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Understanding the mechanisms by which vCA1 orchestrates avoidance behavior

Award Number: F31MH139309
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 02/27/2025
PERIOD OF PERFORMANCE END DATE: 02/26/2027

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Understanding the mechanisms by which vCA1 orchestrates avoidance behavior - PROJECT SUMMARY The approach-avoid dichotomy is inherent in motivated behavior and animal survival; adaptive behavior requires these conflicting drives be appropriately weighed. In many human anxiety disorders, the approach- avoid calculation becomes maladaptive as individuals preferentially elect avoidance even when it is an inappropriate selection. At 32%, the lifetime prevalence of anxiety disorders is the greatest of any psychiatric illness in the United States, and current treatments are only effective in a subset of individuals—there is an unmet need for therapeutics that effectively ameliorate symptoms of anxiety. It is thought that the neural substrates underlying anxiety are conserved across phylogeny; therefore, understanding how non-human brains navigate approach-avoid conflicts can shed light on the mechanisms human brains use when faced with conflicts that contribute to the human anxiety state. The ventral hippocampus (vHPC) in rodents and the analogous structure in humans, the anterior hippocampus (aHPC), plays a central role in the approach-avoid calculation. Over a decade ago, simple lesion and manipulation experiments identified a functional gradient along the HPC axis; dorsal HPC was linked to spatial learning and memory, and vHPC was deemed a regulator of unconditioned avoidance responses. Since then, the development and use of innovative neuroscience tools has illuminated the extensive role vHPC, and particularly the vCA1 subregion, plays in coordinating a diverse array of approach-avoid behaviors. Still, one of the most well-studied properties of vCA1 is its capacity to represent experiences imbued with motivation to avoid; vCA1 encodes representations of innately anxiogenic environments, drives avoidance of these areas, and is necessary for many forms of fear learning. But the extent to which this circuitry contributes to avoidance behavior is unknown. One question that has been severely underexplored: how does vCA1 orchestrate avoidance of learned cues that predict aversive outcomes? Here, I describe how I will use circuit manipulation tools to determine the causal effect of vCA1 network activity on learned avoidance. I then describe how I will use microendoscopy technology to examine vCA1 network dynamics as animals learn to associate a neutral cue with an aversive outcome, and ultimately learn to avoid the cue. Given that maladaptive avoidance is relevant to the human anxiety state, findings from this research could provide direction for future therapeutic interventions. I will be conducting these experiments in the Kheirbek lab, where all the techniques necessary for my project have been previously setup and validated. The Kheirbek lab is located at the University of California, San Francisco, which is a world-renowned biomedical facility. I am well positioned to successfully complete the described project and graduate from UCSF as an impactful scientist.


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 = $49,538 )
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	2	2/13/2026	NON-COMPETING CONTINUATION	$49,538
														Subtotal = $49,538

Issue Date FY: 2024 ( Subtotal = $48,974 )
2024	2024	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	001	1	8/27/2024	NEW	$0
2024	2024	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	8/27/2024	NEW	$48,974
														Subtotal = $48,974

Grand Total All Awards = $98,512

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Understanding the mechanisms by which vCA1 orchestrates avoidance behavior

Award Number: F31MH139309

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 02/27/2025

PERIOD OF PERFORMANCE END DATE: 02/26/2027

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