Thursday, November 21, 2024
11/21/2024
Project Summary / Abstract Cognitive and executive 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 FASD. Our objective is to use circuit tracing and slice electrophysiology to determine the long-term impact of third trimester-equivalent alcohol exposure (TTAE) on components of the cerebro-cerebellar system involved in executive function. Our working hypotheses are that 1) TTAE reduces glutamatergic input from the orbitrofrontal cortex—a brain region implicated in FASD-linked executive function deficits—to the cerebellar cortex via pontine nuclei neurons and 2) TTAE decreases glutamatergic output from the cerebellum to the orbitofrontal cortex via the deep cerebellar nuclei and the thalamus. Our rationale for using circuit mapping is to characterize the effects of TTAE on the function of reciprocal orbitofrontal cortex↔cerebellum connections. This proof-of-principle R21 proposal will establish a strong foundation for an R01 grant application to extend this work. In Aim 1, we will determine the effects of TTAE on the function of the cerebro-cerebellar system feed-forward limb. We will use anterograde transsynaptic labeling, slice electrophysiology, and optogenetics to test the hypothesis that TTAE persistently reduces glutamatergic transmission at synapses between pontine nuclei neurons (that receive input from the orbitofrontal cortex) and cerebellar granule cells (lobule VI) while also reducing feed-forward disynaptic inhibition at pontine nuclei neuron→Golgi cell→cerebellar granule cell synapses. In Aim 2, we will determine the effects of TTAE on the function of the cerebro-cerebellar system feedback limb. We will use an intersectional approach consisting of anterograde viral tracing coupled with retrobead labeling to test the hypothesis TTAE persistently reduces monosynaptic glutamatergic and disynaptic GABAergic transmission at synapses between deep cerebellar nuclei neurons—that receive input from lobule VI Purkinje neurons—and thalamic neurons that project to the orbitofrontal cortex. 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 cerebro-cerebellar network. The proposed research is significant because it will elucidate novel functional neurobiological mechanisms underlying fetal alcohol exposure-induced executive function deficits, and identify specific biological targets for interventions to ameliorate these deficits.
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