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Mechanisms underlying memory regulation by 17beta-estradiol, canonical Wnt signaling, and BDNF in male and female mice

Award Number: R01MH107886
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Memory deficits plague patients with numerous mental disorders, yet a fundamental lack of knowledge about the neural mechanisms regulating memory formation has hampered the development of therapies to reduce this memory dysfunction. The sex steroid hormone 17ß-estradiol (E2) is a potent modulator of hippocampal synaptic plasticity and memory, and likely contributes to sex differences in the prevalence, progression, and severity of many psychiatric and neurodegenerative diseases. However, the neural mechanisms through which E2 regulates memory are poorly understood. Thus, there is an urgent need to identify molecular mechanisms through which E2 regulates learning and memory processes in both sexes. Our long-term goal is to pinpoint the key neural mechanisms through which estrogens regulate hippocampal memory formation in males and females. The overall objective of this application, which is the next step toward attainment of our goal, is to determine the extent to which canonical Wnt signaling and BDNF contribute to the memory enhancing effects of E2. Our central hypothesis is that E2 enhances memory by promoting Wnt signaling, which then epigenetically regulates the transcription and translation of BDNF. These hypotheses were formulated on the basis of published data indicating that Wnt signaling increases BDNF expression6, and our own published data showing that canonical Wnt signaling is necessary for hippocampal memory consolidation in male mice7, histone acetylation is necessary for E2 to enhance hippocampal memory consolidation in female mice8, and that E2 increases hippocampal BDNF protein and H3 acetylation at Bdnf promoters in female mice7. Guided by our strong preliminary data, our hypothesis will be tested in three specific aims designed to: 1) determine the extent to which estrogenic regulation of canonical Wnt signaling facilitates hippocampal memory consolidation, 2) establish the extent to which canonical Wnt signaling and BDNF interact to regulate hippocampal memory consolidation, and 3) identify the molecular mechanisms through which E2 mediates BDNF expression and memory formation. This research is innovative because it utilizes a hypothesis-driven approach that integrates behavioral and biochemical analyses to identify mechanistic relationships among modulatory pathways that regulate hippocampal memory formation in both males and females. The proposed research is significant because it is the first step in a continuum of research designed to provide foundational knowledge about the molecular mechanisms through which E2 regulates memory formation. This work will provide sorely needed insights about estrogenic regulation of memory formation in both sexes that could lead to the generation of novel therapies specifically tailored to reduce memory dysfunction in patients of each sex. Such therapeutic advances would greatly improve the quality of life for millions of patients and their families.


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 = $0 )
2024	2020	UNIVERSITY OF WISCONSIN SYSTEM	3203 N DOWNER AVE # 273	MILWAUKEE	WI	53211	MILWAUKEE	USA	Mental Health Research Grants	000	5	3/4/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	UNIVERSITY OF WISCONSIN SYSTEM	3203 N DOWNER AVE STE 273	MILWAUKEE	WI	53211	MILWAUKEE	USA	Mental Health Research Grants	000	5	6/7/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $373,750 )
2020	2020	UNIVERSITY OF WISCONSIN SYSTEM	3203 N DOWNER AVE STE 273	MILWAUKEE	WI	53211	MILWAUKEE	USA	Mental Health Research Grants	000	5	7/6/2020	NON-COMPETING CONTINUATION	$373,750
														Subtotal = $373,750

Issue Date FY: 2019 ( Subtotal = $373,750 )
2019	2019	UNIVERSITY OF WISCONSIN SYSTEM	3203 N DOWNER AVE STE 273	MILWAUKEE	WI	53211	MILWAUKEE	USA	Mental Health Research Grants	000	4	7/4/2019	NON-COMPETING CONTINUATION	$373,750
														Subtotal = $373,750

Issue Date FY: 2018 ( Subtotal = $373,750 )
2018	2018	UNIVERSITY OF WISCONSIN SYSTEM	3203 N DOWNER AVE STE 273	MILWAUKEE	WI	53211	MILWAUKEE	USA	Mental Health Research Grants	000	3	8/7/2018	NON-COMPETING CONTINUATION	$373,750
														Subtotal = $373,750

Issue Date FY: 2017 ( Subtotal = $373,750 )
2017	2017	UNIVERSITY OF WISCONSIN SYSTEM	3203 N DOWNER AVE STE 273	MILWAUKEE	WI	53211	MILWAUKEE	USA	Mental Health Research Grants	000	2	7/18/2017	NON-COMPETING CONTINUATION	$373,750
														Subtotal = $373,750

Issue Date FY: 2016 ( Subtotal = $373,750 )
2016	2016	UNIVERSITY OF WISCONSIN MILWAUKEE	P.O. BOX 340	MILWAUKEE	WI	53201	MILWAUKEE	USA	Mental Health Research Grants	000	1	9/20/2016	NEW	$373,750
														Subtotal = $373,750

Grand Total All Awards = $1,868,750

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Mechanisms underlying memory regulation by 17beta-estradiol, canonical Wnt signaling, and BDNF in male and female mice

Award Number: R01MH107886

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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