Ghrelin receptor and striosomal interactions in stress-induced decision-making

/Abstract Our daily lives require constant decision-making in which we pursue potential rewards at the expense of potential costs. The integration of costs and benefits is an essential component of decision-making. Abnormal decision- making, including increased pursuit of high cost/ high reward options, is a transdiagnostic symptom of multiple psychiatric and neurological disorders including depression, post-traumatic stress disorder, addiction and many others. Stress exposure can induce these disorders and lead to long-term alterations in decision-making. Here, we will explore interactions between neural circuits and endocrine mechanisms that contribute to the pursuit of high cost/high reward options in mouse models of chronic stress exposure. Our previous work showed that the striosomal patches of the dorsomedial striatum are essential for integration of cost and benefit and that dysregulated activity in striosomal inputs contributes to persistent pursuit of high cost-high reward options in previously stressed rodents. Our previous work also showed that ghrelin receptor activity contributes to processing of reward and cost, and that the ghrelin receptor is present within the striatum. Here, we hypothesize that striosomal projection neuron hyperactivity is a key factor in stress-induced cost insensitivity, and activation of ghrelin receptor in the striosomes plays a causal role in this shift in decision- making. Using a naturalistic cost-benefit decision-making task that does not require food deprivation as motivation, we will examine decisions to pursue high costs paired with rewards and lower costs paired with rewards. We will record from striosomal projection neurons within and following different types of chronic stressor exposures to identify the “tipping point” at which abnormal striosomal activity and altered decision-making first emerge. We will use optogenetics to manipulate activity patterns in stress-exposed mice to “correct” stress- induced changes in decision-making and to “mimic” stress-induced striosomal firing patterns in unstressed mice to induce cost insensitivity. We will pharmacologically activate ghrelin receptors and determine whether this is sufficient to induce cost insensitivity and striosomal hyperactivity in unstressed mice. We will perform virus- mediated knockdown of the ghrelin receptor in striosomes and determine whether this is sufficient to prevent stress-induced changes in decision-making in stress-exposed mice. The goal of our proposed work is to identify a mechanistic basis for the shift in circuit activity and decision-making after repeated exposure to stressors, thereby advancing towards our long-term goals of predicting individuals who are at-risk for altered decision- making, and providing new peripheral and central targets for intervention to restore normal decision-making in the face of trauma and psychiatric illness. Project Number: 1R01MH142540-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Mental Health (NIMH) | Principal Investigator: Ki Goosens (+1 co-PI) | Institution: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI, NEW YORK, NY | Award Amount: $827,879 | Activity Code: R01 | Study Section: Neurobiology of Motivated Behavior Study Section[NMB] View on NIH RePORTER: https://reporter.nih.gov/project-details/11269067