Role of the anterior insula in decision making under reward versus punishment conflict

The National Institute on Alcohol Abuse and Alcoholism awarded the University of Pittsburgh $158,378 on February 4, 2027, under the Alcohol Research Programs (CFDA 93.273) to investigate the role of the anterior insular cortex in decision making under reward versus punishment conflict.

The project examines how dysfunction in anterior insula activity may underlie maladaptive decision making in alcohol use disorder, particularly persistent ethanol drinking despite negative consequences. The research employs in vivo calcium imaging and optogenetic manipulations in mouse models to determine how the anterior insular cortex facilitates learning of tasks where animals decide whether to continue or abort reward-seeking behavior when punishment is at stake. This work aims to develop a neurobiological foundation for improved treatment strategies for individuals with alcohol use disorder.

Performance occurs at the University of Pittsburgh in Pittsburgh, Pennsylvania, with a period of performance extending through August 31, 2028. The award is structured as a project grant, the assistance type used for discrete, time-limited research initiatives under the NIAAA program.

Abstract

Alcohol use disorder (AUD) is a highly prevalent and debilitating psychiatric condition, which is in part characterized by persistent reward seeking despite negative consequences. This dysfunction in processing cost and benefits can present a significant barrier to treatment, highlighting the importance of understanding the neurobiological underpinnings of adaptive and maladaptive decision making under reward versus punishment conflict. Investigation of the neural circuity that underlies this decision making is therefore critical for developing effective treatments for all individuals with AUD. The anterior insular cortex (AIC) may act as a potential hub for balancing adaptive and maladaptive decision making, since IT is a critical interoception and punishment responsive brain region implicated in the neurobiology of AUD. Human imaging studies show increased AIC activity during punishment receipt, punishment learning, in response to punishment-predictive cues, and when there is conflict between reward seeking and punishment receipt. Preclinical models indicate the AIC is responsive to reward (sucrose) and punishment (foot-shock), crucial for ethanol consumption, processing interoceptive effects of ethanol, and aversion-resistant ethanol drinking. Deficits in reward versus punishment decision-making could thus be mediated by AIC dysfunction and could contribute to maladaptive persistent behaviors in AUD. I hypothesize that dysfunction in AIC activity underlies maladaptive decision making under reward/punishment conflict, including persistent ethanol drinking despite negative consequences. Aim 1 tests this hypothesis by investigate the role of the AIC in learning punishment avoidance. I will use in vivo calcium imaging and optogenetic manipulations to determine how the AIC facilitates learning of a task where mice decide whether to continue or abort reward seeking when a punishment-predictive CUE is presented. Aim 2 will determine the role of the AIC in punishment-resistant ethanol self-administration. I will use in vivo calcium imaging and optogenetic manipulations to determine whether dysfunctional AIC activity facilitates continued ethanol seeking despite punishment receipt. This research training project will measure reward seeking behavior for both a naturalistic reward (aim 1, sucrose) and a drug of abuse (aim 2, ethanol), thus assessing the impact of AIC activity on a spectrum of adaptive to maladaptive decision-making. This research training plan was developed with my mentor, DR. Susanne ahmari, and CO-sponsor DR. Mary torregrossa, and has the full support of the university of pittsburgh's department of psychiatry. Training through this fellowship will build on my predoctoral work in addiction behavioral neuroscience and provide a critical opportunity to gain technical expertise (calcium imaging, optogenetics, mouse behavioral models of decision making) and professional development (scientific writing, mentorship, presentation skills, and networking) that will equip me with the skills necessary to transition from a postdoctoral fellow to an independent researcher.