Role of amygdala inhibitory circuit neuromodulation in stress disorders

项目标题：杏仁核抑制环路神经调节在应激障碍中的作用 项目摘要 创伤应激暴露可导致长期应激障碍，并代表着相当大的风险因素 自杀。应激障碍，如创伤后应激障碍(PTSD)和酒精使用障碍 与自杀有关，以神经回路和神经化学信号的可塑性为特征 杏仁核，尤其是杏仁核的基底外侧复合体(BLA)。BLA集成了来自 多来源，并通过建立不同的信息流为信息分配情感价位 外流。BLA电路根据兴奋/抑制平衡设置处理输入以形成情感记忆 通过向BLA的主要输出神经元的相对兴奋性和抑制性突触输入。而当 兴奋性突触的增强是记忆形成的基础，抑制电路调节 兴奋/抑制平衡控制突触增强，神经调制信号调节突触 互动。去甲肾上腺素能调节被认为是唤醒的信号，并对情绪有重大贡献 杏仁核处理的信息的突显性。我们在小鼠身上的初步临床前发现表明 去甲肾上腺素(NE)对GABA能小白蛋白(PV)和缩胆囊素的强大调节作用 (CCK)抑制传入BLA主神经元，这种控制在创伤后受到损害 压力暴露。我们建议表征去甲肾上腺素对PV和CCK突触输入的调制 并明确去甲肾上腺素能调节突触抑制在BLA中的作用 调节恐惧记忆的形成。我们将针对去甲肾上腺素能传入调节PV和CCK 使用化学发生和光发生策略的神经元间回路。我们会审问当地的PV和CCK 应用膜片钳技术研究去甲肾上腺素能神经调节中BLA神经元间抑制性突触信号的传递 杏仁核切片上的录音。我们将使用行为范式来确定去甲肾上腺素能 BLA抑制回路在恐惧巩固和消退中的调制。最后，我们将测试创伤应激- 去甲肾上腺素能抑制环路的可塑性及其对PV和CCK环路的调节 害怕学习。这些研究将共同揭示去甲肾上腺素对BLA回路的调制机制 并对不同的骨周抑制回路在血乳酸控制中的作用(S)提供了重要的见解。 依赖恐惧记忆的形成，以及创伤应激暴露是如何扰乱这些回路的。

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.