Tuesday, September 16, 2025 9/16/2025

Roles of nuleus accumbens CREB and Kappa function in depression

Award Number: R01MH063266
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/17/2021
PERIOD OF PERFORMANCE END DATE: 07/31/2026

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Roles of nuleus accumbens CREB and Kappa function in depression - SUMMARY This application is for competitive renewal of a grant that over its 20-year course has elucidated the ways in which the function of the transcription factor CREB and kappa-opioid receptor (KOR) systems within the nucleus accumbens (NAc) are changed by experience, including stress exposure, and how alterations in their function affect behavior. We have shown that (a) stress upregulates NAc CREB and KOR signaling, (b) these effects are sufficient to produce characteristic features of mood and anxiety disorders, and (c) disruption of CREB or blockade of KORs produces antidepressant- and anxiolytic-like effects. Recently we have also shown a role for these systems in sleep and biological (diurnal) rhythms, which are dysregulated across many types of psychiatric illness. Our work has provided a basis for clinical trials of KOR antagonists to treat depression, which thus far show great promise. Major goals for Years 21-25 are to further characterize the ways in which NAc CREB and KOR systems regulate complex behavior and responses to different forms of stressors, including a type of immune stress relevant to the COVID-19 pandemic, while prioritizing the use of endpoints in rodents with improved alignment to those used in humans. In Aim 1, we will examine the mechanisms of CREB-mediated depressive behavior using a new version of a cognitive control task (called the Flanker task) that we developed to enable testing rats and humans using virtually identical procedures. Specifically, we will determine how alterations in NAc CREB function in D1- and/or D2-medium spiny neurons (MSNs) affect task performance and event-related potentials (ERPs)—endpoints known to be aberrant in human depression—in male and female rats. In Aim 2, we will determine if a regimen of early immune activation (EIA) that produces long-lasting depressive-like effects in mice causes persistent alterations in NAc CREB and KOR systems. Specifically, we will use single-nucleus RNA sequencing to comprehensively examine EIA-induced alterations in NAc cell populations, including MSNs and microglia, and compare and contrast effects in males and females. While upregulation of NAc CREB and KOR systems is commonly associated with depressive phenotypes, in Aims 3-4 we will examine possible roles in stress resilience. For Aim 3, we will examine how KORs expressed on microglia, which regulate immune function, affect sensitivity to stress. Specifically, we will examine how ablation of KORs from microglia affects the ability of chronic stress to disrupt sleep and diurnal rhythms of activity and body temperature. Similarly, in Aim 4 we will characterize the effects of altering the function of the CREB target DFosB in D1- or D2-MSNs on stress-induced disruption of sleep and diurnal rhythms, while in parallel examining effects on CREB, DYN, and KOR expression in NAc MSNs and microglia. All of these studies involve endpoints (behavioral, molecular) that can also be studied in humans or human tissues. This work will improve our understanding of the mechanisms by which NAc CREB and KOR function affect domains that are frequently dysregulated in mood and anxiety disorders, and may enable new ways to diagnose and treat these conditions.


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 = $569,913 )
2025	2025	THE MCLEAN HOSPITAL CORPORATION	115 MILL ST	BELMONT	MA	02478	MIDDLESEX	USA	Mental Health Research Grants	000	25	7/15/2025	NON-COMPETING CONTINUATION	$569,913
														Subtotal = $569,913

Issue Date FY: 2024 ( Subtotal = $569,913 )
2024	2024	THE MCLEAN HOSPITAL CORPORATION	115 MILL ST	BELMONT	MA	02478	MIDDLESEX	USA	Mental Health Research Grants	000	24	8/13/2024	NON-COMPETING CONTINUATION	$569,913
														Subtotal = $569,913

Issue Date FY: 2023 ( Subtotal = $512,923 )
2023	2023	MCLEAN HOSPITAL CORPORATION, THE	115 MILL ST	BELMONT	MA	02478	MIDDLESEX	USA	Mental Health Research Grants	000	23	7/25/2023	NON-COMPETING CONTINUATION	$512,923
														Subtotal = $512,923

