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

女性雌二醇介导的风险厌恶的神经生物学机制的研究

• 批准号: 10587322
• 负责人: Caitlin Anne Orsini
• 金额: $ 59.08万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10587322
• 关键词: Ablation; Abstinence; Address; Agonist; Amygdaloid structure; Animal Model; Attenuated; Aversive Stimulus; Behavior; Cells; Chronic; Circulation; Clinical; Cocaine; Cognition; Data; Decision Making; Dopamine D2 Receptor; Drug Exposure; Drug usage; Electrophysiology (science); Estradiol; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Receptors; Exhibits; Female; Fiber; Foundations; Genetic; Goals; Hormonal; Hormones; Hypersensitivity; Impairment; Interneurons; Investigation; Knowledge; Lead; Mediating; Modeling; Neurons; Parvalbumins; Pharmaceutical Preparations; Photometry; Physiological; Positioning Attribute; Poverty; Process; Punishment; RNA Interference; Rattus; Receptor Activation; Receptor Gene; Receptor Signaling; Regulation; Relapse; Reporting; Research; Rewards; Risk; Risk Taking; Rodent Model; Role; Sex Differences; Substance Use Disorder; Testing; Translating; Work; behavioral pharmacology; cost; drug relapse; efficacy evaluation; efficacy testing; experimental study; in vivo; male; neural; neurobiological mechanism; neuromechanism; optogenetics; preclinical study; programs; receptor function; response; selective expression; small hairpin RNA; substance use; substance user

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.

项目总结/摘要 决策不当和冒险行为增加可能是由于长期药物暴露，并导致持续的 药物使用和/或促进复发。动物模型在确定这种高风险是否 服用是由药物诱导的神经基质的改变引起的，所述神经基质在药物初始状态下控制冒险（即， 药物暴露前）。虽然在回答这些问题方面取得了重大进展，但我们仍然面临着 这是将这些发现转化为临床环境的重大障碍。我们对神经系统的理解 基于仅使用男性的研究，风险承担的基质，但先前的研究也主要集中在如何 对奖励的超敏反应（与对惩罚的低敏反应相反）促进了药物后风险的增加 使用.关于女性冒险行为背后的神经基质知之甚少，更不用说这种基质是如何 在药物暴露后会发生改变我们研究的长期目标是揭示神经和激素 调解涉及女性惩罚风险的决策的机制，以确定这些机制是如何发挥作用的。 过程会因物质的使用而受到损害。为了实现这一目标，我们将使用一个风险承担的大鼠模型， 女性比男性更厌恶风险，对惩罚风险表现出更大的敏感性。在这个模型中， 女性的风险规避主要由雌二醇（E2）介导，这种E2依赖性风险规避需要雌激素 受体β。我们还确定了基底外侧杏仁核（BLA）在促进风险规避中的作用。 行为初步数据显示，BLA中D2多巴胺受体（D2 R）的激活导致风险规避。 女性，而不是男性，表明BLA功能的差异可能是风险承担的性别差异的基础。这 与基线时女性的总体BLA活性高于男性一致， 厌恶性刺激先前的工作表明，女性特异性BLA活性和BLA依赖性行为是由于E2的 调节BLA功能的能力。因此，我们的总体假设是，女性的风险厌恶取决于 E2通过调节ERβ和D2 R的功能及抑制中间神经元对BLA兴奋性的调节作用 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BLA中，使用行为药理学，在体内有助于E2依赖性女性风险规避 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 使用基因消融和光遗传学操作调节BLA D2 R功能以规避女性风险 选择性表达D2 Rs的BLA神经元。目的3探讨BLA小清蛋白表达在肿瘤发生中的作用 使用纤维光度学和光遗传学研究E2依赖性女性风险规避中的中间神经元。完成这些 实验将揭示E2介导女性风险规避的机制。此信息将 重要的是，它将提供必要的基础，我们可以从中评估目标的有效性 E2依赖性神经机制，以减轻与物质使用相关的高风险行为。