Project Summary / Abstract Cognitive function deficits are among the most devastating consequences of fetal alcohol exposure. Currently available treatments against these deficits have limited efficacy. Our long-term goal is to identify specific functional mechanisms underlying the cognitive deficits associated with FASDs, so that circuit-specific treatments can be developed to prevent and correct them. Our objective is to leverage both in vitro and in vivo electrophysiological approaches to determine the long-term impact of third trimester-equivalent ethanol exposure (TTAE) on the limbic memory system. Our central hypothesis is that TTAE disrupts the balance of excitatory and inhibitory synaptic transmission at hippocampal formation→retrosplenial cortex (RSC) and RSC↔anterior thalamic nucleus (ATN) synapses, leading to deficits in information flow within and between these brain regions. Our rationale for the use of complementary in vitro and in vivo electrophysiological approaches is to provide a multi- scale view of the effects of TTAE on functional hippocampal CA1, subiculum (SUB), RSC and ATN connectivity. In Aim 1, we will determine the effects of TTAE on the function of CA1→RSC and SUB→RSC pathways. We will use slice electrophysiology, retrograde labeling, and optogenetics to test the hypothesis that TTAE persistently reduces glutamatergic transmission at SUB→RSC synapses, and increases direct monosynaptic long-range inhibition (CA1→RSC) and indirect feedforward di-synaptic inhibition (SUB→RSC interneurons→RSC pyramidal neurons). We will also use high-density silicone electrode recordings in freely behaving mice to test the hypothesis that ethanol exposure reduces the number, efficiency, and information content of high frequency oscillatory bursts in the RSC that are important for memory. In Aim 2, we will determine the effects of TTAE on the function of ATN↔RSC pathways. We will test the hypothesis that TTAE persistently reduces glutamatergic transmission at reciprocal monosynaptic connections between the ATN and RSC, without affecting di-synaptic feedforward inhibition at RSC→thalamic reticular nuclei→ATN synapses. We will also test the hypothesis that TTAE disrupts the activity of ATN and RSC neurons specifically modulated by an animal’s head direction that are essential in spatial learning and memory. The research proposed in this application is innovative because it will systematically characterize, for the first time, the developmental effects of ethanol on interactions among key components of the limbic memory network. The proposed research is significant because it will elucidate novel functional neurobiological mechanisms underlying developmental ethanol exposure- induced cognitive deficits, and identify specific biological targets for interventions to ameliorate them.