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

项目摘要/摘要 糟糕的决策和冒险的增加可能是由于长期接触药物，并导致持续 吸毒和/或促进复发。动物模型在确定这种升高的风险是否 吸食源于药物诱导的神经底物的改变，该神经底物在药物幼稚状态下支配冒险行为(即， 在接触毒品之前)。尽管在回答这些问题方面取得了重大进展，但我们仍然面临 将这些发现转化为临床环境的一个重要障碍。不仅是我们对神经的理解 冒险的基础是基于只使用男性的研究，但之前的研究也主要集中在如何 对奖赏的高度敏感(而不是对惩罚的低敏感)会增加吸毒后的风险。 使用。对女性承担风险的神经底物知之甚少，更不用说这些底物是如何 在接触毒品后会发生改变。我们研究的长期目标是揭示神经和荷尔蒙 调解涉及惩罚风险的女性决策的机制，以确定这些 过程会受到物质使用的影响。为了实现这一目标，我们将使用风险承担的大鼠模型 哪些女性比男性更厌恶风险，对惩罚风险表现出更高的敏感性。在这个模型中， 女性的风险厌恶很大程度上是由雌激素(E_2)介导的，这种依赖于E_2的风险厌恶需要雌激素 受体(ER)β。我们还确定了杏仁基底外侧核(BLA)在促进风险厌恶中的作用 行为。初步数据显示，BLA中D2多巴胺受体(D2R)的激活导致风险厌恶 女性，而不是男性，这表明血乳酸功能的差异可能是风险承担的性别差异的基础。这 无论是在基线还是在反应中，女性的总体血乳酸活性都高于男性 厌恶的刺激。先前的工作表明，女性特有的血乳酸活性和血乳酸依赖行为是由雌二醇组S引起的 调节血乳酸功能的能力。因此，我们的首要假设是，女性的风险厌恶取决于 E_2‘S通过调节ER、β和D2R功能及抑制中间神经元来调节血乳酸兴奋性 活动。这一假设将通过追求三个具体目标来检验。目标1将确定ER机制 在体内，使用行为药理学在促进E2依赖的女性风险厌恶的血乳酸中 电生理学和RNA干扰介导的ER基因减少。目标2将确定E2的贡献 基因消融和光基因操作对BLA-D2R功能对女性风险厌恶的调节 选择性表达D2Rs的BLA神经元。目的3将评估BLA小白蛋白表达的作用 用纤维光度和光遗传学研究雌激素依赖型女性风险厌恶中的中间神经元。完成这些工作 实验将揭示雌二醇调节女性避险情绪的机制。这一信息将是 意义重大，因为它将提供必要的基础，使我们能够评估目标的效力。 E2依赖的神经机制，以减轻与物质使用相关的风险增加。

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.