Samuel W Centanni - US grants

DESCRIPTION (provided by applicant): The prefrontal cortex (PFC) is thought to play an important role in the cognitive processes that are negatively impacted by alcohol exposure. Compared to other brain regions, the neuronal connections of the PFC undergo a critical period of reorganization and refinement during adolescence and this coincides with improvement in cognitive control and decision making. Environmental insults that occur during this period may be particularly damaging to prefrontal cortex, resulting in aberrant neurodevelopment along with long-lasting effects on cognitive functioning that negatively impacts decision-making and behavioral control. Experimentation with alcohol typically begins during adolescence when it is often consumed in excessive binge-like episodes resulting in a cycle of very high levels of intoxication followed by a short period of abstinence. This proposal will examine the effects of binge-like adolescent alcohol exposure on development of GABAA receptor-mediated neurotransmission in the PFC. Strong supportive preliminary data is presented that suggests that a specific tonic current regulated by extrasynaptic delta-GABAA-type receptors is reduced in adult rats exposed to alcohol during adolescence, and we hypothesize that this will impair cognitive function of the PFC. This is supported by additional preliminary data showing that adult rats exposed to alcohol during adolescence exhibited decreases in behavioral flexibility on an operant set-shifting task. This proposal will use biochemical, electrophysiological and behavioral approaches to examine the effect of adolescent alcohol abuse on the development of GABAergic neurotransmission and cognitive function and in particular, behavioral flexibility of the adult PFC. The overarching hypothesis of this proposal is that binge-like alcohol exposure during adolescence results in disruption of development of GABAergic neurotransmission in the adult PFC and cognitive function. The proposed studies and related training plan will not only further the career development of the applicant, but the results obtained from these studies will significantly advance our understanding of the long- term consequences of adolescent alcohol abuse on prefrontal function and cognitive control of behavior in the adult.

PROJECT SUMMARY/ABSTRACT Alcohol use disorder (AUD) afflicts millions of individuals and their families each year. AUD is frequently comorbid with anxiety and depression, indicating potential sources for the motivation to consume alcohol. Alcoholics commonly list stressors and negative affective states as leading triggers of cravings and relapse, and severity of the disease state correlates with relapse susceptibility. The health and financial burden associated with AUD highlights the pressing need for more research focused on understanding the interaction between AUD and negative affective disturbances. Identifying key neuroadaptations driving this debilitating disease is essential for developing better diagnostic tools and treatments for affective symptoms in alcohol abstinence. Converging evidence suggests the transition from social use to negative reinforcement-driven alcohol seeking involves a set of brain structures collectively referred to as the extended amygdala. The bed nucleus of the stria terminalis (BNST), a component of the extended amygdala network, is a critical node for stress-related disorders such as anxiety, depression, and addiction. The BNST plays a prominent role in many facets of alcohol addiction including binge drinking and cravings in withdrawal. The BNST interacts with many cortical, subcortical, midbrain, and hindbrain regions to determine general affect. Our recent work identified a functional connection between the insular cortex (insula) and the BNST. The insula is involved in interoceptive awareness, cognitive control, and sensory processing, and mounting evidence suggests a role for the insula in alcoholism and negative affective disturbances. We used a mouse model of chronic drinking followed by forced abstinence (CDFA) to outline a definitive role for the insula-BNST pathway in abstinence-induced negative affect, and this proposal will significantly build on this foundational evidence. We will combine in vivo calcium fiber photometry and ex vivo electrophysiology with genetic mouse lines and a variety of sophisticated viral- genetic techniques to isolate circuit-specific neuronal ensembles. The mentored (K99) phase will provide training in fiber photometry and complex viral-genetic manipulation strategies to determine the functional and physiological state of BNST neurons receiving insular inputs (Aim 1) and insular neurons that project to the BNST (Aim 2) in the protracted abstinence phase of CDFA. The independent (R00) phase will identify 2nd order inputs onto insulaàBNST neurons, with the goal of further delineating the complex neurocircuitry regulating abstinence-induced negative affect. The proposed studies and related career development training plan in this Pathway to Independence Award collectively provide the ideal mechanism to transition the applicant to a career as an independent addiction neuroscientist. The results will significantly advance our understanding of the neural adaptations that occur in protracted abstinence following chronic alcohol abuse.