Study On The Circuit Mechanism Of Amygdala In Post-Traumatic Stress Disorder In Mice

Post-traumatic stress disorder(PTSD)is a common anxiety disorder which refers to the delayed and persistent mental disorders that occur after severe physical or psychological trauma exposure.The amygdala is a key region involved in producing negative emotion including fear and anxiety in higher animals,and the dysfunction of amygdala is highly relevant to a series of psychiatric diseases including PTSD.Thus,the exploration of structural and functional changes of amygdala neurons and the underlying neurological mechanisms in trauma-induced PTSD is of great significance to understand the pathogenesis of PTSD and develop relevant clinical treatment strategies.Based on neuronal projection target regions and gene expression properties,recent studies have shown that amygdala neurons are highly heterogeneous in circuit connection and function.Projection neurons(PNs)have specific projection target regions,and play distinct or even opposite functions in emotional processes.For example,the basolateral amygdala(BLA)neurons projecting to nucleus accumbens(NAc)(BLA→NAc PNs)is mainly responsible for positive emotions encoding and reward behavior regulation,while the neurons projecting to the ventral hippocampus(v HPC)(BLA→v HPC PNs)are responsible for negative emotions encoding and the regulation of anxiety and social behavior.However,the above behavioral findings are obtained under normal physiological conditions by manipulating the activity of such neurons,while in pathological state like PTSD,the effects of traumatic stress on different PNs in the amygdala remain largely unknown.In this study,we injected retrobeads into NAc and v HPC,to label BLA→v HPC PNs and BLA→NAc PNs within BLA.The PTSD model was established by foot shock(FS)paradigm.By using neuronal fluorescence tracing,morphological and electrophysiological techniques,the effects and potential mechanisms of FS on the neuronal activity of BLA→v HPC PNs and BLA→NAc PNs were explored.The results showed that FS significantly increased anxiety-like behavior in mice,which accompanied by an increase in the expression of the immediate early gene c-fos(a marker of neuronal activity)in the BLA.Further study indicated that the increased expression of c-fos caused by FS mainly appeared in BLA→v HPC PNs,but not in BLA→NAc PNs.In addition,whole-cell patch-clamp recordings from in vitro brain slices showed that FS obviously increased the intrinsic excitability of BLA→v HPC PNs,but not that of BLA→NAc PNs.These results suggest that FS exerts differential regulation on neuronal activity of BLA.In order to further explore the mechanism underlying such differential regulation of excitability,we next examined the after hyperpolarization potential(AHP)of neurons and found that the mAHP of BLA→v HPC PNs in FS mice was significantly reduced,while those of BLA→NAc PNs remained unaltered.Taken together,we speculate that FS can selectively reduce the mAHP of BLA→v HPC PNs,thereby increasing their excitability and neural activity,and the persistent activation of the BLA→v HPC circuit ultimately leading to PTSD-like symptoms in mice.Our study demonstrates that the differential regulation mechanism of traumatic stress on specific BLA projection neurons in the PTSD model,which provides theoretical basis for understanding the pathogenesis of PTSD,and offers a new potential circuit target for the precise treatment of PTSD.