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Endocannabinoid Modulation of the Habenular Stress Response

Award Number: R01MH122844
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2020
PERIOD OF PERFORMANCE END DATE: 10/31/2025

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Endocannabinoid Modulation of the Habenular Stress Response - PROJECT SUMMARY Stress is a pervasive aspect of daily life and a significant risk factor for a host of mental illnesses, including major depression. In the brain, chronic stress causes adaptations in the mesolimbic dopamine system that increase vulnerability for developing depression and depression-related behaviors in clinical populations and preclinical animal models, respectively. One area of the brain that has gained attention as of late is the lateral habenula (LHb), in part because of its ability to tightly constrain dopamine activity. Notably, the LHb is hyperactive in individuals suffering from major depression, while restoring normal activity in this area has emerged as a viable therapeutic strategy in treatment-resistant patients. Although we still do not know how chronic stress leads to LHb dysfunction, one intriguing possibility is through stress-induced alterations in the endogenous cannabinoid (ECB) system. The primary role of the ECB system in the brain is to provide activity- dependent, on-demand negative feedback, which helps to maintain synaptic homeostasis. Our data indicate that chronic stress augments ECB signaling in the LHb, while local activation of this system elicits a passive- despair-like coping strategy, impairs behavioral flexibility in an attentional set-shifting task, and decreases the firing rate of dopamine neurons located in the ventral tegmental area. However, the precise role of the ECB system in the LHb and the mechanisms by which this system modulates stress-related behaviors has yet to be formally evaluated. In the current proposal, we will fill this important gap in knowledge by systematically examining how the ECB system modulates LHb function and identifying whether chronic stress-induced alterations in this system are necessary to produce deficits in dopamine cell firing and the expression of depression-related behaviors. In Aim 1, we will perform site-specific pharmacological manipulations of the ECB system in tandem with in vivo electrophysiology recordings of dopamine cell activity in freely behaving rats to uncover how stress-induced alterations in LHb ECB signaling may contribute to deficits in behavioral flexibility. In Aim 2, we will use ex vivo electrophysiology combined with retrograde labeling of LHb projections to identify the role of the ECB system in modulating excitatory and inhibitory LHb inputs and examine how chronic stress alters ECB control of synaptic strength at projectionally defined LHb synapses. In Aim 3, we will use a combinatorial viral approach to determine effects of acute, circuit-specific activation of LHb neurons on stress coping and behavioral flexibility, and test whether chronic, long-term LHb activation recapitulates the behavioral effects of chronic stress in an ECB-dependent manner. Broadly stated, the proposed research will fill a significant gap in the field by identifying how the ECB system regulates the activity of a key circuit that has been implicated in various domains of mental health, and the neurophysiological and behavioral consequences of stress-induced alterations in this system. Moreover, this work will pave the way for future studies exploring the involvement of this system in brain function and disease.


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: 2025 ( Subtotal = $325,125 )
2025	2025	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Mental Health Research Grants	000	5	11/1/2024	NON-COMPETING CONTINUATION	$325,125
														Subtotal = $325,125

Issue Date FY: 2024 ( Subtotal = $382,500 )
2024	2024	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Mental Health Research Grants	000	4	10/18/2023	NON-COMPETING CONTINUATION	$344,250
2024	2024	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Mental Health Research Grants	001	4	6/27/2024	NON-COMPETING CONTINUATION	$38,250
														Subtotal = $382,500

Issue Date FY: 2023 ( Subtotal = $382,500 )
2023	2023	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Mental Health Research Grants	000	3	12/1/2022	NON-COMPETING CONTINUATION	$344,250
2023	2023	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Mental Health Research Grants	001	3	3/10/2023	NON-COMPETING CONTINUATION	$38,250
														Subtotal = $382,500

Issue Date FY: 2022 ( Subtotal = $382,500 )
2022	2022	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Mental Health Research Grants	000	2	10/29/2021	NON-COMPETING CONTINUATION	$344,250
2022	2022	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Mental Health Research Grants	001	2	6/7/2022	NON-COMPETING CONTINUATION	$38,250
														Subtotal = $382,500

Issue Date FY: 2021 ( Subtotal = $382,500 )
2021	2021	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Mental Health Research Grants	000	1	11/19/2020	NEW	$382,500
														Subtotal = $382,500

Grand Total All Awards = $1,855,125

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Endocannabinoid Modulation of the Habenular Stress Response

Award Number: R01MH122844

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2020

PERIOD OF PERFORMANCE END DATE: 10/31/2025

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