The Neural Circuits Of Subthalamic Nucleus Regulating Fear And Sleep

Stress-related psychiatric disorders have high comorbidity with abnormal fear and sleep disorder,suggesting the involvement of common neural circuits in the occurrence and development of stress-related psychiatric diseases.However,research on the neural connection basis and molecular mechanism of these circuits is lacking in the neurobiology of the above-mentioned diseases Corticotropin-releasing hormone（CRH）neurons in the medial part of subthalamus nucleus（mSTN）control the innate fear responses to acute threats and mediate an adaptive increase in REM sleep induced by sustained stress,indicating that the mSTN-CRH neurons are the key circuit regulating fear and sleep.However,the function of CRH peptide and the specific connectivity of these mSTN-CRH neurons has not been defined.Here,we illustrated the role of CRH in regulating fear and sleep by optogenetics and administration of CRH receptor type 1 antagonist.We also illustrated a whole-brain map of inputs to mSTN-CRH neurons by using the TRIO（tracing the relationship between input and output）virus strategy.In this study,by using fluorescence in situ hybridization and immunohistochemical staining,we showed that mSTN neurons were mostly glutamatergic neurons,and 80 % of CRH neurons are glutamatergic.By optogenetically activation of mSTN-CRH neurons and administration of CRH-R1 antagonist in the external globus pallidus（GPe）,we confirmed that the mSTN-CRHGPe pathway mediates innate fear responses and sleep behaviors through the CRH/CRH-R1 system.Furthermore,we investigated the inputs to the mSTN-CRH neurons with different projections.The results showed that multiple brain regions involved in the regulation of threat,stress response,and sleep-wake states,project to mSTN-CRH neurons.Furthermore,we suggested that there may be four subtypes of mSTN-CRH neurons based on the inputs and outputs connectivity features.Finally,we systematically examined the distribution of excitatory and inhibitory cells projecting to mSTN.In summary,these data showed that CRH peptide release play a key role in the fear and sleep responses to stress controlled by mSTN-CRH neurons.These data also indicated complex architecture of presynaptic inputs are integrated by mSTN-CRH neurons to produce fine control of behaviors.These results not only help us to understand the neural mechanism of mSTN-CRH neurons as the common circuit regulating fear and sleep,but also provide biological basis and a potential target for the treatment of psychiatric disorders associated with fear and sleep disorders.