Friday, November 22, 2024 11/22/2024

The role of sex- and cell-type specific protein degradation increases in the amygdala in fear memory formation

Award Number: R01MH122414
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By:

View Award Abstract

Project Summary/Abstract The broad goal of this proposal is to understand how fear memories are formed and stored in the brain. Post- traumatic stress disorder (PTSD) affects nearly 5% of the world population, however, current treatments have limited efficacy in reversing the symptoms of this disorder. Furthermore, females are more likely than males to develop PTSD, though the mechanisms controlling this sex-dependent predisposition remain equivocal. Recently, work from our group and others have implicated protein degradation mediated by the ubiquitin- proteasome system (UPS) in fear memory formation in the amygdala, the primary brain region involved in emotional processing. However, the functional role of protein degradation in fear memory formation has yet to be identified. Furthermore, previous studies on UPS-mediated protein degradation have focused exclusively on males, so little is known about whether similar UPS mechanisms control the formation of fear memories in females. In our preliminary studies, we found that in males protein degradation was localized to the nucleus of amygdala cells following fear learning, suggesting a potential role in transcriptional control, though this has never been directed tested. Surprisingly, females did not show any changes in UPS-mediated protein degradation in the amygdala following fear learning though did have elevated baseline ubiquitin-proteasome activity in comparison with males, which was associated with increased DNA 5-hydroxymethylation (5-hmc) of Uba52, one of the ubiquitin coding genes. This suggests that elevated baseline UPS activity in females could be regulated by altered DNA methylation of Uba52 and may be sufficient for them to acquire fear memories. The work in this proposal is designed to answer these important questions about sex-dependent differences in the role of nuclear protein degradation in transcriptional control during fear memory formation. Using a combination of pharmacology and sophisticated CRISPR-dCas9 manipulations of proteasome activity in combination with mass spectrometry and whole genome next generation RNA-seq technology, Aim 1 will test whether nuclear protein degradation is involved in transcriptional control during fear memory formation and whether this varies between males and females. Aim 2 will use cutting-edge CRISPR-dCas9 technology to control the methylation state of Uba52 and will test how this effects baseline differences in ubiquitin- proteasome activity in the amygdala of males and females. Finally, in Aim 3 we will using CRISPR-dCas9 technology to test whether increased baseline protein degradation in the amygdala of females primes them to acquire fear memories. Collectively, this study will answer important questions about sex-dependent differences in the role of protein degradation in fear memory formation. The results obtained from this project could have important implications for understanding the etiology of sex-related differences in fear memory formation and lead to the development of novel therapeutic strategies to treat major psychiatric disorders.


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: 2024 ( Subtotal = $494,308 )
2024	2024	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Mental Health Research Grants	000	4	10/26/2023	NON-COMPETING CONTINUATION	$347,527
2024	2024	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Mental Health Research Grants	002	4	12/4/2023	SUPPLEMENT FOR EXPANSION	$79,633
2024	2024	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Mental Health Research Grants	003	4	6/26/2024	NON-COMPETING CONTINUATION	$38,615
2024	2024	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Mental Health Research Grants	001	4	11/7/2023	SUPPLEMENT FOR EXPANSION	$28,533
														Subtotal = $494,308

Issue Date FY: 2023 ( Subtotal = $488,245 )
2023	2023	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Mental Health Research Grants	002	3	11/10/2022	SUPPLEMENT FOR EXPANSION	$70,793
2023	2023	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Mental Health Research Grants	003	3	1/20/2023	NON-COMPETING CONTINUATION	$38,651
2023	2023	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Mental Health Research Grants	000	3	11/8/2022	NON-COMPETING CONTINUATION	$347,854
2023	2023	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Mental Health Research Grants	001	3	11/9/2022	SUPPLEMENT FOR EXPANSION	$30,947
														Subtotal = $488,245

Issue Date FY: 2022 ( Subtotal = $497,494 )
2022	2022	VIRGINIA POLYTECHNIC INSTITUTE AND STATE UNIVERSITY	300 TURNER ST NW STE 4200	BLACKSBURG	VA	24061	MONTGOMERY	USA	Mental Health Research Grants	006	2	6/8/2022	NON-COMPETING CONTINUATION	$38,736
2022	2022	VIRGINIA POLYTECHNIC INSTITUTE AND STATE UNIVERSITY	300 TURNER ST NW STE 4200	BLACKSBURG	VA	24061	MONTGOMERY	USA	Mental Health Research Grants	001	2	10/27/2021	SUPPLEMENT FOR EXPANSION	$67,886
2022	2022	VIRGINIA POLYTECHNIC INSTITUTE AND STATE UNIVERSITY	300 TURNER ST NW STE 4200	BLACKSBURG	VA	24061	MONTGOMERY	USA	Mental Health Research Grants	005	2	5/23/2022	SUPPLEMENT FOR EXPANSION	$0
2022	2022	VIRGINIA POLYTECHNIC INSTITUTE AND STATE UNIVERSITY	300 TURNER ST NW STE 4200	BLACKSBURG	VA	24061	MONTGOMERY	USA	Mental Health Research Grants	002	2	11/19/2021	NON-COMPETING CONTINUATION	$0
2022	2022	VIRGINIA POLYTECHNIC INSTITUTE AND STATE UNIVERSITY	300 TURNER ST NW STE 4200	BLACKSBURG	VA	24061	MONTGOMERY	USA	Mental Health Research Grants	000	2	10/26/2021	NON-COMPETING CONTINUATION	$348,612
2022	2022	VIRGINIA POLYTECHNIC INSTITUTE AND STATE UNIVERSITY	300 TURNER ST NW STE 4200	BLACKSBURG	VA	24061	MONTGOMERY	USA	Mental Health Research Grants	004	2	5/12/2022	SUPPLEMENT FOR EXPANSION	$0
2022	2022	VIRGINIA POLYTECHNIC INSTITUTE AND STATE UNIVERSITY	300 TURNER ST NW STE 4200	BLACKSBURG	VA	24061	MONTGOMERY	USA	Mental Health Research Grants	003	2	5/11/2022	SUPPLEMENT FOR EXPANSION	$42,260
														Subtotal = $497,494

Issue Date FY: 2021 ( Subtotal = $453,649 )
2021	2021	VIRGINIA POLYTECHNIC INSTITUTE AND STATE UNIVERSITY	300 TURNER ST NW STE 4200	BLACKSBURG	VA	24061	MONTGOMERY	USA	Mental Health Research Grants	000	1	11/10/2020	NEW	$416,710
2021	2021	VIRGINIA POLYTECHNIC INSTITUTE AND STATE UNIVERSITY	300 TURNER ST NW STE 4200	BLACKSBURG	VA	24061	MONTGOMERY	USA	Mental Health Research Grants	001	1	6/25/2021	SUPPLEMENT FOR EXPANSION	$36,939
														Subtotal = $453,649

Grand Total All Awards = $1,933,696

Top

All Categories

About

Search

Reports

Data Submission

Award Information

The role of sex- and cell-type specific protein degradation increases in the amygdala in fear memory formation

Award Number: R01MH122414

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer