Molecular genetic dissection of amygdala microcircuitry controlling decision-making

 描述（由申请人提供）：定义控制决策的脑回路，例如社会互动和反社会行为之间的决策，是神经科学中与人类健康高度相关的重要问题。这些神经回路位于进化上古老的大脑区域，如杏仁核。在人类中，社交互动减少是自闭症等精神疾病的一个关键症状领域，并被认为涉及杏仁核。杏仁核是一个复杂的结构，由至少12个不同的亚区组成。杏仁核的基底外侧和中央杏仁核中控制条件性恐惧的杏仁核回路已经得到了深入的研究。然而，我们对这些回路的理解与控制社会互动的不同杏仁核亚核中的回路之间仍然存在差距。后者被认为位于杏仁核的内侧亚部（MeA）。为了填补这一空白， 我们将开始剖析MeA回路的功能，它控制着社会互动和重复性自我修饰（一种反社会行为）之间的平衡。这种平衡很重要，因为自闭症等疾病通常会增加重复性的反社会行为，以及减少社会互动。长期的目标是在全脑水平上理解这种平衡的电路级控制。本申请的总体目标是定义不同MeA神经元亚群的作用，这些亚群对抗性地控制社会互动与重复的自我梳理，并了解这种对抗作用的电路。本研究的主要目的是研究内侧杏仁核内GABA能和谷氨酸能神经元亚群如何调节这些对手的活动。这项研究的基本原理是，它将揭示与人类健康相关的大脑区域中神经回路功能的基本机制。为了实现我们的目标，我们将分别绘制控制社交互动与重复自我梳理的vGAT+和VGLUT2 + MeApd神经元的功能投射（目标1）;检验社交互动由去抑制回路控制的假设并绘制该回路（目标2）;确定社交互动的功能投射（目标2）。 vGAT+和vGLUT2+亚群对社交与自我梳理行为发挥拮抗控制的机制（目的3）;确定这些亚群中的每一个执行的双重功能是否来自共同或不同的细胞类型（目的4）。我们的贡献将是应用最先进的基于遗传学的工具来剖析MeA中控制社会与重复性反社会行为的回路水平机制。这一贡献意义重大，因为它将在尚未达到的细胞特异性水平上，推动对杏仁核回路控制社会互动的研究。贡献是创新的，因为它调查的杏仁核电路，我们最近发现涉及兴奋：抑制平衡的新功能。因此，本申请中提出的工作将推进我们对神经回路功能组织的基本理解，并阐明杏仁核神经元亚群和可能与影响社会互动的人类疾病相关的回路的细节。

 DESCRIPTION (provided by applicant): Defining brain circuits that control decisions, such as those between social interactions and asocial behaviors is an important problem in neuroscience with high relevance to human health. These neural circuits are located in evolutionarily ancient brain regions, such as the amygdala. In humans, decreased social interactions are a key symptom domain in psychiatric disorders such as autism, and are thought to involve the amygdala. The amygdala is a complex structure consisting of at least 12 distinct subregions. The amygdala circuits that control conditioned fear in the basolateral and central amygdala have been intensively studied. However a gap remains between our understanding of these circuits, and those in different amygdala subnuclei that control social interactions. The latter are thought to be located in the medial subdivision of the amygdala (MeA). To fill this gap, we will begin to dissect the function of MeA circuits that control the balance between social interactions and repetitive self-grooming, an asocial behavior. This balance is important because disorders such as autism often feature increased repetitive asocial behaviors, as well as decreased social interactions. The long-term goal is to understand the circuit-level control of this balance at a brain-wide level. The overall objective of this application is to define the roleof different MeA neuronal subpopulations that antagonistically control social interactions vs. repetitive self-grooming, and to understand the circuitry through which this antagonism is exerted. The central objective of this proposal is to study how GABAergic and glutamatergic neuronal subpopulations in the medial amygdala reciprocally regulate these opponent activities. The rationale for this research is that it will reveal fundamental mechanisms of neural circuit function in a brain region that is relevant to human health. To achieve our objective, we will map the functional projections of vGAT+ and VGLUT2+ MeApd neurons that control social interactions vs. repetitive self-grooming, respectively (Aim 1); test the hypothesis that social interactions are controlled by a dis-inhibition circuit and map that circuit (Aim 2); determine the mechanism by which vGAT+ and vGLUT2+ subpopulations exert antagonistic control of social vs. self-grooming behaviors (Aim 3); determine whether the dual functions performed by each of these subpopulations derive from common or distinct cell types (Aim 4). The contribution will be to apply state-of-the- art genetically based tools to dissect circuit-level mechanisms in MeA that control social vs. repetitive asocial behaviors. This contribution is significant because it will oen up the study of amygdala circuitry controlling social interactions, at a level of cellular specificty that has not yet been achieved. The contribution is innovative, because it investigates novel features of amygdala circuitry that we have recently uncovered involving the excitation:inhibition balance. The work proposed in this application will therefore both advance our basic understanding of neural circuit functional organization, and shed light on the particulars of amygdala neuronal subpopulations and circuitry that may relevant to human disorders affecting social interactions.