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Insula-Striatal Circuit Mechanisms Underlying Stress Effects on Reward Processing

Award Number: K99MH146231
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/03/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Insula-Striatal Circuit Mechanisms Underlying Stress Effects on Reward Processing - Project Summary Depression is the leading cause of disability worldwide and can be triggered by chronic stress in vulnerable individuals. One debilitating symptom of chronic stress-related disorders is anhedonia, which encompasses a lack of pleasure in previously pursued activities and reduced motivation to pursue goals. The neurobiological mechanisms underlying the effects of chronic stress on motivation remain poorly understood. A growing body of evidence implicates the anterior insular cortex (aIC), a key hub in the salience network, in reward processing and anhedonia. The aIC integrates sensory, cognitive, and limbic information to create representations of internal states, and is one of the most commonly identified brain regions in human imaging studies of stress-related psychiatric disorders. Despite its importance, the cellular and circuit-level mechanisms through which chronic stress alters aIC function remain unknown. A promising candidate is the pathway from the aIC to the dorsal striatum, which may link the aIC’s representations of emotional state to the dorsal striatum’s role in action. Preliminary evidence suggests that this pathway is particularly vulnerable to chronic stress. The goal of this research project is to define the role of the aIC-striatal circuit in reward-related behavior and determine the effects of chronic stress on its activity, function, and molecular makeup. Our central hypothesis is that the aIC-striatal pathway encodes and enhances motivation, and that chronic stress disrupts its activity, structure, and gene expression profile. We additionally hypothesize that circuit- and molecular-level interventions in this pathway can rescue motivational deficits in stressed mice. To test these hypotheses, we will first use 2-photon calcium imaging to record single-cell activity of the aIC-striatal subpopulation during motivated behavior and test its function in motivation using optogenetics (Aim 1). Then, we will compare imaging results and dendritic spine morphology before and after chronic stress and test the ability of optogenetic stimulation to rescue motivational deficits in stressed mice (Aim 2). Finally, we will purify aIC-striatal nuclei for RNA sequencing after stress to identify affected gene programs and attempt to rescue motivational deficits by manipulating gene expression in the pathway (Aim 3). Training in 2-photon imaging, optogenetics, and motivated behavior will be provided by the primary mentor Dr. Liston and consultant Dr. Stuber. Drs. Liston and Fusi will supervise academic instruction in linear algebra and machine learning to facilitate high-level neural population activity analysis, and Drs. Tilgner and Macosko will provide instruction in RNA sequencing. Mentors and consultants will guarantee a seamless transition to research independence by assessing progress regularly and promoting professional development seminars, conference presentations, and timely publication of results. This work, using a powerful combination of circuit- and molecular-level tools, will enhance our knowledge of the aIC’s susceptibility to chronic stress, and provide the foundation for a successful career investigating the neurobiological basis of depression.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $125,280 )
2026	2026	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Mental Health Research Grants	000	1	9/4/2026	NEW	$125,280
														Subtotal = $125,280

Grand Total All Awards = $125,280

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Insula-Striatal Circuit Mechanisms Underlying Stress Effects on Reward Processing

Award Number: K99MH146231

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/03/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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