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: 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
• 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

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 高风险不仅有助于物质使用障碍（SUD）的发展， 复发的可能性已经有重大进展，在划定神经基板的基础上， 因果关系尽管如此，我们仍然面临着一个重大障碍，将这些发现转化为 临床环境，因为关于该主题的大多数工作都使用男性受试者。尽管如此，好- 在风险承担和SUD方面建立了性别差异。这一重大限制在科学 进步可以通过检查决策背后的神经生物学机制来补救， 女性我们实验室的长期目标是确定女性风险行为的神经机制 以及激素是如何参与这些过程的。为了达到这个目标，我将使用一个啮齿动物模型的风险承担， 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）及其向大脑皮质的投射的作用。 核壳（NAc）在促进风险厌恶行为。初步数据显示D2的激活 BLA中的多巴胺受体（D2 Rs）增加女性的风险厌恶，但不增加男性的风险厌恶。这些发现表明 BLA功能的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，在BLA依赖性行为的性别差异是由于E2的调节能力， BLA活性和功能。考虑到BLA在风险承担中的作用以及它被E2有效调节的事实， 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， 基于风险的决策因此，本提案的总体目标是解剖神经系统， E2促进女性风险规避的机制。我假设E2介导女性风险厌恶 通过调节BLA中的ERβ和D2 R功能及其向NAc壳的投射。我将测试我的 通过实现三个实验目标来验证假设。在目标1中，我会指出雇员关系在基本生活津贴中的贡献 使用RNA干扰介导的ER基因减少，在女性中E2依赖的风险规避。在目标2中，我将 使用光遗传学鉴定BLA中D2 R功能的E2调节对于女性风险规避的必要性 操纵选择性表达D2 Rs的BLA神经元。在目标3中，我将确定E2的贡献 使用这种光遗传学操作来调节BLA向NAc壳的投射，以在女性中规避风险。 电路.这个项目意义重大，因为获得的知识将促进我们对神经系统的理解。 E2介导女性风险规避的机制，并提供了一个基础，我们可以从中确定 这些过程的中断是否会导致与SUD相关的风险承担增加。

项目成果

Cocaine intake correlates with risk-taking behavior and affects estrous cycling in female Sprague-Dawley rats.

• DOI: 10.3389/fnbeh.2023.1293226
• 发表时间: 2023
• 期刊: FRONTIERS IN BEHAVIORAL NEUROSCIENCE
• 影响因子: 3
• 作者: Truckenbrod, Leah M.;Cooper, Emily M.;Wheeler, Alexa-Rae;Orsini, Caitlin A.
• 通讯作者: Orsini, Caitlin A.