| In today’s society,with the rapid development of the economy,people’s material living standards have been significantly improved,which is followed by the continuous increase in the pressure of life and work.Under the state of high stress,people’s physical and mental health are seriously damaged,leading to a significant increase in the incidence of anxiety,depression and other mental diseases.In particular,the stress panic and infection brought about by the COVID-19 outbreak in recent years have caused the global prevalence of anxiety and depression to exceed 25%.Therefore,it is of great significance to understand the pathogenesis of anxiety and depression and provide new therapeutic strategies for their treatment.Stress is one of the important factors that lead to negative emotions such as anxiety and depression.It is worth noting that different individuals have significantly different responses to the same stressful event or thing due to factors such as different genetic backgrounds and different growth experiences.In general,most people have a strong tolerance for various stresses in life and work,but a few people are significantly susceptible to them and cause the onset of mental disorders such as anxiety and depression.Obviously,exploring the brain mechanism of individual response to stress from the perspective of stress tolerance and susceptibility can help us understand the neural mechanism behind the onset of stress related mental diseases.A large number of studies have shown that the amygdala,located deep in the temporal lobe of the brain,is the core brain area that regulates stress responses.Changes in the structure and function of neurons in the basolateral area of the amygdala(BLA)are closely related to emotional development.However,it is unclear whether the amygdala brain region is involved in regulating the formation of individual differences in response to stress? If so,through what neural mechanism does it function? Therefore,in the first part of the research,we used inescapable electric shocks to establish a learned helplessness stress model to distinguish mice into the Helpless group(susceptible group)and the Resilient group(tolerant group).At the same time,combined with immunohistochemistry,electrophysiology,chemistry,genetics,single cell group,transcriptome sequencing and q PCR,we explored the amygdala circuit mechanism of differential regulation of individual negative emotions by stress.Our results show that: 1)Inescapable shock stress can lead to learned helplessness in some mice,accompanied by anxiety like behavior;2)Through screening the expression of c-Fos(a marker of neuronal activity)in multiple brain regions,it was found that the increased effect of stress on the expression of c-Fos in BLA and ventral hippocampus(v HPC)of Helpless group mice was significantly higher than that of Na?ve and Resilient group mice;3)Stress also caused a significant increase in intrinsic excitability and glutamatergic synaptic transmission of BLA neurons in the Helpless group;4)The above increase mainly occurred in the neurons projecting into the ventral hippocampus within the BLA(BLA→v HPC),but had no significant effect on the neurons projecting to the nucleus accumbens(BLA→NAc);5)Further research has found that the increased intrinsic excitability of BLA→v HPC neurons rather than BLA → NAc neurons is significantly correlated with the increased learned helplessness induced by stress in mice.Downregulation of BLA→v HPC neuronal activity through chemical genetics can reverse the learned helplessness in mice;6)Single cell transcription sequencing and single cell q PCR experiments showed that after stress,the Kcnh7 gene encoding one of the potassium ion channels in the BLA → v HPC neurons of Helpless mice was significantly downregulated compared to Na?ve and Resilient mice.These results suggest that inescapable electrical stress mediates learned helplessness in mice by regulating synaptic transmission and intrinsic excitability of BLA neurons,and our research demonstrates that the overactivation of BLA→v HPC neurons plays an important role in mediating these behaviors.In addition,in view of the important role of physiological inflammatory stress such as infection and pain in inducing anxiety and depression,and in combination with our recent findings that inflammatory stress can cause synaptic transmission and intrinsic excitatory dysfunction of BLA neurons,in the second part of the study,we continue to focus on the BLA of the amygdala to explore the potential therapeutic value of regulating the physiological function of BLA neurons by using harmine,a natural Chinese herbal active ingredient with anxiolytic and antidepressant effects.We found that: 1)Harmine intervention can reverse anxiety-and depression-like behaviors induced by LPS;2)Harmine intervention can effectively alleviate the inflammatory response of BLA induced by LPS;3)Harmine intervention can reverse the enhancement of excitatory synaptic transmission of BLA PNs induced by LPS without affecting inhibitory synaptic transmission;4)Harmine can significantly inhibit the enhancement of excitatory synaptic transmission efficiency of BLA PNs derived from medial prefrontal cortex inputs;5)Harmine intervention can reverse the decrease in after depolarization potential of BLA PNs induced by LPS,thereby blocking the increase in intrinsic excitability of BLA PNs mediated by LPS.These results on the one hand suggest that targeting the regulation of synaptic transmission and intrinsic excitability of BLA neurons is expected to provide new strategy for the treatment of inflammatory related anxiety and depression disorder,and provide new evidence for understanding the anxiolytic and antidepressant mechanisms of harmine.In summary,we found that the plasticity of BLA neurons plays an essential role in mediating stress-induced negative emotions such as anxiety and depression in mice.Targeting the plasticity of BLA neurons in amygdala has potential therapeutic value for the prevention and treatment of negative emotions such as anxiety and depression. |
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