Issue Date FY: 2022 ( Subtotal = $541,416 )
2022	2022	MCLEAN HOSPITAL CORPORATION, THE	115 MILL ST	BELMONT	MA	02478	MIDDLESEX	USA	Mental Health Research Grants	002	22	8/19/2022	NON-COMPETING CONTINUATION	$541,416
2022	2021	MCLEAN HOSPITAL CORPORATION, THE	115 MILL ST	BELMONT	MA	02478	MIDDLESEX	USA	Mental Health Research Grants	001	21	5/25/2022	COMPETING CONTINUATION	$28,910
2022	2020	MCLEAN HOSPITAL CORPORATION, THE	115 MILL ST	BELMONT	MA	02478	MIDDLESEX	USA	Mental Health Research Grants	000	20	5/25/2022	NON-COMPETING CONTINUATION	-$28,910
														Subtotal = $541,416

Issue Date FY: 2021 ( Subtotal = $569,913 )
2021	2021	MCLEAN HOSPITAL CORPORATION, THE	115 MILL ST	BELMONT	MA	02478	MIDDLESEX	USA	Mental Health Research Grants	001	21	9/17/2021	COMPETING CONTINUATION	$569,913
2021	2020	MCLEAN HOSPITAL CORPORATION, THE	115 MILL ST	BELMONT	MA	02478	MIDDLESEX	USA	Mental Health Research Grants	000	20	9/16/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $569,913

Issue Date FY: 2020 ( Subtotal = $405,000 )
2020	2020	MCLEAN HOSPITAL CORPORATION, THE	115 MILL ST	BELMONT	MA	02478	MIDDLESEX	USA	Mental Health Research Grants	000	20	3/23/2020	NON-COMPETING CONTINUATION	$405,000
														Subtotal = $405,000

Issue Date FY: 2019 ( Subtotal = $405,000 )
2019	2019	MCLEAN HOSPITAL CORPORATION, THE	115 MILL ST	BELMONT	MA	02478	MIDDLESEX	USA	Mental Health Research Grants	000	19	3/21/2019	NON-COMPETING CONTINUATION	$405,000
														Subtotal = $405,000

Issue Date FY: 2018 ( Subtotal = $405,000 )
2018	2018	MCLEAN HOSPITAL CORPORATION, THE	115 MILL ST	BELMONT	MA	02478	MIDDLESEX	USA	Mental Health Research Grants	000	18	4/19/2018	NON-COMPETING CONTINUATION	$405,000
														Subtotal = $405,000

Issue Date FY: 2017 ( Subtotal = $405,000 )
2017	2017	MCLEAN HOSPITAL CORPORATION, THE	115 MILL ST	BELMONT	MA	02478	MIDDLESEX	USA	Mental Health Research Grants	000	17	3/16/2017	NON-COMPETING CONTINUATION	$364,500
2017	2017	MCLEAN HOSPITAL CORPORATION, THE	115 MILL ST	BELMONT	MA	02478	MIDDLESEX	USA	Mental Health Research Grants	001	17	7/25/2017	NON-COMPETING CONTINUATION	$40,500
														Subtotal = $405,000

Issue Date FY: 2016 ( Subtotal = $405,000 )
2016	2016	MCLEAN HOSPITAL	115 MILL STREET	BELMONT	MA	02478	MIDDLESEX	USA	Mental Health Research Grants	000	16	4/21/2016	COMPETING CONTINUATION	$405,000
														Subtotal = $405,000

Issue Date FY: 2015 ( Subtotal = $478,658 )
2015	2015	MCLEAN HOSPITAL	115 MILL STREET	BELMONT	MA	02478	MIDDLESEX	USA	Mental Health Research Grants	000	15	3/13/2015	NON-COMPETING CONTINUATION	$478,658
														Subtotal = $478,658

