There is growing evidence that moderate exposure to alcohol during development can lead to behavioral and cognitive deficits that can persist throughout the lifespan. The cognitive impairments associated with Fetal Alcohol Spectrum Disorders (FASDs) include abnormalities in learning and memory, executive control and social behaviors^""""""""^ and are often characterized by a hyper-focus on one particular task or aspect of a task, to the detriment of other important behaviors. Measures of cortically-mediated cognition have been shown to be sensitive to high dose ethanol (EtOH) exposure during development in rodents, but little is known regarding the mechanisms responsible for executive function alterations associated with FASD. We propose to investigate the impact of prenatal ethanol exposure on corticostriatal-mediated behavior and learning related cortical and striatal physiology by integrating highly translatable touch-screen behavioral measures previously shown to recruit dorsal striatum and orbitofrontal cortex with in vivo and ex vivo electrophysiology in prenatally exposed and control mice. We hypothesize that moderate prenatal EtOH exposure will decrease activation of neuronal circuits in the orbito-frontal cortex (OFC) impairing executive control behavior and releasing the dorsal striatal (dS) from cortical control, resulting in hyper-focused, unregulated learning. In order to test this hypothesis we propose three specific aims. First, we will investigate whether moderate prenatal ethanol exposure impairs reversal learning by measuring choice learning and shifting in adolescent mice after moderate prenatal alcohol exposure using touch screen paradigm. Next, we will examine whether this ethanol exposure impairs the function of dS neuronal circuits by both performing in vivo multi-electrode array electrophysiological recording to examine dS neuronal firing activity during choice learning and shifting and utilizing in vitro slice electrophysiological techniques to examine synaptic transmission and plasticity in the dS after choice learning and shifting. Finally, we will investigate whether PAE impairs the function of OFC neuronal circuits during reversal learning by performing in vivo recording of OFC neuronal firing activity during choice learning and shifting and performing in vitro slice electrophysiology to measure synaptic transmission and AMPAR/NMDAR ratios in the OFC after choice learning and shifting. Taken together, the completion of these aims will allow us to better understand the mechanisms of cognitive impairment in FASD and provide an important tool for developing more effective therapies for executive dysfunction.
There is growing evidence that moderate prenatal alcohol exposure can lead to behavioral and cognitive deficits that can persist throughout the lifespan. However, little is known regarding the mechanisms responsible for these deficits in Fetal Alcohol Spectrum Disorder. This project seeks to understand how prenatal alcohol exposure disrupts normal brain circuitry leading to behavioral impairments and provide important tools for developing more effective therapies for executive dysfunction.
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