CRCNS: Modeling Acquisition and Extinction of Fear Memories in Amygdala Circuits

描述（由申请人提供）：拟议的跨学科研究的总体目标是使用综合计算/实验方法来研究哺乳动物恐惧回路的神经成分中条件性恐惧关联的获得和消退。我们提出了一个相互依赖的系列实验和生物现实的模拟，使用“从生物学到模型，预测，并回到生物学”的主题，实验将约束模型的设计（“从生物学到模型”）和模型之间的差异和预期的结果将导致制定的假设（“预测”），将实验测试（“回到生物学”）。计算模型将使用来自两个神经科学Co-PI实验室的实验数据开发。我们小组在21/2年的时间里开发的初步模型表明，它们可以为与条件恐惧中的学习和神经可塑性相关的内在和突触机制提供重要的见解。本研究的主要目的是：1.利用生物学上的计算模型，研究杏仁核中与条件恐惧获得和消除相关的学习和神经可塑性的潜在机制，并在实验中验证模型预测。从生物学到模型：使用已发表的生物学数据（体外和体内），研究杏仁核（包括外侧杏仁核（LA），基底杏仁核（BA），嵌入细胞（ITC）和中央核（CeM和CeL））的单细胞模型的神经计算特性。从生物学到模型和预测：使用包括单细胞模型的生物现实网络模型，研究关键的杏仁核如何相互作用以获得和消除条件性恐惧记忆。做出预测，以量化从LA到CeM的各种预测的相对贡献，以及其他机制。从预测到生物学（和回）：评估恐惧条件反射和消退对从LA到CeL和CeL到CeM的投射中突触反应的影响，在体外切片制备中（将在Par实验室进行）。结合实验结果并完善模型。2.研究腹内侧前额叶皮层对杏仁核依赖性条件反射和消退恐惧记忆的调节机制，使用生物学上真实的计算模型，并在实验中检验模型预测。从生物学到模型：使用已发表的生物学数据（体外和体内），研究腹内侧前额叶皮层（vmPFC）的前边缘（PL）和边缘下（IL）区域中单细胞和网络的神经计算特性。从生物学到模型和预测：通过开发一个包括vmPFC和杏仁核的整体生物现实模型，确定vmPFC如何调节杏仁核依赖的恐惧和灭绝记忆（来自具体目标1）。预测vmPFC和杏仁核之间可能调节这些记忆的联系，以及vmPFC失活对BA和Ce神经元的音调反应的影响。从预测到生物学（以及返回）：评估vmPFC失活对恐惧条件反射和消退期间BA和Ce神经元的音调反应的影响（将在Quirk实验室进行）。整合实验结果，并在单一背景下完善杏仁核的vmPFC调节模型。智力优势。这项跨学科的研究将是第一个开发恐惧回路的生物学现实计算模型的研究。这将有助于发现学习和神经可塑性机制，这些机制是哺乳动物条件性恐惧获得和消除的基础，并将导致有价值的预测和实验研究的新方向。所提出的方法也将导致更好地理解控制恐惧回路的系统和设计原则。更广泛的影响。所提出的计算模型将提供对一系列精神疾病的新见解和理解，包括创伤后应激障碍和焦虑症，这些疾病被认为是由恐惧回路中的缺陷引起的。它也将成为开发治疗此类疾病的新型药物和策略的关键工具。最后，这项合作还将有助于为本科生、研究生和医学生教育以及K-12学生制定新的课程和材料。

DESCRIPTION (provided by applicant): The overall objective of the proposed cross-disciplinary research is to use an integrated computational/experimental approach to study the acquisition and extinction of conditioned fear associations in the neural components of the fear circuit of mammals. We propose an interdependent series of experiments and biologically realistic simulations, using a 'from biology to model, to predictions, and back to biology' theme where experiments will constrain the design of the models ('from biology to model') and discrepancies between the models and expected outcomes will lead to the formulation of hypotheses ('to predictions') that will be tested experimentally ('back to biology'). The computational models will be developed using experimental data from laboratories of two neuroscience Co-PIs. Preliminary models, developed by our group over a period of 21/2 years demonstrate that they can provide significant insights into the intrinsic and synaptic mechanisms associated with learning and neuroplasticity in conditioned fear. The proposed research will expand this collaboration with the following specific aims: 1.To investigate the underlying mechanisms of learning and neuroplasticity in the amygdala related to the acquisition and extinction of conditioned fear using a biologically realistic computational model, and to test model predictions in experiments. From biology to model: Use published biology data (in vitro and in vivo), to investigate neurocomputational properties of single cell models of amygdala nuclei including lateral amygdala (LA), basal amygdala (BA), intercalated cells (ITC), and central nucleus (CeM and CeL). From biology to model and to predictions: Investigate how the key amygdala nuclei interact to acquire and extinguish conditioned fear memories using a biologically realistic network model that includes the single cell models. Make predictions to quantify the relative contributions of the various projections from LA to CeM, and about other mechanisms. From predictions to biology (and back): Assess the effects of fear conditioning and extinction on synaptic responses in the projections from LA to CeL, and CeL to CeM, in an in vitro slice preparation (to be performed in the Par¿ lab). Incorporate findings from experiments and refine the model. 2. To investigate the mechanisms involved in the regulation of amygdala-dependent conditioning and extinction fear memory by the ventro medial prefrontal cortex, using a biologically realistic computational model, and to test model predictions in experiments. From biology to model: Use published biology data (in vitro and in vivo), to investigate the neurocomputational properties of single cells and networks in the pre-limbic (PL) and infra-limbic (IL) regions of the ventral medial prefrontal cortex (vmPFC). From biology to model and to predictions: Determine how the vmPFC regulates amygdala-dependent fear and extinction memories by developing an overall biologically realistic model including the vmPFC and the amygdala (from specific aim 1). Make predictions about the possible connections between vmPFC and the amygdala that may regulate these memories, and the effect of vmPFC inactivation on the tone responses of BA and Ce neurons. From predictions to biology (and back): Assess the effects of vmPFC inactivation on tone responses of BA and Ce neurons during fear conditioning and extinction (to be performed in Quirk lab). Incorporate findings from experiments and refine the model of vmPFC regulation of the amygdala in a single context. Intellectual Merit. The proposed interdisciplinary research will be the first to develop a biologically realistic computational model of the fear circuit. It will facilitate discovery of the learning and neuroplasticity mechanisms that underlie acquisition and extinction of conditioned fear in mammals, and will lead to valuable predictions, and novel directions for experimental research. The approach proposed will also lead to a better understanding of the systems and design principles governing the fear circuit. Broader Impact. The proposed computational model will provide new insights and understanding of a spectrum of psychiatric disorders including PTSD and anxiety disorders, which are thought to arise from deficits in the fear circuit. It will also be a key tool for the development of novel agents and strategies for the treatment of such disorders. Finally, the collaboration will also contribute to the generation of new curricula and materials for undergraduate, graduate and medical student education, and for K-12students.