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

基本信息

批准号：
10649473
负责人：
Leah Marie Truckenbrod
金额：
$ 4.45万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
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/10649473
关键词：
Abstinence Amygdaloid structure Behavior Behavioral Mechanisms Chronic Circulation Clinical Data Decision Making Development Dopamine Dopamine D2 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 Physiological Positioning Attribute Predisposition Process Proestrus Punishment RNA Interference Rattus Receptor Gene Regulation Relapse Research Rewards Risk Risk Taking Rodent Model Role Scientific Advances and Accomplishments Sex Differences Substance Use Disorder Testing Translating Work career experience experimental study insight knock-down male neural neurobiological mechanism neuromechanism optogenetics preclinical study receptor function receptor sensitivity remediation selective expression sex small hairpin RNA substance use

项目摘要

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.

项目概要冒险行为的增加不仅会导致物质使用障碍（SUD）的发展，还会导致复发的可能性在描述其背后的神经基质方面已经取得了重大进展。尽管如此，我们在将这些发现转化为因果关系时仍然面临着重大障碍。临床环境，因为该主题的大部分工作都使用男性受试者，尽管情况良好。确定了风险承担和 SUD 方面的性别差异，这在科学上存在重大局限性。可以通过检查决策背后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冒险的神经机制。以及激素如何促进这些过程，为了实现这一目标，我将使用啮齿类动物的冒险模型。在此模型中，女性比男性更厌恶风险并且对惩罚风险表现出更高的敏感性。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我们还确定了基底外侧杏仁核 (BLA) 的作用及其对大脑的投射。伏核 (NAc) 壳在促进风险厌恶行为方面的作用初步数据表明 D2 的激活。 BLA 中的多巴胺受体 (D2R) 会增加女性的风险厌恶程度，但不会增加男性的风险厌恶程度。 BLA 功能的差异可能是冒险行为中性别差异的基础，特别是促进风险规避先前的研究表明，BLA 依赖性行为的性别差异是由于 E2 的调节能力造成的。 BLA 的活性和功能鉴于 BLA 在冒险中的作用以及它受到 E2 的有效调节这一事实，它是因此可以想象，女性的风险厌恶可能是由于 E2 对 BLA 活动的调节所必需的。基于风险的决策进行了检查，该提案的总体目标是剖析神经网络。 E2促进女性风险规避的机制。通过它对 BLA 中 ERβ 和 D2R 功能的调节以及它对 NAc 壳的投射，我将测试我的。在目标 1 中，我将确定 ER 在 BLA 中的贡献。在目标 2 中，我将使用 RNA 干扰介导的 ER 基因减少来降低女性的 E2 依赖性风险规避。使用光遗传学确定 BLA 中 D2R 功能的 E2 调节对于女性规避风险的必要性操纵选择性表达 D2R 的 BLA 神经元在目标 3 中，我将确定 E2 的贡献。使用光遗传学操作调节 BLA 投射到 NAc 壳以规避女性的风险这个项目很重要，因为获得的知识将增进我们对神经网络的理解。 E2 介导女性风险规避的机制，并为我们提供确定的基础这些流程的中断是否会导致与 SUD 相关的风险增加。