Investigation of the neurobiological mechanisms underlying estradiol-mediated risk aversion in females

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Project Summary/Abstract Poor decision making and elevated risk taking may be due to chronic drug exposure and contribute to continued drug use and/or promote relapse. Animal models have been invaluable in identifying whether such elevated risk taking arises from drug-induced alterations in neural substrates that govern risk taking in drug-naïve states (i.e., prior to drug exposure). Although there has been significant progress in answering such questions, we still face a significant barrier in translating these findings to the clinical setting. Not only is our understanding of the neural substrates of risk taking based on studies using only males, but prior studies have also primarily focused on how hypersensitivity to reward (as opposed to hyposensitivity to punishment) promotes elevated risk taking after drug use. Little is known about the neural substrates underlying risk taking in females, let alone how such substrates are altered after drug exposure. The long-term goal of our research is to uncover the neural and hormonal mechanisms mediating decision making involving risk of punishment in females in order to identify how these processes become compromised by substance use. To meet this goal, we will use a rat model of risk taking in which females are more risk averse and exhibit greater sensitivity to risk of punishment than males. In this model, female risk aversion is largely mediated by estradiol (E2) and such E2-dependent risk aversion requires estrogen receptor (ER) β. We have also established a role for the basolateral amygdala (BLA) in promoting risk averse behavior. Preliminary data show activation of D2 dopamine receptors (D2R) in the BLA leads to risk aversion in females, but not males, suggesting differences in BLA function may underlie sex differences in risk taking. This would be consistent with greater overall BLA activity in females than males either at baseline or in response to aversive stimuli. Prior work shows female-specific BLA activity and BLA-dependent behavior are due to E2’s ability to modulate BLA function. Hence, our overarching hypothesis is that female risk aversion depends on E2’s ability to regulate BLA excitability via modulation of ERβ and D2R function and suppression of interneuron activity. This hypothesis will be tested by pursuing three specific aims. Aim 1 will determine the ER mechanisms in the BLA that contribute to E2-dependent female risk aversion using behavioral pharmacology, in vivo electrophysiology and RNA interference-mediated ER gene reduction. Aim 2 will identify the contribution of E2 modulation of BLA D2R function to female risk aversion using genetic ablation and optogenetic manipulation of BLA neurons that selectively express D2Rs. Aim 3 will evaluate the role of BLA parvalbumin-expressing interneurons in E2-dependent female risk aversion using fiber photometry and optogenetics. Completion of these experiments will reveal mechanisms by which E2 mediates risk aversion in females. This information will be significant because it will provide the necessary foundation from which we can assess the efficacy of targeting E2-dependent neural mechanisms to alleviate elevated risk taking associated with substance use.