权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Plasticity of amygdala intercalated cell microcircuits in fear learning

杏仁核嵌入细胞微电路在恐惧学习中的可塑性

基本信息

批准号：
272758458
负责人：
Professorin Dr. Ingrid Ehrlich
金额：
--
依托单位：
Institut für Pharmakologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2015
资助国家：
德国
起止时间：
2014-12-31 至 2019-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/272758458?language=en
关键词：
Plasticity amygdala intercalated cell microcircuits

项目摘要

Anxiety spectrum disorders result from abnormal regulation of neural networks that support fear learning. A key brain region is the amygdala, which is composed of several nuclei with unique inputs and outputs. To study fear learning in the laboratory, Pavlovian fear conditioning is the most widely used model, where a neutral conditioned stimulus (CS) is associated with an aversive unconditioned stimulus (US). Conditioned fear responses are acquired through activity-dependent plasticity at glutamatergic sensory synapses on principal neurons of the basolateral amygdala. While increasing evidence also indicates a critical role for modulation and plasticity of inhibitory neurons, specific functions and plasticity mechanisms of different types of amygdala GABAergic neurons are still poorly understood. Recently, clusters of GABAergic projection neurons, the intercalated cells (ITC) received particular attention as crucial players in extinction learning. ITCs are ideally positioned to integrate information from the somatosensory system and neuromodulators such as dopamine, which has a critical role in acquisition and expression of fear. Our recent findings show that dorsal ITCs are also activated by fear learning, are a site of convergence for glutamatergic CS- and US-related sensory inputs, and send efferents to several local (amygdala) and extra-amygdala targets. Our key hypothesis is that salient sensory stimuli directly drive ITC neuronal plasticity and activity, which in turn affects multiple target areas to control conditioned fear behavior.Here, we propose an integrated approach to investigate fear learning-related synaptic plasticity in ITC networks, and to understand how ITC activity and outputs contribute to distinct acquired fear states in mice. First, we will elucidate functional and molecular mechanisms of sensory input plasticity onto dorsal ITCs following fear learning and memory retrieval using ex vivo electrophysiology and high-resolution imaging. Next, we will determine the role of physiologically released dopamine in modulating ITC plasticity by employing a specific optogenetic approach. Thirdly, for all recorded ITCs we will identify innervated brain regions and targeted cell types using anatomical techniques. As we hypothesize that subsets of dorsal ITCs with specific outputs are activated during distinct fear states, we will examine activation of ITCs with defined target regions upon high and low fear states by combining behavioral analysis with retrograde tracing and activity mapping. Lastly, to establish a causal link between ITC activity and distinct fear states, we will use a pharmacogenetic approach to attenuate ITC activity specifically during fear learning, memory retrieval, and extinction. Our data will provide important new insights into the layout, plasticity mechanisms, and role of these specialized GABAergic ITC microcircuits in the amygdala in distinct acquired fear states.

焦虑谱系障碍是由支持恐惧学习的神经网络的异常调节引起的。杏仁核是大脑的一个关键区域，它由几个具有独特输入和输出的核团组成。为了在实验室中研究恐惧学习，巴甫洛夫恐惧条件反射是最广泛使用的模型，其中中性条件刺激（CS）与厌恶的非条件刺激（US）相关联。条件性恐惧反应是通过基底外侧杏仁核主要神经元上的神经元感觉突触的活动依赖可塑性获得的。虽然越来越多的证据也表明抑制性神经元的调制和可塑性的关键作用，不同类型的杏仁核GABA能神经元的具体功能和可塑性机制仍然知之甚少。最近，GABA能投射神经元簇，即闰细胞（ITC）作为灭绝学习的关键参与者受到特别关注。ITCs的理想位置是整合来自躯体感觉系统和神经调节剂（如多巴胺）的信息，多巴胺在恐惧的获得和表达中起着关键作用。我们最近的研究结果表明，背侧ITCs也被激活的恐惧学习，是一个网站的收敛性CS和US相关的感觉输入，并发送传出神经到几个本地（杏仁核）和杏仁核外的目标。我们的主要假设是，显着的感觉刺激直接驱动ITC神经元的可塑性和活动，这反过来又影响多个目标领域，以控制条件性恐惧behaviors.Here，我们提出了一个综合的方法来研究恐惧学习相关的突触可塑性在ITC网络，并了解如何ITC活动和输出有助于不同的获得性恐惧状态的小鼠。首先，我们将阐明的功能和分子机制的感觉输入可塑性到背ITCs恐惧学习和记忆检索使用离体电生理学和高分辨率成像。接下来，我们将通过采用特定的光遗传学方法来确定生理释放的多巴胺在调节ITC可塑性中的作用。第三，对于所有记录的ITC，我们将使用解剖技术识别受神经支配的脑区域和靶细胞类型。由于我们假设具有特定输出的背侧ITCs的子集在不同的恐惧状态下被激活，因此我们将通过结合行为分析与逆行追踪和活动映射来研究具有定义的目标区域的ITCs在高和低恐惧状态下的激活。最后，为了建立ITC活动和不同的恐惧状态之间的因果关系，我们将使用药物遗传学方法来减弱ITC活动，特别是在恐惧学习，记忆恢复和灭绝。我们的数据将提供重要的新见解的布局，可塑性机制，以及这些专门的GABA能ITC微电路在杏仁核在不同的获得性恐惧状态的作用。