社交恐惧是众多神经精神疾病的一个高度共有病征，其发生机制不甚清楚，且目前尚无令人满意的疗法。过去的研究清楚地表明杏仁核在恐惧情绪记忆中起着决定性的作用。与此同时，杏仁核接受大脑皮层以及皮层下众多脑区的功能调控。最近的研究显示前额叶皮层在恐惧记忆中发挥着重要的调控作用。大脑皮层神经网络活动依赖兴奋性和抑制性的精确平衡，需要抑制性神经元的密切参与。然而，到目前为止，人们对前额叶皮层参与社交恐惧记忆调控的抑制性环路机制却并不清楚。我们将利用转基因小鼠，结合清醒动物多通道电生理纪录、光遗传学和动物行为学，系统地研究前额叶皮层主要类型抑制性神经元在社交恐惧记忆条件化过程中的活动规律，以及它们活动水平的改变对社交恐惧记忆的直接影响，从而明确特定类型抑制性神经元在社交恐惧记忆中的具体功能作用。我们的研究结果将加深我们对情感记忆形成机制的理解，并为改善相关神经精神疾病的社交恐惧症状的医学实践提供理论指导。

Social fear is a highly prevalent behavioral symptom among many neuropsychiatric disorders. Its pathological mechanism is poorly understood and there are no satisfactory therapeutic options available. Previous studies have fully demonstrated the determinant role of the amygdala in fear memory. At the same time, the amgdala are under functional modulation of various cortical and subcortical inputs. Recent evidence has revealed a critical role of prefrontal cortex in the modulation of fear memory. The cortical network activities rely on a delicate balance between excitation and inhibition and require the involvement of inhibitory neurons. However the inhibitory circuits underlying the modulation of prefrontal cortex in social fear memory is not clear. Combining multichannel recording and optogenetic approaches with the availability of mouse lines expressing Cre in specific subtypes of inhibitory neurons, we will systematically study the functional roles of prefrontal cortical inhibitory neuron subtypes in social fear memory acquisition. First, we will investigate the activity patterns of major types of prefrontal cortical inhibitory neurons during social fear conditioning. For the inhibitory interneuron subtypes that display salient change in their firing rate, we will further investigate the impact of their activation and inactivation on the animal’s social fear acquisition. To achieve a better understanding of inhibitory circuits in prefrontal cortex underlying social fear, we will also characterize the structural and functional connections of major subtypes of inhibitory neurons with principal neurons and other subtypes of inhibitory neurons. Together, these studies will help understand the neural substrate of social fear memory from the perspective of inhibitory circuits. The findings from our proposed studies will advance the development of future therapies for patients with social fear.

社交恐惧是众多神经精神疾病的一个高度共有病征，其发生机制不甚清楚，且目前尚无令人满意的疗法。过去的研究清楚地表明杏仁核在恐惧情绪记忆中起着决定性的作用。与此同时，杏仁核接受大脑皮层以及皮层下众多脑区的功能调控。最近的研究显示前额叶皮层在恐惧记忆中发挥着重要的调控作用。大脑皮层神经网络活动依赖兴奋性和抑制性的精确平衡，需要抑制性神经元的密切参与。然而，到目前为止，人们对前额叶皮层参与社交恐惧记忆调控的抑制性环路机制却并不清楚。本项目中，我们利用转基因小鼠，结合清醒动物多通道电生理纪录、光纤钙测量技术、药理遗传学和动物行为学，系统地研究前额叶皮层主要类型抑制性神经元（包括PV神经元、SOM神经元和VIP神经元）在社交恐惧表达过程中的活动规律，以及它们活动水平的改变（激活PV神经元或者抑制SOM神经元）对社交恐惧记忆的直接影响。我们发现社交恐惧表达时，前额叶皮层兴奋性神经元和PV神经元活动水平分别升高和降低，而失活兴奋性神经元或者激活PV神经元，小鼠恐惧程度均下降。同时，我们发现PV神经元活动水平降低是由于SOM神经元而不是VIP神经元活动升高引起的。与此相一致，我们发现SOM神经元的失活也能有效降低小鼠的社交恐惧程度。基于这些实验结果，我们认为社交恐惧表达时，SOM神经元首先被激活，被激活的SOM神经元通过抑制PV神经元的活性从而去抑制了兴奋性神经元，造成前额叶皮层的过度兴奋，进而驱动社交恐惧行为的发生。因此，我们发现了一条新的前额叶皮层去抑制性神经微环路，介导了社交恐惧的表达。这些研究结果加深了我们对情感记忆形成机制的理解，并为改善相关神经精神疾病的社交恐惧症状的医学实践提供理论指导。