Role of amygdala inhibitory circuit neuromodulation in stress disorders

项目名称：杏仁核抑制回路神经调节在应激障碍中的作用 项目摘要 创伤性应激暴露可导致长期应激障碍，并代表了一个相当大的风险因素， 自杀应激障碍如创伤后应激障碍（PTSD）和酒精使用障碍具有显著的 与自杀倾向有关，其特征是神经回路和神经化学信号的可塑性。 杏仁核，特别是杏仁核基底外侧复合体（BLA）。BLA整合了来自 多个来源，并通过建立不同的信息流来为信息分配情感效价 外流BLA回路根据兴奋/抑制平衡集处理输入以形成情感记忆 通过对BLA的主要输出神经元的相对兴奋性和抑制性突触输入。而 兴奋性突触的增强是记忆形成的基础，抑制性回路调节兴奋性突触的增强。 兴奋/抑制平衡来控制突触增强，神经调节信号调节突触增强。 交互.去甲肾上腺素能调节被认为是唤醒的信号，并对情绪产生显著影响。 杏仁核处理信息的显著性。我们在小鼠中的初步临床前研究结果表明， 去甲肾上腺素（NE）对GABA能小清蛋白（PV）和胆囊收缩素（CCK）发挥强有力的调节控制作用 (CCK)BLA主要神经元的抑制性输入，并且这种控制在创伤后受到损害。 压力暴露我们提出去甲肾上腺素能调制PV和CCK突触输入的特点， 的BLA主要神经元，并确定在BLA突触抑制的去甲肾上腺素能调制的作用， 介导的恐惧记忆形成。我们将靶向PV和CCK的去甲肾上腺素能传入调节 使用化学遗传学和光遗传学策略的神经元间回路。我们会询问当地的PV和CCK 应用膜片钳技术研究BLA中神经元间抑制性突触信号对去甲肾上腺素能神经元的调节作用 记录在杏仁核切片上。我们将使用行为范例来确定去甲肾上腺素能神经元在 BLA抑制回路在恐惧巩固和消退中的调制。最后，我们要做创伤压力测试- 抑制回路的去甲肾上腺素能调节和PV和CCK回路调节的诱导可塑性 害怕学习。这些研究将揭示BLA回路的去甲肾上腺素能调节机制 并提供了重要的见解不同的体周抑制回路在控制BLA的作用， 依赖性恐惧记忆的形成，以及这些回路是如何被创伤性压力暴露所破坏的。

Project Title: Role of amygdala inhibitory circuit neuromodulation in stress disorders Project Summary Traumatic stress exposure can lead to long-term stress disorders and represents a considerable risk factor for suicide. Stress disorders such as posttraumatic stress disorder (PTSD) and alcohol use disorder have significant links with suicidality and are characterized by plasticity of neural circuits and neurochemical signaling in the amygdala, particularly in the basolateral complex of the amygdala (BLA). The BLA integrates neural inputs from multiple sources and assigns emotional valence to information by establishing distinct streams of information outflow. BLA circuits process inputs to form emotional memories based on the excitation/inhibition balance set by the relative excitatory and inhibitory synaptic inputs to the principal output neurons of the BLA. While potentiation at excitatory synapses is the foundation of memory formation, inhibitory circuits regulate the excitation/inhibition balance to control synaptic potentiation, and neuromodulatory signals tune the synaptic interactions. Noradrenergic modulation is thought to signal arousal and contribute significantly to the emotional salience of information processed in the amygdala. Our preliminary preclinical findings in mice suggest that norepinephrine (NE) exerts robust regulatory control over GABAergic parvalbumin (PV) and cholecystokinin (CCK) inhibitory inputs to the BLA principal neurons, and that this control is compromised following traumatic stress exposure. We propose to characterize the noradrenergic modulation of PV and CCK synaptic inputs to the BLA principal neurons, and to define the role of noradrenergic modulation of synaptic inhibition in BLA- mediated fear memory formation. We will target the noradrenergic afferent regulation of PV and CCK interneuronal circuits using chemogenetic and optogenetic strategies. We will interrogate local PV and CCK interneuron inhibitory synaptic signaling in the BLA for noradrenergic neuromodulation using patch clamp recordings in slices of amygdala. We will use behavioral paradigms to determine the role of the noradrenergic modulation of BLA inhibitory circuits in fear consolidation and extinction. Finally, we will test for traumatic stress- induced plasticity of the noradrenergic modulation of inhibitory circuits and the PV and CCK circuit regulation of fear learning. These studies together will reveal the mechanisms of the noradrenergic modulation of BLA circuits and provide important insights into the role(s) of distinct perisomatic inhibitory circuits in the control of BLA- dependent fear memory formation, as well as into how these circuits are disrupted by traumatic stress exposure.