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Hippocampal-thalamo-prefrontal circuitry damage and therapeutic intervention in a model of FASD

Award Number: R01AA027269
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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ABSTRACT Fetal alcohol spectrum disorders (FASD) are estimated to affect 3-5% of the US population (1). Prenatal alcohol exposure (AE) leads to significant perturbations of brain circuitry and persisting cognitive deficits (2, 3) that include abnormalities in executive functioning (EF) and working memory (4, 5). These abnormalities stem from orchestrated structural changes in several key brain regions including the prefrontal cortex (PFC) and hippocampus (HPC). While HPC and PFC have long been implicated in effective cognitive functioning, the role of the thalamic nucleus reuniens (Re), that controls information flow between these structures, has only recently been appreciated. The Re serves as a functional bridge between PFC and the HPC which are crucial for EF (6-9). Our preliminary data using a rat model of binge AE during the third trimester revealed persistent structural damage of Re, highly correlated to behavioral deficits consistent with fronto-hippocampal damage. The proposed research will test the hypothesis that binge AE during the third trimester produces neuronal loss as well as dendritic and synaptic reorganization in the Re and mPFC, which ultimately produces dysfunctional connectivity among mPFC-Re-HPC circuitry that is associated with EF deficits. In addition, we will evaluate if mPFC-Re-HPC dysfunction is mitigated via a therapeutic strategy, wheel-running (WR) followed by environmental complexity (EC), which has been successful in alleviating the deleterious AE effects on other behaviors disrupted in FASD(10-14) .Using our combined expertise in experience- dependent brain plasticity, developmental alcohol exposure and in vivo electrophysiology in freely moving rats during memory tasks, we aim to reveal AE vulnerability of the PFC-Re-HPC circuit and determine the cellular components and factors involved in plasticity of this circuit. integrity of the Re and PFC in a binge third trimester Aim 1 will establish the contributions of alcohol dose on structural AE rat model. Aim 2 working spatial memory deficits. Connectivity-behavior relationships will be will test the hypothesis that AE induces determined within the same animals via virus labeling to test the hypothesis that AE disrupts the structural connectivity between the Re, HPC and PFC. In addition, we will test the prediction that behavioral intervention (WR/EC) reduces AE-related deficits in behaviors that are dependent on the integrity of the PFC-Re-HPC circuit by enhancing neuroplasticity. We will assess whether neuroplasticity is critically dependent on increased expression of neurotrophic factors in the structural components of the circuitry. Finally, Aim 3 will determine whether AE-induced Re damage leads to reduced oscillatory synchrony between the dorsal HPC and PFC during a spatial working memory task and if WR/EC can reinstate mPFC-HPC synchrony. and in vivo Significance and Innovation : The proposed research is innovative. It will use viral neural circuit mapping multisite recording to fill a critical gap in our understanding of the mechanisms through which AE alters mPFC-Re-HPC circuitry and thus leads to cognitive impairment. Furthermore, because EF deficits are observed in children with FASD, these aims will elucidate the crucial role of mPFC-Re-HPC circuitry in the constellation of FASD deficits; thus this network may be a critical therapeutic target in FASD treatment.


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: 2023 ( Subtotal = $380,172 )
2023	2023	UNIVERSITY OF DELAWARE	220 HULLIHEN HALL	NEWARK	DE	19716	NEW CASTLE	USA	Alcohol Research Programs	000	5	8/25/2023	NON-COMPETING CONTINUATION	$380,172
														Subtotal = $380,172

Issue Date FY: 2022 ( Subtotal = $397,545 )
2022	2022	UNIVERSITY OF DELAWARE	220 HULLIHEN HALL	NEWARK	DE	19716	NEW CASTLE	USA	Alcohol Research Programs	000	4	8/19/2022	NON-COMPETING CONTINUATION	$397,545
														Subtotal = $397,545

Issue Date FY: 2021 ( Subtotal = $392,249 )
2021	2021	UNIVERSITY OF DELAWARE	220 HULLIHEN HALL	NEWARK	DE	19716	NEW CASTLE	USA	Alcohol Research Programs	000	3	8/16/2021	NON-COMPETING CONTINUATION	$392,249
														Subtotal = $392,249

Issue Date FY: 2020 ( Subtotal = $432,920 )
2020	2020	UNIVERSITY OF DELAWARE	220 HULLIHEN HALL	NEWARK	DE	19716	NEW CASTLE	USA	Alcohol Research Programs	000	2	8/26/2020	NON-COMPETING CONTINUATION	$432,920
														Subtotal = $432,920

Issue Date FY: 2019 ( Subtotal = $385,928 )
2019	2019	UNIVERSITY OF DELAWARE	220 HULLIHEN HALL	NEWARK	DE	19716	NEW CASTLE	USA	Alcohol Research Programs	000	1	8/27/2019	NEW	$385,928
														Subtotal = $385,928

Grand Total All Awards = $1,988,814

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Hippocampal-thalamo-prefrontal circuitry damage and therapeutic intervention in a model of FASD

Award Number: R01AA027269

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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