Neurobiology of risk taking in females: hormonal modulation of basolateral amygdala function

女性冒险的神经生物学：基底外侧杏仁核功能的激素调节

• 批准号: 10538387
• 负责人: Leah Marie Truckenbrod
• 金额: $ 4.35万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10538387
• 关键词: Amygdaloid structure; Behavior; Behavioral Mechanisms; Blood Circulation; Chronic; Clinical; Data; Decision Making; Development; Dopamine; Dopamine D2 Receptor; Dopamine Receptor; Drug usage; Estradiol; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Receptors; Exhibits; Female; Foundations; Goals; Hormonal; Hormones; Impairment; Individual; Knowledge; Laboratories; Lead; Mediating; Modeling; Neurobiology; Neurons; Nucleus Accumbens; Ovariectomy; Pharmaceutical Preparations; Phenotype; Physiological; Positioning Attribute; Predisposition; Process; Proestrus; Punishment; RNA Interference; Rattus; Receptor Gene; Regulation; Relapse; Research; Rewards; Risk; Risk-Taking; Rodent Model; Role; Sex Differences; Substance Use Disorder; Testing; Translating; Work; base; career; experience; experimental study; insight; knock-down; male; neurobiological mechanism; neuromechanism; optogenetics; preclinical study; receptor function; receptor sensitivity; relating to nervous system; selective expression; sex; small hairpin RNA; substance use

Project Summary Elevated risk taking contributes not only to the development of substance use disorder (SUD) but also the likelihood of relapse. There has been significant progress in delineating the neural substrates underlying this causal relationship. Nonetheless, we are still faced with a significant barrier in translating these findings to the clinical setting because the majority of the work on this topic has used male subjects. This is despite the well- established sex differences in risk taking and aspects of SUD. This significant limitation in scientific advancement can be remediated by examining neurobiological mechanisms underlying decision making in females. The long-term goal of our lab is to identify the neural mechanisms mediating risk taking in females and how hormones contribute to these processes. To meet this goal, I will use a rodent 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) and its projections to the nucleus accumbens (NAc) shell in promoting risk averse behavior. Preliminary data reveal that activation of D2 dopamine receptors (D2Rs) in the BLA increases risk aversion in females, but not males. These findings suggest that differences in BLA function may underlie sex differences in risk taking, and specifically, promote risk aversion in females. Prior work shows sex differences in BLA-dependent behavior are due to the ability of E2 to modulate BLA activity and function. Given the role of the BLA in risk taking and the fact it is potently modulated by E2, it is therefore conceivable that risk aversion in females may be due to E2 regulation of BLA activity necessary for risk-based decision making. Consequently, the overall objective of this proposal is to dissect the neural mechanisms by which E2 promotes risk aversion in females. I hypothesize that E2 mediates female risk aversion through its modulation of ERβ and D2R function in the BLA and its projections to the NAc shell. I will test my hypothesis by carrying out three experimental aims. In Aim 1, I will identify the contributions of ERs in the BLA to E2-dependent risk aversion in females using RNA interference-mediated ER gene reduction. In Aim 2, I will identify the necessity of E2 modulation of D2R function in the BLA for risk aversion in females using optogenetic manipulation of BLA neurons that selectively express D2Rs. In Aim 3, I will identify the contribution of E2 modulation of BLA projections to the NAc shell to risk aversion in females using optogenetic manipulation of this circuit. This project is significant because the knowledge gained will advance our understanding of the neural mechanisms by which E2 mediates female risk aversion and provide a foundation from which we can determine whether a disruption in these processes contributes to elevated risk taking associated with SUDs.

项目摘要 冒险的升高不仅有助于吸毒障碍（SUD）的发展 退休的可能性。在描述这一点的神经底物方面取得了重大进展 尽管如此，我们仍然面临着将这些发现转化为的重大障碍 临床环境是因为大部分关于该主题的工作都使用了男性受试者。这是dospite 既定的性别差异在冒险和SUD方面存在。科学的重大限制 可以通过检查基于决策的神经生物学机制来补救进步 我们实验室的长期目标是确定介导女性风险的神经机制 以及骑马如何为这些过程做出贡献。为了实现这一目标，我将使用啮齿动物的风险模型 哪些女性比男性更具风险，对惩罚风险表现出更大的敏感性。在这个模型中， 女性风险规避在很大程度上是由雌二醇（E2）介导的，这种依赖E2的风险避免需要雌激素 受体（ER）β。我们还为基础型杏仁核（BLA）及其项目确立了角色 伏隔核（NAC）壳在促进风险避开行为方面。初步数据表明D2的激活 BLA中的多巴胺受体（D2RS）增加了女性的风险厌恶，而不是男性。这些发现表明 BLA功能的这种差异可能是风险承担的性别差异的基础，特别是促进风险规避 在女性中。先前的工作表明，依赖BLA的行为的性别差异是由于E2调节的能力 BLA活动和功能。鉴于BLA在冒险中的作用以及它可能由E2调节的事实，这是 因此，可以想象，女性的风险规避可能是由于E2对BLA活性的调节所必需的 基于风险的决策。因此，该提议的总体目标是剖析神经 E2促进女性风险厌恶的机制。我假设E2介导女性风险规避 通过调节BLA中的ERβ和D2R功能及其对NAC壳的项目。我会测试我的 通过执行三个实验目标来假设。在AIM 1中，我将确定ERS在BLA中的贡献 使用RNA干扰介导的ER基因还原的女性中E2依赖性风险规避。在AIM 2中，我会 使用光遗传学确定BLA中D2R功能的E2调制的必要 选择性表达D2RS的BLA神经元的操纵。在AIM 3中，我将确定E2的贡献 使用对此的光遗传操纵，将BLA项目调节为NAC外壳有风险厌恶女性 电路。该项目很重要，因为获得的知识将提高我们对神经的理解 E2介导女性风险规避并提供基础的机制，我们可以确定 这些过程中的破坏是否导致与SUD相关的风险增加。