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Network mechanisms of impaired adult hippocampal neurogenesis in a mouse model of prenatal alcohol exposure

Award Number: R01AA027462
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY/ABSTRACT The overall goal of this proposal is to establish the relevance of adult hippocampal neurogenesis as a potential therapeutic target for fetal alcohol spectrum disorder (FASD), utilizing a well-characterized mouse model of prenatal alcohol exposure (PAE). The significance for adult hippocampal neurogenesis as a potential therapeutic target in fetal alcohol spectrum disorder (FASD) is based on preclinical rodent models that demonstrate long- lasting deficits in neurogenesis following developmental alcohol exposure, the critical role of neurogenesis in many hippocampal-dependent behaviors that are also disrupted in clinical FASD, and recent evidence that neurogenesis continues throughout life in the human hippocampus. Using voluntary drinking paradigms to model PAE in mice, our laboratory previously demonstrated marked impairment of the neurogenic response to enriched environment (EE) that is associated with disruption of neurochemical, morphological and electrophysiological indices of EE-mediated network activity. Experiments outlined in this proposal are designed to test the overall hypothesis that impaired EE-mediated neurogenesis is relevant for deficits in behavior and hippocampal network mechanisms in PAE, and can be restored using genetic and/or pharmacological therapeutic approaches. This hypothesis will be tested by addressing the following specific aims. Specific Aim 1: To determine whether impaired EE-mediated neurogenesis is directly correlated with impaired pattern discrimination learning in PAE mice. We will utilize two complex neurogenesis-dependent cognitive tasks in which pattern discrimination/separation is tested in both contextual and spatial domains. Behavioral performance will be correlated with impaired neurogenesis in PAE-EE mice, and with immediate early gene expression as a readout of network activation. Specific Aim 2: To determine whether impaired EE-mediated neurogenesis in PAE mice leads to compensatory remodeling of afferent synaptic input to aDGCs. We will utilize neuroanatomical approaches including rabies-based retrograde tracing to determine whether dendritic complexity and/or the distribution of monosynaptic afferent inputs to aDGCs are selectively altered in PAE-EE mice. Specific Aim 3: To determine whether sensitivity to EE-mediated neurogenesis in PAE mice is restored by genetic and/or pharmacological intervention. We will utilize a genetic gain-of-function approach to augment the survival of aDGCs in an attempt to restore EE-mediated neurogenesis in PAE mice. In addition, we will test whether the neurogenic antidepressant, fluoxetine (FLX), restores EE-mediated neurogenesis and behavior in PAE. If so, causal relationships between neurogenesis and FLX-mediated behavioral improvement will be tested by selective, genetic silencing of aDGCs.


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 = $340,875 )
2024	2024	UNIVERSITY OF NEW MEXICO	1 UNIVERSITY OF NEW MEXICO	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Alcohol Research Programs	000	5	7/19/2024	NON-COMPETING CONTINUATION	$340,875
														Subtotal = $340,875

Issue Date FY: 2023 ( Subtotal = $340,875 )
2023	2023	UNIVERSITY OF NEW MEXICO	1 UNIVERSITY OF NEW MEXICO	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Alcohol Research Programs	000	4	7/25/2023	NON-COMPETING CONTINUATION	$340,875
														Subtotal = $340,875

Issue Date FY: 2022 ( Subtotal = $340,875 )
2022	2022	UNIVERSITY OF NEW MEXICO	2500 MARBLE DR NE	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Alcohol Research Programs	000	3	7/25/2022	NON-COMPETING CONTINUATION	$340,875
														Subtotal = $340,875

Issue Date FY: 2021 ( Subtotal = $340,875 )
2021	2021	UNIVERSITY OF NEW MEXICO	2500 MARBLE DR NE	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Alcohol Research Programs	000	2	7/21/2021	NON-COMPETING CONTINUATION	$340,875
														Subtotal = $340,875

Issue Date FY: 2020 ( Subtotal = $340,875 )
2020	2020	UNIVERSITY OF NEW MEXICO	2500 MARBLE DR NE	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Alcohol Research Programs	000	1	8/5/2020	NEW	$340,875
														Subtotal = $340,875

Grand Total All Awards = $1,704,375

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Network mechanisms of impaired adult hippocampal neurogenesis in a mouse model of prenatal alcohol exposure

Award Number: R01AA027462

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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