Issue Date FY: 2014 ( Subtotal = $478,523 )
2014	2014	MCLEAN HOSPITAL	115 MILL STREET	BELMONT	MA	02478	MIDDLESEX	USA	Mental Health Research Grants	000	14	3/7/2014	NON-COMPETING CONTINUATION	$360,023
2014	2014	MCLEAN HOSPITAL	115 MILL STREET	BELMONT	MA	02478	MIDDLESEX	USA	Mental Health Research Grants	001	14	3/12/2014	SUPPLEMENT FOR EXPANSION	$118,500
														Subtotal = $478,523

Issue Date FY: 2013 ( Subtotal = $345,496 )
2013	2013	MCLEAN HOSPITAL	115 MILL STREET	BELMONT	MA	02478	MIDDLESEX	USA	Mental Health Research Grants	001	13	6/4/2013	NON-COMPETING CONTINUATION	$21,594
2013	2013	MCLEAN HOSPITAL	115 MILL STREET	BELMONT	MA	02478	MIDDLESEX	USA	Mental Health Research Grants	000	13	4/12/2013	NON-COMPETING CONTINUATION	$323,902
														Subtotal = $345,496

Issue Date FY: 2012 ( Subtotal = $359,763 )
2012	2012	MCLEAN HOSPITAL	115 MILL STREET	BELMONT	MA	02478	MIDDLESEX	USA	Mental Health Research Grants	000	12	3/22/2012	NON-COMPETING CONTINUATION	$359,763
														Subtotal = $359,763

Issue Date FY: 2011 ( Subtotal = $359,638 )
2011	2011	MCLEAN HOSPITAL	115 MILL STREET	BELMONT	MA	02478	MIDDLESEX	USA	Mental Health Research Grants	001	11	6/17/2011	COMPETING CONTINUATION	$359,638
2011	2010	MCLEAN HOSPITAL	115 MILL STREET	BELMONT	MA	02178		USA	Mental Health Research Grants	000	10	6/14/2011	NON-COMPETING CONTINUATION	$0
														Subtotal = $359,638

Issue Date FY: 2010 ( Subtotal = $246,222 )
2010	2010	MCLEAN HOSPITAL	115 MILL STREET	BELMONT	MA	02478	MIDDLESEX	USA	Mental Health Research Grants	000	10	7/16/2010	NON-COMPETING CONTINUATION	$246,222
														Subtotal = $246,222

Issue Date FY: 2009 ( Subtotal = $246,222 )
2009	2009	MCLEAN HOSPITAL	115 MILL STREET	BELMONT	MA	02478	MIDDLESEX	USA	Mental Health Research Grants	000	9	7/23/2009	NON-COMPETING CONTINUATION	$246,222
														Subtotal = $246,222

Issue Date FY: 2008 ( Subtotal = $246,222 )
2008	2008	MCLEAN HOSPITAL	115 MILL STREET	BELMONT	MA	02178		USA	Mental Health Research Grants	000	8	7/14/2008	NON-COMPETING CONTINUATION	$246,222
														Subtotal = $246,222

Issue Date FY: 2007 ( Subtotal = $246,222 )
2007	2007	MCLEAN HOSPITAL	115 MILL STREET	BELMONT	MA	02178		USA	Mental Health Research Grants	000	7	7/24/2007	NON-COMPETING CONTINUATION	$246,222
														Subtotal = $246,222

Issue Date FY: 2006 ( Subtotal = $276,075 )
2006	2006	MCLEAN HOSPITAL	115 MILL STREET	BELMONT	MA	02178		USA	Mental Health Research Grants	000	6	9/6/2006	COMPETING CONTINUATION	$276,075
														Subtotal = $276,075

Issue Date FY: 2005 ( Subtotal = $197,500 )
2005	2005	MCLEAN HOSPITAL	115 MILL STREET	BELMONT	MA	02178		USA	Mental Health Research Grants	000	5	7/29/2005	NON-COMPETING CONTINUATION	$197,500
														Subtotal = $197,500

Issue Date FY: 2004 ( Subtotal = $197,500 ) (Continued on the next page)
Grand Total All Awards = $9,084,619

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Roles of nuleus accumbens CREB and Kappa function in depression

Award Number: R01MH063266

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/17/2021

PERIOD OF PERFORMANCE END DATE: 07/31/2026

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