Characterization of NAc D1 MSNs in Encoding Reward, Aversion, and Decision-Making During Conflict

NAc D1 MSN 在编码奖励、厌恶和冲突期间决策中的表征

• 批准号: 10276180
• 负责人: Rodolfo Flores Garcia
• 金额: --
• 依托单位: U.S. NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10276180
• 关键词: Characterization; NAc; D1; MSNs; Encoding

PROJECT SUMMARY Impaired reward and aversion processing underlie the symptomatology of a diverse set of psychiatric disorders. However, the precise neural basis of reward and aversive stimuli remains to be elucidated. The nucleus accumbens (NAc) is a key brain region implicated in hedonic processing, encoding reward and aversion signals via medium spiny neurons (MSNs) that express dopamine D1 receptors (D1) or dopamine D2 receptors (D2). The canonical view of NAc functioning is that D1- MSNs encode reward, and D2- MSNs encode aversion. However, recent work has challenged this view, as D1 MSNs have been found to encode aversive states or inhibit reward seeking. Our preliminary data using single unit recording with miniscope imaging, revealed that only some NAc D1 MSNs activate in response to a footshock whereas others do not. NAc D1-MSNs project to the LH, VTA, and VP, whereas D2-MSNs only project to the VP. Hence, one possibility is that there are subsets of D1 MSNs that encode both reward and aversion based depending on their output regions. To address this gap, we propose that NAc D1 MSNs encode reward or aversion based on their efferent organization and participate in adaptive decision -making during conflict between reward and aversion. This hypothesis will be tested in two specific aims: Aim 1 tests the hypothesis that different ensembles of NAc D1 MSNs encode reward or aversion depending on efferent organization. In Aim 2, we will test the hypothesis that D1 MSNs encode decision making during motivational conflict between reward and aversion, advancing our understanding of D1 MSNs independent of the outcomes obtained in Aim 1. To test the hypothesis, these experiments will combine novel methods, such as transgenic/viral approaches, single-cell Ca2+ imaging, optogenetics, and machine learning. Thus, I will gain training in in these techniques forming a strong foundation for my independent research program to answer questions in line with my interests in motivation and decision making in a technically elegant and translationally relevant manner. These results will contribute to our understanding of motivational and emotional neural circuits implicated in the pathophysiology of psychiatric disorders, such as depression and addiction.

项目概要 奖赏和厌恶处理受损是多种精神病症状的基础 失调。然而，奖励和厌恶刺激的精确神经基础仍有待阐明。这 伏隔核 (NAc) 是大脑的一个关键区域，参与享乐处理、编码奖励和 通过表达多巴胺 D1 受体 (D1) 或多巴胺的中型多棘神经元 (MSN) 发出厌恶信号 D2 受体 (D2)。 NAc 功能的规范观点是 D1- MSN 编码奖励，D2- MSN 编码奖励 编码厌恶。然而，最近的工作对这一观点提出了挑战，因为 D1 MSN 被发现可以编码 厌恶状态或抑制奖励寻求。我们使用微型显微镜单个单元记录的初步数据 成像显示，只有一些 NAc D1 MSN 会响应足部震动而激活，而其他的则会激活 不是。 NAc D1-MSN 投射到 LH、VTA 和 VP，而 D2-MSN 仅投射到 VP。因此，一 可能性是，存在 D1 MSN 的子集，它们编码基于奖励和厌恶的依赖 在他们的输出区域。为了解决这一差距，我们建议 NAc D1 MSN 编码奖励或厌恶 基于他们的传出组织并在冲突期间参与适应性决策 奖励和厌恶。该假设将在两个具体目标中进行检验： 目标 1 检验以下假设： 不同的 NAc D1 MSN 集合根据传出组织编码奖励或厌恶。在 目标 2，我们将测试 D1 MSN 编码动机冲突期间决策的假设 奖励和厌恶之间的关系，增进我们对 D1 MSN 的理解，而与结果无关 在目标 1 中获得。为了检验假设，这些实验将结合新方法，例如 转基因/病毒方法、单细胞 Ca2+ 成像、光遗传学和机器学习。这样，我将收获 这些技术的培训为我的独立研究计划回答问题奠定了坚实的基础 问题符合我对动机和决策的兴趣，以技术优雅和 翻译相关的方式。这些结果将有助于我们理解动机和 情绪神经回路与精神疾病的病理生理学有关，例如抑郁症和 瘾。