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Defining Orbitofrontal Circuit Function in Health and Depression

Award Number: K99MH146164
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/11/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Defining Orbitofrontal Circuit Function in Health and Depression - PROJECT SUMMARY The orbitofrontal cortex (OFC) is central to approach–avoidance decision-making, integrating reward- and punishment-related information to guide the decision to approach or avoid. Aberrant OFC signaling is implicated in depression, manifesting as reduced motivation toward rewards and heightened sensitivity to punishment. However, the circuit mechanisms by which the OFC drives these computations, and how they are disrupted in depression, remain poorly understood. This proposal develops a mechanistic model of human OFC function in health and depression and leverages this framework to develop a strategy for neuromodulation. Aim 1 employs intracranial recordings from neurosurgical patients performing a gamified approach–avoidance task to develop a normative, anatomically constrained circuit model of OFC activity during approach-avoidance decision-making. Aim 2 applies this framework to patients with treatment-resistant depression, testing how OFC computations become biased toward avoidance in the depressed state. Aim 3 establishes causality between OFC activity and behavior by testing neuromodulation strategies designed to suppress avoidance-related activity and enhance approach- related signaling. This approach will provide a mechanistically informed strategy for restoring balanced decision- making in treatment-resistant depression. The resulting circuit framework will define the logic of OFC computations, delineate their disruption in depression, and pioneer mechanistically grounded neuromodulation strategies. This work advances basic neuroscience while providing a translational roadmap for targeted intervention in refractory psychiatric disorders, directly supporting the NIMH mission to transform the understanding and treatment of mental illness.


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 = $118,641 )
2026	2026	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Mental Health Research Grants	000	1	9/14/2026	NEW	$118,641
														Subtotal = $118,641

Grand Total All Awards = $118,641

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Defining Orbitofrontal Circuit Function in Health and Depression

Award Number: K99MH146164

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/11/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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