Fronto-insular network in cognitive-affective interactions during decision-making

决策过程中认知情感交互的额岛网络

• 批准号: 10452214
• 负责人: Kuan Hong Wang
• 金额: $ 51.32万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA CRUZ
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-05 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10452214
• 关键词: Affect; Affective; Anterior; Area; Attention; Brain; Brain imaging; Brain region; Calcium; Chromosome Mapping; Chronic stress; Cognitive; Complex; Data; Decision Making; Dendritic Spines; Dopamine; Electrophysiology (science); Etiology; Goals; Human; Image; Immediate-Early Genes; Impairment; Knowledge; Label; Lesion; Literature; Measures; Medial; Mental disorders; Midbrain structure; Modeling; Modernization; Monitor; Morphology; Motor; Mus; Neuroanatomy; Neurons; Outcome; Pathway interactions; Pattern; Pharmacogenetics; Pharmacology; Predisposition; Prefrontal Cortex; Presynaptic Terminals; Process; Publishing; Risk Factors; Sensory; Societies; Stress; Structure; System; Techniques; Testing; Ventral Tegmental Area; Viral; base; comparative; developmental genetics; dopaminergic neuron; flexibility; frontal lobe; imaging study; in vivo; in vivo calcium imaging; in vivo imaging; innovation; nerve supply; neural circuit; neuromechanism; neuroregulation; optogenetics; performance tests; success; therapeutic target; tool; two-photon

PROJECT SUMMARY Complex decision-making often encompasses both cognitive and affective components. Cognitive and affective processes engage distinct but interacting systems in the brain, and both systems are effected by stress, a prevalent problem in modern society and a well-known risk factor for psychiatric disorders. Human brain imaging studies suggest a network of brain regions as the potential interface between cognitive and affective processing, particularly the medial prefrontal cortex (mPFC), the anterior insular cortex (aIC), and midbrain dopamine (DA) regions such as the ventral tegmental area (VTA). However, these studies lack causality tests at the neural circuit level. Comparative neuroanatomy and developmental genetics have identified in mice evolutionarily related mPFC, aIC, and DA regions. The structure and function of these regions are also disturbed by stress. These findings open the venue to use mouse as a model species for causal studies of the fundamental functions of these brain regions with precise circuit manipulation tools. Our overall goal is to elucidate the fronto-insular circuit mechanisms underlying cognitive-affective interactions during decision-making and the impact of stress on such mechanisms in mice. Our proposal is based on published literature and preliminary data showing: 1) mPFC, aIC and VTA are engaged in cognitive and affective decision-making; 2) mPFC and aIC are directly connected and both receive DA inputs from VTA; 3) stress affects mPFC and aIC neurons as well as DA release in these areas; 4) DA modulates mPFC and aIC activity and decision-making. By combining projection-specific viral labeling of neural circuits with in vivo imaging/electrophysiology and optogenetic/pharmacogenetic manipulations, we will test the central hypothesis that mPFC-aIC interaction is crucial for decision-making, which is disrupted by chronic stress but rescuable via DA modulation. Specifically, in Aim 1, we will determine the function of mPFC-aIC connections during decision-making in the attentional set-shifting test. In Aim 2, we will examine how stress affects mPFC-aIC connectivity and function. In Aim 3, we will define impact of stress on DA modulation of mPFC and aIC function, and explore the possibility to rescuing decision-making by selectively restore DA modulation in mPFC or aIC in stressed mice. The successful outcomes of this project will not only provide fundamental knowledge about the circuit mechanisms underlying higher brain functions, but also point out potential therapeutic targets for alleviating the detrimental effects of stress and psychiatric illnesses.

项目摘要 复杂的决策通常包含认知和情感成分。认知和 情感过程在大脑中参与不同但相互作用的系统，并且两个系统都受到压力的影响， 现代社会中的一个普遍问题，也是众所周知的精神疾病风险因素。人脑 成像研究表明，大脑区域网络是认知和情感之间的潜在接口 加工，尤其是内侧前额叶皮层（MPFC），前岛皮层（AIC）和中脑 多巴胺（DA）区域，例如腹侧盖区（VTA）。但是，这些研究缺乏因果关系测试 神经电路水平。在小鼠中发现了比较神经解剖学和发育遗传学 进化相关的MPFC，AIC和DA区域。这些区域的结构和功能也受到干扰 通过压力。这些发现为使用鼠标作为模型物种开放了基本研究的模型物种 这些大脑区域的功能具有精确的电路操纵工具。我们的总体目标是阐明 决策过程中认知影响相互作用的基础额 - 额 - 互联电路机制 以及压力对小鼠这种机制的影响。我们的建议基于已出版的文献和 初步数据显示：1）MPFC，AIC和VTA从事认知和情感决策； 2） MPFC和AIC直接连接，并且都从VTA接收DA输入； 3）压力影响MPFC和AIC 神经元以及在这些区域释放； 4）DA调节MPFC，AIC活动和决策。经过 将神经回路的投影特异性病毒标记与体内成像/电生理学和 光遗传学/药物遗传操作，我们将测试MPFC-AIC相互作用的中心假设 对于决策至关重要，这受到慢性压力的破坏，但可以通过DA调制挽救。 具体而言，在AIM 1中，我们将在决策过程中确定MPFC-AIC连接的功能 注意设置转移测试。在AIM 2中，我们将研究压力如何影响MPFC-AIC连接性和功能。在 AIM 3，我们将定义压力对MPFC和AIC功能调制的影响，并探索可能性 通过在压力小鼠中选择性恢复MPFC或AIC中的DA调制来挽救决策。这 该项目的成功结果不仅将提供有关电路机制的基本知识 较高的大脑功能是基本的，但也指出了缓解有害的潜在治疗靶标 压力和精神病的影响。