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Research Component 3: Frontolimbic Circuitry, Behavioral Flexibility, and Adolescent Alcohol History

Primary Investigator: Dr. Charlotte Boettiger

Co-Investigator(s): Dr. Donita Robinson

Binge drinking accounts for over half of all alcohol-related deaths and most of the economic costs of alcohol misuse. Adolescent binge drinking is of particular concern, as animal studies suggest that adolescent brains are developmentally vulnerable to the neurotoxic effects of binge alcohol, leading to persistent deficits. In the previous funding cycle, we found that binge drinking during adolescence is associated with specific phenotypes in adulthood, including 1) heightened sensitivity to reward conditioning and 2) reduced frontal connectivity and hyper meso-cortical connectivity. Further, using adolescent intermittent ethanol (AIE) in rats to directly study neural consequences of binge alcohol, we found that AIE exposure results in 1) enhanced approach to reward-associated cues and 2) reduced baseline frontal connectivity, but enhanced connectivity in response to an alcohol challenge. Substance use disorders (SUDs), including alcohol use disorder (AUD), have been linked to heightened sensitivity to reward conditioning and formation of habit-based, stimulus-response (S-R) action selection strategies. Although both behaviors are considered signs of behavioral flexibility deficits, it is unknown whether sensitivity to reward conditioning and overuse of habitual action-selection are two facets of a single endophenotype, or if they reflect distinct pathologies associated with AUD. This distinction impacts our understanding of risk for AUD as well as potential treatments. We hypothesize that adolescent binge alcohol promotes both more habitual action-selection and greater sensitivity to reward conditioning in adulthood via common alterations in shared underlying neural circuits; and that the relationship between proneness to habit and proneness to reward conditioning is mediated by neural circuit changes impairing top-down control of responses to salient exogenous cues. The following translational, multi-faceted aims test these hypotheses.

Aim 1: Test the hypothesis that more habitual action-selection and greater sensitivity to reward conditioning behaviorally overlap and are influenced by adolescent alcohol history.

We will assess action-selection strategy in humans using the Hidden Association Between Images Task (HABIT) to index S-R strategy use, and we will assess reward conditioning sensitivity in humans with the Reward-Driven Attentional Capture (RDAC) task. We will test subjects with and without a history of adolescent binge drinking to determine whether adolescent drinking associates with these two measures of behavioral flexibility deficits and whether these deficits correlate across individuals. To test the causal role of AIE, we will assess habitual action-selection and reward conditioning sensitivity in rats, using tasks that parallel the HABIT and RDAC tasks: reversal of a learned S-R association and Pavlovian conditioned approach. The rat studies will test whether AIE is sufficient to promote habitual action-selection and sensitivity to reward cues, guiding interpretation of our human study results. We predict that adolescent binge alcohol impairs behavioral flexibility in adulthood, evident as both perseveration when action outcomes change, and hypersensitivity to reward conditioning.

Aim 2: Test the hypothesis that more habitual action-selection and hypersensitivity to reward conditioning share underlying neural circuit perturbations influenced by adolescent alcohol history.

We will collect resting-state, functional connectivity MRI (fcMRI) in the human subjects from Aim 1 to test whether intrinsic brain connectivity patterns mediate the relationship between habitual action-selection and reward conditioning susceptibility, and whether adolescent binge drinking moderates these relationships. In parallel rat studies, we will assess brain connectivity through rodent fcMRI to define how AIE alters connectivity across regions homologous to those identified in the human studies. We will also directly measure neuronal firing with multielectrode arrays in prefrontal subregions during behavioral tasks from Aim 1. We predict that shared patterns of brain activity will mediate the relationship between more habitual action-selection and hypersensitivity to reward conditioning promoted by adolescent binge alcohol exposure.

Aim 3: Test the hypothesis that frontal regions mediate top-down control over action-selection strategy and expression of reward conditioning, moderated by adolescent binge alcohol exposure.

To enhance top-down control, during the behavioral tasks from Aim 1, we will apply transcranial alternating current stimulation (tACS) at 5 Hz (theta) to bilateral DLPFC in humans and we will optogenetically stimulate prelimbic and orbitofrontal inputs to the striatum in rats. In rats, we will further determine how activation alters corticostriatal connectivity via fcMRI. To reduce top-down control, during the Aim 1 behavioral tasks, we will apply 10 Hz (alpha) tACS to bilateral DLPFC of humans, and we will chemogenetically inhibit prelimbic and orbitofrontal inputs to the striatum in rats. We predict that manipulating the activity of select prefrontal regions will bi-directionally modulate top-down control over automatic behaviors and thereby bi-directionally alter action-selection strategy and expression of reward conditioning; we anticipate that adolescent binge alcohol exposure moderates these effects.

The UNC ARC goal is to increase understanding of the mechanisms of pathogenesis in AUD. Within this goal, Project 3 uses an explicitly translational approach to determine the enduring consequences of adolescent binge alcohol exposure on behavioral flexibility and to delineate the neural circuit bases of these consequences. By directly comparing humans and rodents, we will advance the translation of basic science to clinical application.