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

项目摘要 复杂的决策通常包括认知和情感两个部分。认知和 情感过程涉及大脑中不同但相互作用的系统，这两个系统都受到压力的影响， 这是现代社会的一个普遍问题，也是众所周知的精神疾病风险因素。人脑 影像学研究表明，大脑区域网络是认知和情感之间的潜在界面。 处理，特别是内侧前额叶皮层（mPFC），前岛叶皮层（aIC）和中脑 多巴胺（DA）区域，如腹侧被盖区（VTA）。然而，这些研究缺乏因果关系检验， 神经回路水平。比较神经解剖学和发育遗传学已经在老鼠身上发现了 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 压力。这些发现为使用小鼠作为模型物种进行基本的因果关系研究打开了大门。 这些大脑区域的功能与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-情感相互作用的额-岛回路机制 以及压力对小鼠这种机制的影响。我们的建议是基于已发表的文献， 初步数据显示：1）mPFC，aIC和VTA参与认知和情感决策; 2） mPFC和aIC直接相连，均接受VTA的DA输入; 3）应力影响mPFC和aIC 4）DA调节mPFC和aIC的活动和决策。通过 将神经回路的投射特异性病毒标记与体内成像/电生理学相结合， 通过光遗传学/药物遗传学操作，我们将检验中心假设，即mPFC-aIC相互作用是 这对决策至关重要，它会被慢性压力破坏，但可以通过DA调节来挽救。 具体而言，在目标1中，我们将确定mPFC-aIC连接在决策过程中的功能。 注意定势转移测验在目标2中，我们将研究压力如何影响mPFC-aIC连接和功能。在 目的3：明确应激对DA调节mPFC和aIC功能的影响，并探讨其可能性 通过选择性恢复应激小鼠mPFC或aIC中的DA调节来挽救决策。的 该项目的成功结果不仅将提供有关电路机制的基础知识， 潜在的更高的大脑功能，但也指出了潜在的治疗目标，以减轻有害的 压力和精神疾病的影响。

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.