageous; however, when excessive it becomes maladaptive. Pathological impulsive behavior (IB) is one of the factors underlying the etiology of dysregulated eating and its pathogenesis. Eating is essential for survival, but maladaptive patterns of food intake can modify the reward value of food and food-related cues. Binge eating is a dysfunctional pattern of feeding behavior that usually consists of consuming palatable foods rich in sweets and fats. Studies have shown that the insular cortex's (IC) circuitry may be altered in binge eating disorder. The IC has been associated with impulsive actions and classified as a neurobiological gate for the development of impulsivity related disorders. The anterior IC – also known as gustatory cortex (GC) – is also involved in the processing of taste, expectation of reward, and in decision making regarding food consumption. This evidence suggests that the GC is an ideal regional circuit to investigate the mechanisms that may underlie the deficits in impulse control, particularly in relation to food intake. The goal of this proposal is to test the hypothesis that altered levels of tonic GABAergic inhibition, which contributes to regulating neural circuit excitability, play a central role in mediating taste-dependent impulsive choices. This hypothesis will be addressed by utilizing the neurosteroid allopregnanolone as a pharmacological tool to investigate the role of tonic inhibition on GC circuit excitability and on IB. To assess the neural mechanisms for IB, I will examine the pattern of expression of extrasynaptic GABAARs in GC using histological assays, quantify possible differences in sensitivity of extrasynaptic GABAARs to neurosteroids, and use selective manipulations of GABAARs subunit expression to determine the contribution of extrasynaptic inhibition to IB. My preliminary data show substantial expression of extrasynaptic GABAARs and of tonic current in neurons of the GC, and changes in licking behavior by neurosteroid infusions in GC. The findings of this proposal will provide vital insights into differences in neural network physiological properties underlying taste-dependent IB. A clearer understanding of the mechanisms underlying deficits of inhibitory control will provide novel biomarkers for the diagnosis, treatment and prevention of impulsivity- related neuropsychiatric disorders improving the lives of patients and their families.