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Role of Cyclic Nucleotide Signaling in Age-related Decline of Social Memories

Award Number: R01AG061200
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/15/2019
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Role of Cyclic Nucleotide Signaling in Age-related Decline of Social Memories - PROJECT SUMMARY: Compartmentalization of Cyclic Nucleotide Signaling in the Ventral Hippocampus After the age of 60, nearly all individuals experience some form of cognitive decline—particularly memory deficits—and no drugs are able to prevent or reverse this loss. Age-related cognitive impairment, even in absence of dementia, increases health care costs and risk for disability. Cognitive decline is not a uniform process, with variability in symptom severity observed across individuals and across cognitive domains. Associative long-term memories (aLTMs)—particularly those involving experiences with family and friends— are more susceptible to age-related cognitive decline than are recognition long-term memories (rLTMs) for reasons that are not well understood. The lack of knowledge of the molecular mechanisms that govern age- related decline slows the development of novel therapeutics. Phosphodiesterase 11A (PDE11A) is an enzyme that breaks down cAMP and cGMP, and PDE11A may be an important molecular mechanism for regulating social aLTMs. PDE11A is almost exclusively expressed in a small area of the brain called the ventral hippocampus, which is a brain region that is required for the proper storage of social aLTMs. We have shown that hippocampal PDE11A4 expression dramatically increases across the lifespan in mice, rats, and humans. This raises the question of whether this age-related increase reflects a breakdown in physiological control of the hippocampus or an attempt of the brain to protect itself. In preliminary studies, we have shown that mice that lack or express very little PDE11A are completely protected against age-related cognitive decline of social aLTMs. Based on these and other preliminary studies, we hypothesize that age-related increases in hippocampal PDE11A4 occur in a subcellular compartment-specific manner and impair social aLTM. Across the 3 aims, we take an integrative experimental approach by coupling in vivo genetic manipulations with in vivo behavioral tests as well as ex vivo molecular and biochemical endpoints. In Specific Aim 1, we will determine if preventing or reversing age- related increases in PDE11A4 can rescue age-related impairments in social aLTMs. In Specific Aim 2, we will identify the circuit, cell type, and subcellular compartment where age-related increases in PDE11A4 expression occur and identify the posttranslational modifications that drive these compartment-specific effects. In Specific Aim 3, we will define the signals that drive age-related increases in PDE11A4 expression. These innovative studies will provide much needed insight into the fundamental mechanisms of social memory as well as the function and regulation of PDE11A in the brain. Targeting PDE11A may be a way to selectively restore cyclic nucleotide signaling in a specific brain region that regulates social memories, without affecting signaling elsewhere. This may relieve social deficits without causing unwanted side effects.


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 = $0 )
2025	2023	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Aging Research	000	6	11/25/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $475,146 )
2023	2023	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Aging Research	000	6	1/6/2023	NON-COMPETING CONTINUATION	$475,146
														Subtotal = $475,146

Issue Date FY: 2022 ( Subtotal = $1,122,881 )
2022	2022	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Aging Research	004	5	9/2/2022	SUPPLEMENT FOR EXPANSION	$234,094
2022	2022	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Aging Research	003	5	6/14/2022	SUPPLEMENT FOR EXPANSION	$0
2022	2022	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Aging Research	000	5	12/15/2021	NON-COMPETING CONTINUATION	$452,354
2022	2022	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Aging Research	001	5	4/21/2022	NON-COMPETING CONTINUATION	$50,262
2022	2022	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Aging Research	002	5	5/23/2022	SUPPLEMENT FOR EXPANSION	$386,171
														Subtotal = $1,122,881

Issue Date FY: 2021 ( Subtotal = $482,303 )
2021	2021	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST # 414	COLUMBIA	SC	29208	RICHLAND	USA	Aging Research	001	3	5/28/2021	NON-COMPETING CONTINUATION	-$391,191
2021	2021	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Aging Research	003	4	6/11/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$11,016
2021	2021	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST # 414	COLUMBIA	SC	29208	RICHLAND	USA	Aging Research	000	3	2/23/2021	NON-COMPETING CONTINUATION	$482,303
2021	2021	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Aging Research	006	4	7/13/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$214,457
2021	2021	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST # 414	COLUMBIA	SC	29208	RICHLAND	USA	Aging Research	005	3	7/13/2021	NON-COMPETING CONTINUATION	-$91,112
2021	2021	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Aging Research	002	4	6/10/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$402,207
2021	2020	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST # 414	COLUMBIA	SC	29208	RICHLAND	USA	Aging Research	004	2	7/13/2021	NON-COMPETING CONTINUATION	-$123,345
														Subtotal = $482,303

Issue Date FY: 2020 ( Subtotal = $471,308 )
2020	2020	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST # 414	COLUMBIA	SC	29208	RICHLAND	USA	Aging Research	001	2	1/23/2020	NON-COMPETING CONTINUATION	$47,129
2020	2020	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST # 414	COLUMBIA	SC	29208	RICHLAND	USA	Aging Research	000	2	12/23/2019	NON-COMPETING CONTINUATION	$424,179
														Subtotal = $471,308

Issue Date FY: 2019 ( Subtotal = $511,759 )
2019	2019	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST # 414	COLUMBIA	SC	29208	RICHLAND	USA	Aging Research	002	1	8/10/2019	NEW	$34,895
2019	2019	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST # 414	COLUMBIA	SC	29208	RICHLAND	USA	Aging Research	001	1	3/5/2019	NEW	$33,927
2019	2019	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST # 414	COLUMBIA	SC	29208	RICHLAND	USA	Aging Research	000	1	2/12/2019	NEW	$442,937
														Subtotal = $511,759

Grand Total All Awards = $3,063,397

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Role of Cyclic Nucleotide Signaling in Age-related Decline of Social Memories

Award Number: R01AG061200

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/15/2019

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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