The objective of the proposed research plan is to investigate the effects of gestational ethanol (EtOH) exposure on dorsal striatal circuitry that contribute to some of the behavioral abnormalities, such as impaired decision making, increased impulsivity, and motor deficits that observed in Fetal Alcohol Spectrum Disorder (FASD). Using a mouse model, we will expose individuals via a vapor chamber to ethanol throughout the embryonic and early postnatal period in order to mimic the three trimesters of human development (gestational EtOH) and examine the disposition of dorsal striatal circuitry and associated behaviors during adulthood. Preliminary findings to date indicate that in adult mice that were exposed to gestational EtOH display decreased GABAergic transmission in the dorsal lateral striatum (DLS) that appears to involve increased modulation by endocannabinoids. We observed no gestational EtOH-induced effect of glutamatergic transmission. Gestational EtOH also impairs habit learning; a type of associative instrumental conditioning that involves the DLS. 1 will determine the mechanisms underlying these gestational EtOH effects by accomplishing the following specific aims: 1) Determine the synaptic specificity of aberrant GABAergic microcircuits in the DLS of mice exposed to gestational EtOH. To accomplish this 1 propose viral, optogenetic, and electrophysiological experiments to examine the three major GABAergic synapses onto striatal medium spiny neurons (MSNs), those formed by parvalbumin interneurons, those formed by other MSNs, and those formed by low-threshold spiking somatostatin interneurons. 2) Rescue of gestational EtOH exposure on associative learning and striatal neurotransmission: possible avenues for treatment. Using the information gained in specific aim 1,1 will use pharmacological agents to decrease endocannabinoid tone to rescue the impaired habit learning and GABAergic neurotransmission.Taken together, the completion of this project will lay the groundwork for assessing how disruptions of the GABAergic microcircuitry of the striatum underlie many of the behavioral abnormalities seen in FASD and suggest approaches to compensate for these effects.
With an estimated 1/750 infants/year born with Fetal Alcohol Syndrome and another 50,000 born with less severe symptoms, alcohol is the leading cause of preventable birth defects. Gestational ethanol can lead to a spectrum of physical, mental, and behavioral defects. This project examines the effects of gestational ethanol on the neural circuitry of the dorsal striatum, impairment of which may underlie some of the observed behavioral abnormalities.
