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

CRCNS：模拟杏仁核回路中恐惧记忆的获取和消除

基本信息

批准号：
8081062
负责人：
Satish S Nair
金额：
$ 24.03万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-31 至 2013-04-30
项目状态：
已结题

项目摘要

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.

描述（由适用提供）：拟议的跨学科研究的总体目标是使用综合计算/实验方法研究哺乳动物恐惧回路神经成分中条件恐惧关联的获取和扩展。我们提出了一系列相互依存的实验和生物学上逼真的模拟，使用“从生物学到模型，预测到生物学”主题，在该主题中，实验将限制模型的设计（“从生物学到模型”），模型和预期之间的差异将导致假设（预测''的生物群体''''''''''''''''''''）。计算模型将使用来自两个神经科学Co-Pis实验室的实验数据开发。我们小组在21/2年内开发的初步模型表明，它们可以对条件恐惧中的学习和神经质性相关的内在和突触机制提供重要的见解。拟议的研究将以以下特定目的扩展这种合作：1。研究与使用生物学上现实的计算模型的获取和扩展条件恐惧有关的杏仁核中学习和神经质性的潜在机制，并在实验中测试模型预测。从生物学到模型：使用已发表的生物学数据（体外和体内），研究杏仁核核的单细胞模型的神经计算特性，包括外侧杏仁核（LA），碱性杏仁核（碱性杏仁核（BA）（BA）（BA），插入式细胞（ITC）和Central Nucus（Cem and Cem和Cel）。从生物学到模型再到预测：研究关键杏仁核如何使用包含单细胞模型的生物学现实网络模型来获取和扑灭条件的恐惧记忆。做出预测以量化从LA到CEM以及其他机制的各种投影的相对贡献。从预测到生物学（和背面）：在体外切片制备中评估恐惧调节和扩展对从LA到CEL的突触反应以及CEL到CEM的突触反应的影响（待在PAR上进行）。结合了实验的发现并完善模型。 2。使用生物学上现实的计算模型以及实验中的模型预测，研究腹膜内侧前额叶皮层调节杏仁核依赖性条件和扩展恐惧记忆的机制。从生物学到模型：使用已发表的生物学数据（体外和体内），研究腹侧培养基前额叶前膜皮层（VMPFC）的limbic（PL）（PL）（PL）和Indra-limbic（IL）区域中单细胞和网络的神经计算特性。从生物学到模型再到预测：确定VMPFC如何通过开发包括VMPFC和杏仁核的整体生物学现实模型来调节杏仁核依赖性的恐惧和扩展记忆（来自特定目标1）。对VMPFC与可能调节这些记忆的杏仁核之间可能的联系进行预测，以及VMPFC失活对BA和CE神经元张力响应的影响。从预测到生物学（和背面）：评估VMPFC失活对恐惧条件和扩展过程中BA和CE神经元张力反应的影响（将在Quirk Lab中进行）。结合了实验中的发现，并在单个情况下完善了杏仁核的VMPFC调节模型。智力优点。拟议的跨学科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。它将促进发现哺乳动物中有条件恐惧的基础的学习和神经塑性机制，并将带来有价值的预测，以及实验研究的新方向。提出的方法还将使人们更好地理解有关恐惧巡回赛的系统和设计原则。更广泛的影响。拟议的计算模型将提供新的见解，并了解包括PTSD和焦虑症在内的一系列精神疾病，这些疾病被认为是由恐惧回路中的定义引起的。它也将是开发新型药物和治疗此类疾病的策略的关键工具。最后，合作还将为本科，研究生和医学生教育以及K-12学生的新课程和材料的生成贡献。