C4-Effects on Corticothalamic function

Impairments in executive function are among the most devastating consequences of prenatal alcohol exposure (PAE), for which there are few effective treatments. Our long-term goal is to identify key neural mechanisms underlying these impairments, to facilitate the development of circuit-specific treatments for Fetal Alcohol Spectrum Disorders (FASDs). Our objective is to leverage in vivo behavioral electrophysiology to determine the impact of PAE on corticothalamic functional coupling, and its relationship to visuospatial working memory, rule learning/switching, myelination and CircRNA/Neuroimmune signaling. Our central hypothesis is that PAE induces alterations in the functional connectivity of reciprocal circuits connecting the mediodorsal thalamic nuclei and the medial prefrontal cortex (MD↔mPFC), which underlie deficits in working memory and cognitive flexibility in FASD, and which are mediated by decreased MD↔mPFC myelination and associated with transcriptional blood biomarkers. Our rationale for the use of in vivo behavioral electrophysiology during the resting-state as well as during visuospatial rule learning/switching is to provide a comprehensive view of the effects of PAE on functional MD↔mPFC connectivity and its impact on behavior. In Aim 1, we will use dual site high-density silicon electrode recordings in freely behaving mice in the home cage to detect and characterize resting state functional connectivity to test the hypothesis that developmental ethanol exposure reduces resting-state neural oscillations associated with cognitive abilities, increases resting-state spiking activity within MD/mPFC microcircuits, and decreases resting-state MD↔mPFC spike-field coherence. In Aim 2, we will determine the effects of PAE on MD↔mPFC function during visuospatial learning/performance and a rule switch to test the hypothesis that PAE disrupts visuospatial working memory and cognitive flexibility within local MD/mPFC microcircuits. We will also use spike/field coherence and phase/amplitude coupling to test the hypothesis that PAE reduces the functional integration of MD-encoded task-relevant information to the mPFC, and vice versa. In Aim 3, we will determine the effects of PAE on the relationship between resting state MD↔mPFC electrophysiology, and visuospatial learning/flexibility, task-based neuronal tuning, white matter integrity, and circRNA/neuroimmune status. These comparisons will collectively test the hypothesis that resting state corticothalamic function predicts (or is predicted by) behavioral performance, neuronal tuning to cues/delays/behavior, and white matter integrity and circRNA/neuroimmune status. 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 cognitive thalamus essential in executive functioning. The proposed research is significant because it will elucidate novel functional neurobiological mechanisms underlying developmental ethanol exposure-induced cognitive and executive function deficits, and identify specific biological targets for interventions to ameliorate these deficits.