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Molecular and functional dissection of prefrontal-hippocampal long-range inhibition

Award Number: R01MH139197
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/10/2026
PERIOD OF PERFORMANCE END DATE: 12/31/2030

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Molecular and functional dissection of prefrontal-hippocampal long-range inhibition - PROJECT SUMMARY Top-down signals from the prefrontal cortex have long been postulated to regulate hippocampal function as part of numerous cognitive and emotional processes, but the specific pathways mediating top-down control have been unclear. We have found a novel long-range GABAergic pathway from prefrontal cortex to hippocampus that represents a potential substrate for top-down control. Notably, this pathway seems to operate in an unusual manner: by inhibiting disinhibitory circuits. Our initial studies found that these prefrontal- hippocampal GABAergic projections can promote object exploration by enhancing hippocampal representations of object locations and associated network oscillations. However, two major questions remain unresolved. First, prefrontal GABAergic neurons which project to the hippocampus are heterogeneous and the significance of this is unknown. Second, the detailed circuit mechanisms through which long-range GABAergic projections from prefrontal cortex alter hippocampal information processing remain unclear. The goal of this project is to first and foremost, elucidate mechanisms through which long-range prefrontal-hippocampal projections shape computation in downstream circuits, and second, relate these to the heterogeneity of long- range GABAergic neurons. This project will specifically test our hypothesis that long-range GABAergic projections exert top-down control over the hippocampus by targeting disinhibitory microcircuits, thereby regulating how competing input regions recruit and entrain feedforward inhibition in the hippocampus. This could explain how hippocampal circuits switch between different information processing modes, each characterized by rhythmic synchronization with a different upstream region. Furthermore, we may identify different subtypes of long-range GABAergic neurons that each promote synchrony with a unique input region, elucidating organizational principles and functional implications for the heterogeneity of long-range GABAergic neurons.


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 = $800,384 )
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	3/10/2026	NEW	$800,384
														Subtotal = $800,384

Grand Total All Awards = $800,384

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Molecular and functional dissection of prefrontal-hippocampal long-range inhibition

Award Number: R01MH139197

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 03/10/2026

PERIOD OF PERFORMANCE END DATE: 12/31/2030

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