Impact of Prenatal Ethanol on BLA Synaptic Plasticity

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Abstract The incidence of alcohol drinking and alcohol abuse during pregnancy is strikingly high which can lead to a spectrum of deficits in offspring termed Fetal Alcohol Spectrum Disorders. One of the most common consequences of prenatal alcohol exposure (PAE) is the emergence of anxiety disorders in adolescence, which are surprisingly observed following exposure to moderate levels of ethanol – a common pattern of alcohol consumption in pregnancy. Despite these compelling epidemiological data, the neurobiological mechanisms underlying moderate PAE-induced anxiety are not well understood. Synaptic activity and plasticity within the basolateral amygdala (BLA) is driven, in part, through inputs from the medial prefrontal cortex (mPFC), and are associated with regulation and expression of anxiety-like behaviors. Additionally, BLA synaptic activity and plasticity is modulated by the dynorphin/kappa opioid receptor (DYN/KOR) system that is also associated with alterations in anxiety-like behaviors. Although studies have shown that PAE can alter mPFC function, increase BLA plasticity, and reduce amygdala KOR levels (an effect opposite of what is seen following exposure to ethanol in adulthood), whether moderate PAE at levels more likely seen in pregnant women affects these targets and the interaction(s) between these alterations during the highly vulnerable developmental period of adolescence are unknown. We have recently characterized a model of moderate PAE using a single exposure to vaporized ethanol on gestational day (G) 12, a developmental epoch during which the amygdala begins to appear, that produces increased social anxiety-like behaviors in adolescent offspring. Based on this, we hypothesize that moderate G12 PAE increases anxiety-like behavior in adolescence through enhanced mPFCBLA synaptic plasticity and reduced DYN/KOR function. To test our hypothesis, Aim 1 will examine the impact of moderate G12 PAE on alterations in mPFCBLA synaptic plasticity using in vitro optogenetic and electrophysiological tools. Aim 2 will test the effect of moderate G12 PAE on KOR modulation of mPFCBLA synaptic plasticity using a combination of molecular, electrophysiological and in vivo optogenetics coupled with behavioral pharmacology. These innovative studies will test novel and unique hypotheses surrounding the long-term effects of moderate PAE and describe neural mechanisms specific to deficits in anxiety-like behaviors.