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

University Of Texas At Austin, Austin TX

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Abstract

Project Summary: This application is for an Administrative Supplement for Continuity of Biomedical and Behavioral Research Among First-Time Recipients of NIH Research Project Grant Awards. 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. Our long-term goal is to uncover the biological mechanisms mediating punishment-based risky decision making in females to identify how these processes become compromised by drug use. To meet this goal, we 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, we find that E2 mediates female risk aversion through estrogen receptor (ER) activation. The basolateral amygdala (BLA) is also necessary for promoting risk averse behavior, and activation of D2 dopamine receptors (D2R) in the BLA leads to risk aversion in females, but not males. This suggests differences in BLA function may underlie sex differences in risk taking, which is consistent with greater overall BLA activity in females than males. Prior work shows female-specific BLA activity and BLA-dependent behavior are due to E2’s ability to modulate BLA function. Our overarching hypothesis is that female risk aversion depends on E2’s ability to regulate BLA excitability via modulation of ERs and D2R function and suppression of interneuron activity. This hypothesis will be tested in 3 aims. Aim 1 will determine the ER mechanisms in the BLA contributing 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 D2R- expressing neurons. Aim 3 will evaluate the role of BLA interneurons in E2-dependent female risk aversion using fiber photometry and optogenetics. The information gained from these experiments 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. This Administrative Supplement will offset the reduction in productivity that occurred when the PI gave birth to her first child five weeks prematurely, resulting in a NICU stay for the newborn and a week-long hospital stay for the PI. .