Saturday, December 21, 2024
12/21/2024
Project Summary Aberrant cognitive function is a hallmark of alcohol use disorders (AUD), disrupting daily function and contributing to alcohol abuse and relapse. Identifying the nature of these deficits is challenged by a lack of understanding of involved cortical circuits and mechanisms. AUD shows altered orbital frontal (OFC) and pre-supplementary motor area (Pre-SMA) cortical function, regions implicated in cognitive functions necessary for decision-making. The mechanisms underlying behavioral and circuit dysfunction are not clear. OFC hypoactivity resulted in a loss of value-based control over goal-directed behavior; however additional cortical circuits have been implicated in behavioral flexibility, including Pre-SMA, whose rodent homologue is the secondary motor cortex (M2), and its output to DS. Increased Pre-SMA/M2 activity is correlated with behavioral inflexibility and impulsivity in AUD; however, no preclinical studies have examined effects of chronic alcohol exposure on M2 circuit function or its output to DS. The overarching hypothesis of this work is that AUD alters OFC and Pre-SMA/M2 circuit function and striatal output, resulting in inflexible behavior underlying dysfunctional decision-making. The current proposal addresses this through three Aims with experiments to be conducted in mice. Aim 1 examines the influence of chronic alcohol on OFC output to M2 contributing to behavioral flexibility. A series of ex vivo slice physiology and in vivo activity monitoring and manipulation experiments will test the hypothesis that chronic intermittent ethanol exposure and repeated withdrawal (CIE) decreases OFC-M2 transmission important for behavioral flexibility. In Aim 2, effects of chronic alcohol on M2 function and its contribution to ethanol self-administration will be examined. By examining effects of chronic ethanol on identified M2 cell type transmission ex vivo and the dynamics and functional contribution of such output to ethanol self-administration in vivo, this aim will address the hypothesis that CIE alters M2 transmission and results in hyperactivity of M2 excitatory populations to contribute to inflexible alcohol self-administration. Lastly, Aim 3 will examine effects of CIE on M2-DS output and control over ethanol-seeking. An integrative ex vivo and in vivo approach will be taken to address the hypothesis that CIE produces aberrant control over striatal processes through increased activation and output of motor-related circuits. Together, these aims will inform how CIE affects cortical circuits and alters their recruitment of striatum to disrupt goal-directed control, thereby identifying novel targets for AUD treatment. Identifying the mechanisms underlying chronic alcohol-induced alterations to cortico-cortical and cortico-striatal circuits is a critical step towards understanding how their disruption contributes to AUD.
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