The central amygdala circuits in fear learning and fear expression

描述（由申请人提供）：杏仁核对恐惧处理和恐惧调节至关重要。中央杏仁核（CeA），曾经被视为杏仁核复合体和下游恐惧效应器之间的被动中继，已成为恐惧学习的积极参与者。特别是，CeA（CeL）的外侧亚部中的神经元，其紧张性地抑制CeA（CeM）的内侧亚部，从而门控恐惧表达，被认为编码学习恐惧。然而，CeL有助于恐惧学习的机制仍然未知。此外，CeL在恐惧学习中的作用与其在恐惧表达中的已知作用之间的联系也不清楚。该项目的目的是阐明中央杏仁核有助于恐惧学习的机制，并在巴甫洛夫恐惧条件反射中协调恐惧表达。我们将专注于不同类别的抑制性神经元的细胞。我们的中心假设是，恐惧条件反射诱导细胞类型特异性突触修饰的细胞回路，作为恐惧记忆的痕迹。我们进一步提出，这些记忆痕迹的行为，以促进抑制CeL输出在恐惧记忆回忆，从而解除抑制CeM和释放恐惧的表达。我们设计了一个综合的方法，结合分子遗传学工具，体外和体内电生理学，光遗传学和化学遗传学技术，以验证我们的假设，具体目的是：1）描绘CeA抑制回路的功能组织，2）确定恐惧条件诱导的CeL突触可塑性的机制，（3）确定特定的CeL抑制回路在恐惧条件反射中的作用。该项目的发现将具有重要的临床意义，因为恐惧调节机制的功能障碍与许多精神疾病有关，包括广泛性焦虑症和创伤后应激障碍。

DESCRIPTION (provided by applicant): The amygdala is critical for fear processing and fear regulation. The central amygdala (CeA), once viewed as a passive relay between the amygdala complex and downstream fear effectors, has emerged as an active participant in fear learning. In particular, neurons in the lateral subdivision of the CeA (CeL), which tonically inhibits the medial subdivision of CeA (CeM) and thereby gates fear expression, are thought to encode learned fear. However, the mechanisms by which CeL contributes to fear learning remain unknown. In addition, the link between the role of CeL in fear learning and its known role in fear expression is also unclear. The objective of the proposed project is to elucidate the mechanisms by which the central amygdala contributes to fear learning and orchestrates fear expression in Pavlovian fear conditioning. We will focus on distinct classes of inhibitory neurons in the CeL. Our central hypothesis is that fear conditioning induces cell type-specific synaptic modifications in CeL circuits that serve as fear memory traces. We further propose that these memory traces act to promote the inhibition of CeL output during fear memory recall, thereby disinhibiting CeM and releasing fear expression. We designed an integrated approach, combining molecular genetic tools, in vitro and in vivo electrophysiology, and optogenetic and chemical-genetic techniques, to test our hypotheses in the following Specific Aims: 1) to delineate the functional organization of the CeA inhibitory circuits; 2) to determine the mechanisms of the fear conditioning-induced synaptic plasticity in CeL; and 3) to determine the role of specific CeL inhibitory circuits in fear conditioning. Findings from this project will have important clinical implications, as dysfunction of fear regulation mechanisms is implicated in a number of psychiatric conditions, including generalized anxiety disorder and post-traumatic stress disorder.