Thalamic Reticular Nucleus Input To The Lateral Habenula Regulates Depression

Depression is the most common psychiatric disorder,with more than 280 million people worldwide suffering from depression.Chronic stress and chronic pain are two major predisposing factors to trigger depression.It has been reported that chronic pain patients have more than 50%of probability to develop major depression,and about 65%of depressed patients also have chronic pain.The vicious circle created by the pain-depression co-morbidity makes some patients with depression difficult to treat.The dissection of the neurocircuitry mechanism of depression will help to develop new targets and new therapeutic options for antidepressants.Glutamic acid and y-aminobutyric acid are the main excitatory and inhibitory neurotransmitters in the nervous system,respectively.The imbalance of Glutamic acid and y-aminobutyric acid neurotransmitters in the lateral habenula is crucial in the pathogenesis of depression.It has been shown that to LHb-induce LHb neural hyperexcitability induced by enhanced excitatory inputs is one of the factors for depression onset.However,the role of LHb inhibitory afferents in depression is unclear.The thalamic reticular nucleus is an important inhibitory nucleus in the brain,which provides the main inhibitory innervation to the thalamus.However,whether it sends inhibitory input to LHb and its role in depression has not been reported.In this study,using virus tracking,immunofluorescence and patch clamp technique,we report that somatostatin-expressing rather than parvalbumin-expressing cells in sensory thalamic reticular nucleus sent inhibitory inputs to glutamatergic neurons in the lateral habenula.Using fiber photometry recording,the SOMsTRNGLULHb inhibitory pathway was found to be activated by multiple aversive stimuli.Activation of the SOM^sTRN-GLU^LHb circuit by optogenetics and chemogenetics alleviated depression-like behaviors in a pain-depression comorbidity model induced by chronic restraint stress or nerve spared injury,but failed to relieve mechanical allodynia in mice.On the contrary,optogenetic and chemogenetic silence of SOM^sTRN-GLU^LHb circuit could induce depression-like behaviors in WT mice.In addition,by using virus tracking and immunofluorescence,we found the sensory thalamic reticular nucleus received inputs from the anterior cingulate cortex,insular cortex,amygdala,basolateral amygdala and ventral medial nucleus.In conclusion,we reveal that the SOM^sTRN-GLU^LHb pathway is involved in the regulation of depressionlike behaviors.The discovery of this circuit provides a possible new target for the treatment of depression.