The Impact of Third Trimester Alcohol Exposure on Memories Encoded by Sharp-Wave Ripples of the Hippocampal-Retrosplenial Cortex Circuit

Project Summary Fetal alcohol spectrum disorder (FASD), which occurs when a fetus is exposed to alcohol, is a neurodevelopmental disorder affecting up to 5% of the US population. One of the most devastating outcomes for children with FASD are learning and memory deficits, the mechanisms of which are little understood.

Essential for learning and memory, sharp wave ripples (SWRs) are high frequency neural oscillatory events observed in the CA1 region of the hippocampus that travel to the retrosplenial cortex (RSC). Third trimester alcohol exposure (TTAE) in particular leads to severe neuronal death in the RSC and dysfunction in neuronal

populations necessary for SWR formation. Despite this clear damage, little is known about how TTAE affects SWRs in the RSC. To fill this gap in knowledge, I propose the use of a mouse model of TTAE together with in vivo electrophysiology and optogenetics to investigate the effects on SWR characteristics across learning.

Electrodes will be implanted in the CA1 and RSC, allowing for data collection while navigating a Barnes maze (BM) spatial navigation learning and memory task. Recordings will continue for 24 hours following the end of the task each day to gather SWRs that occur during Non-Rapid Eye Movement (NREM) sleep when memories

are consolidated. Multiple analytical tools will be used to investigate the impact of TTAE on two key SWR features - amplitude and duration. Additional tools will be used to assess the firing rates and waveforms of individual neurons, to determine the impact of TTAE on the recruitment of excitatory versus inhibitory neurons

by SWRs and the “replay” of these neurons during NREM. A separate and smaller subset of subjects will undergo optogenetic induction of SWRs, principally to evaluate if TTAE leads to alterations in SWR CA1 induction thresholds and/or propagation rates from CA1 to RSC. Collectively, this proposal will determine the

functional mechanisms of key phases of learning and the role of SWRs to these phases: Acquisition, consolidation, retrieval and plasticity. The successful completion of this proposal will provide critical information on the lasting neurological impacts of TTAE on SWRs in the RSC, and how this may affect learning and

memory. Additionally, this work will provide intensive training in awake/behaving electrophysiology, optogenetics, and a wide variety of analytical tools.