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The function of GABA/glutamate co-release in the habenula

Award Number: R01MH132797
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 11/15/2023
PERIOD OF PERFORMANCE END DATE: 10/31/2028

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The function of GABA/glutamate co-release in the habenula - ABSTRACT: Balance of excitation and inhibition is critical for proper function of the nervous system. In many brain regions, there is feedforward and feedback inhibition from interneurons that release the inhibitory transmitter GABA to balance the release of excitatory glutamate from long-range inputs. However, in the lateral habenula (LHb) - a key component of the brain's reward system – there is little, if any, feedforward or feedback inhibition and few inhibitory neurons. Instead, our work suggests that excitatory/inhibitory balance is achieved, at least partly, by co-release of GABA with glutamate from individual inputs arising from the globus pallidus (GPi), a major input to the LHb. The activity of GPi inputs to the LHb and the activity of LHb neurons affect motivational vigor. They are also phasically excited by negative environmental feedback and phasically inhibited by positive environmental feedback, which guide learning. Rats with low motivation and negatively biased feedback sensitivity have elevated LHb activity and unbalanced GABA and glutamate signaling from the GPi to LHb. Based on these observations, we believe that GABA/glutamate balance from GPi to the LHb is important for (1) regulating tonic (basal) LHb activity and motivational vigor, and (2) bidirectional phasic signaling of negative and positive feedback in the LHb and behavioral sensitivity to negative and positive feedback. The objective of this grant is to test these hypotheses by artificially manipulating GABA/glutamate balance from GPi to LHb in mice and measuring (1) tonic LHb activity and motivation, and (2) phasic LHb responses and behavioral sensitivity to negative feedback (reward omission) and positive feedback (reward). Based on studies of GABA/glutamate co- release in the hippocampus, we further hypothesize that long-term changes in tonic and/or phasic LHb activity will induce homeostatic plasticity of GABA/glutamate co-transmission from the GPi to LHb. We believe this study is significant because it will reveal the relationship between excitatory/inhibitory balance and fundamental motivational and learning processes that are affected in many psychiatric disorders, while also investigating the function of GABA/glutamate co-transmission.


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 = $569,154 )
2026	2026	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Mental Health Research Grants	000	3	12/4/2025	NON-COMPETING CONTINUATION	$569,154
														Subtotal = $569,154

Issue Date FY: 2025 ( Subtotal = $565,874 )
2025	2025	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Mental Health Research Grants	000	2	12/6/2024	NON-COMPETING CONTINUATION	$480,993
2025	2025	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Mental Health Research Grants	001	2	9/18/2025	NON-COMPETING CONTINUATION	$84,881
														Subtotal = $565,874

Issue Date FY: 2024 ( Subtotal = $565,874 )
2024	2024	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Mental Health Research Grants	000	1	11/14/2023	NEW	$509,287
2024	2024	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Mental Health Research Grants	001	1	7/10/2024	NEW	$56,587
														Subtotal = $565,874

Grand Total All Awards = $1,700,902

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The function of GABA/glutamate co-release in the habenula

Award Number: R01MH132797

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 11/15/2023

PERIOD OF PERFORMANCE END DATE: 10/31/2028

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