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.
Title Hippocampal-thalamo-prefrontal circuitry damage and therapeutic intervention in a model of FASD Project Narrative Fetal alcohol spectrum disorders (FASD) occur at an alarmingly high rate worldwide with the symptoms that include life-long significant behavioral abnormalities paralleled by brain damage. This project will explore previously undescribed damage to the thalamic nucleus and its role in hippocampal-prefrontal cortex communication following alcohol exposure during the third trimester of human pregnancy. We employ an animal model of alcohol exposure during third trimester to establish the relationship between structure, connectivity, and function of this circuitry and will explore potential therapeutic intervention via exercise and environmental complexity.
