皮层下网络调控恐惧与焦虑的环路机制研究

Negative emotions, such as fear and anxiety, are important for animal survival in response to danger and risk. However, the dysfunctions of emotion processing can cause multiple neuropsychiatric disorders, including excessive anxiety and depression. Interventions of these disorders require systematic dissection of the underlying brain neural circuits. Several subcortical nuclei are closely involved in shaping the behavioral regulation of fear and anxiety. These structures, including the central amygdala, the dorsal raphe, and the habenula, are interconnected and provide widespread projections to the cerebral cortex. Here, we propose to study the functions of these subcortical nuclei by integrating multi-channel single-unit recordings, optogenetics, optical imaging, behavioral assays, virus-based transsynaptic tracing, and whole-brain visualization of neuronal morphology. We intend to investigate cell-type specific neuronal connections, neuronal physiological properties, and the causal relationship between neuronal activity and behavioral output. We will focus on studying how these neural circuits affect innate fear, fear conditioning, and the over-anxiety caused by repetitive activation of fear-related circuit. Our studies have the potential of uncovering the neural circuits underlying the generation and modulation of fear anxiety, and lay important foundation to the further development of effective therapeutic targets against neuropsychiatric disorders.

恐惧、焦虑等负面情绪信号处理异常会导致严重的精神疾病。深入探究中枢神经系统对负面情绪信号的调控机制对有效预防和治疗这些精神症候群至关重要。在中枢神经系统，几个亚皮层核团与恐惧焦虑行为的调控关系非常密切，它们是中心杏仁核、中缝背核、和缰核。这些核团相互连接，并与皮层形成广泛投射，调控着恐惧情感活动的产生。本项目将结合在体多通道电生理、光遗传学、光学成像、行为学、跨突触神经示踪、全脑范围形态学等方法，系统解析与恐惧焦虑密切相关的上述核团间的精密投射网络、细胞电生理特征、神经活动与恐惧及焦虑行为的因果关系。重点解析上述环路在先天性恐惧的快速检测和处理、先天性恐惧条件化形成习得性恐惧、恐惧重复激活和敏感化导致持续性焦虑这三个方面的作用。本研究将揭示恐惧焦虑等负面情绪信号在脑内传递和处理的神经环路基础，为负面情绪的产生和调控提供重要的理论基础，并同时为治疗情绪性相关的精神类疾病提供可能。

恐惧、焦虑等负面情绪信号处理异常会导致严重的精神疾病。深入探究中枢神经系统对负面情绪信号的调控机制对有效预防和治疗这些精神症候群至关重要。在本项目中，我们采用体外膜片钳、在体电生理技术、光遗传学、光学成像、行为学、跨突触神经示踪等方法，系统解析了外侧缰核、内侧缰核和脚间核以及中缝背核的细胞电生理特征、神经活动与恐惧焦虑等负面行为的因果关系。我们发现，内侧缰核胆碱能神经细胞及其突触前膜的GABAB受体对动物恐惧记忆的正常表达和消退具有重要作用。通过一个颠覆传统认识的突触前兴奋作用，这些GABAB受体能够减弱动物的恐惧反应、促进恐惧记忆的消退；与之相关的是，脚间核神经元会被恐惧信号激活并编码了动物对恐惧应答的整个过程，而且其活性还平衡了动物对恐惧的积极和消极应答。同时，负面情绪事件会强烈激活外侧缰核谷氨酸神经元，而编码正面情绪的条件刺激则会抑制这些神经元的发放。此外，通过在体光纤记录和光标法结合的电生理记录，我们揭示了不同类型中缝背核神经元对正面及负面情绪信号的反应。记录显示，多种正面情绪性行为显著激活5-HT神经元，而负面情绪信号则没有激活的效果。相反，同一脑区的GABA神经元被正面情绪抑制而被负面情绪激活。进一步对比分析中缝背核5-HT神经元和腹侧被盖区DA神经元的发放特征，我们发现，负面情绪可以显著降低5-HT神经元和DA神经元对正面刺激的反应，而5-HT神经元负责处理DA神经元未编码的正面情绪期待信息。这些结果揭示了恐惧、焦虑等负面情绪信号在脑内传递和处理的神经环路基础，为治疗情绪信号失调引起的抑郁、过度恐惧和创伤后应激障碍等相关的精神类疾病提供了新的靶点和思路。