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.

项目概要/摘要 决策失误和冒险行为增加可能是由于长期接触药物造成的，并导致持续的 吸毒和/或促进复发。动物模型对于确定这种升高的风险是否存在非常有价值 服用行为是由药物引起的神经基质的改变引起的，神经基质控制着未接触药物状态下的冒险行为（即， 接触药物之前）。尽管在回答这些问题方面已经取得了重大进展，但我们仍然面临 将这些发现转化为临床环境的一个重大障碍。不仅是我们对神经元的理解 冒险的基础基于仅使用男性的研究，但先前的研究也主要集中在如何 对奖励的过度敏感（相对于对惩罚的不敏感）会导致吸毒后冒险行为的增加 使用。人们对女性冒险行为背后的神经底物知之甚少，更不用说这些底物是如何产生风险的了。 接触药物后会发生改变。我们研究的长期目标是揭示神经和荷尔蒙 调解涉及女性受到惩罚风险的决策的机制，以确定这些风险如何 过程因物质使用而受到损害。为了实现这一目标，我们将使用大鼠风险承担模型 与男性相比，女性更厌恶风险并且对惩罚风险表现出更高的敏感性。在这个模型中， 女性风险厌恶很大程度上是由雌二醇（E2）介导的，而这种依赖于 E2 的风险厌恶需要雌激素 受体（ER）β。我们还确定了基底外侧杏仁核 (BLA) 在促进风险规避方面的作用 行为。初步数据显示，BLA 中 D2 多巴胺受体 (D2R) 的激活会导致风险规避 女性而非男性，这表明 BLA 功能的差异可能是冒险行为中性别差异的基础。这 与基线或响应时女性比男性的总体 BLA 活性更大一致 厌恶的刺激。先前的研究表明，女性特有的 BLA 活性和 BLA 依赖性行为是由于 E2 的影响 调节 BLA 功能的能力。因此，我们的总体假设是女性风险厌恶程度取决于 E2 通过调节 ERβ 和 D2R 功能以及抑制中间神经元来调节 BLA 兴奋性的能力 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 中使用行为药理学有助于 E2 依赖性女性风险规避，体内 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 D2R 功能对女性风险规避的影响 选择性表达 D2R 的 BLA 神经元。目标 3 将评估表达 BLA 小白蛋白的作用 使用光纤光度测定和光遗传学研究 E2 依赖性女性风险厌恶中的中间神经元。完成这些 实验将揭示 E2 介导女性风险厌恶的机制。该信息将被 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有效性 E2 依赖性神经机制可减轻与物质使用相关的高风险行为。