Post-traumatic stress disorder-induced behavioral modulation by the medial septum-medial habenula neural pathway

Post-traumatic stress disorder (PTSD) is characterized by anxiety, excessive fear, distress, and weakness as symptoms of a psychiatric disorder. However, the mechanism associated with its symptoms such as anxiety-like behaviors is not well understood. It is aimed to investigate the underlying mechanisms of the medial septum (MS)–medial habenula (MHb) neural circuit modulating the anxiety-like behaviors of PTSD mice through in vivo fiber photometry recording, optogenetics, behavioral testing by open-field and elevated plus maze, fluorescent gold retrograde tracer technology, and viral tracer technology. In the mouse PTSD model induced by compound stress consisting of single-prolonged stress combined with electrical foot shock, the average peak value of the Ca2 + signals in both the MHb and MS glutamatergic neurons significantly increased. The anterograde and retrograde tracer markers were used to indicate the possible connection between MS and MHb via glutamatergic neural pathway. After the optogenetic manipulation of the MS–MHb pathway in mice with PTSD, if the MS–MHb glutamatergic pathway was inhibited, anxiety was relieved based on changes in the various indices of behavioral experiments in mice with PTSD. Moreover, the heart rate of mice decreased. In conclusion, both glutamatergic neurons located in MS and MHb can be engaged in the development of PTSD anxiety-like behavior, and the MS–MHb can be related to the regulation of PTSD anxiety-like behavior and cardiac function through the glutamatergic neural pathway. •MS glutamatergic neurons are involved in the regulation of PTSD.•MHb glutamatergic neurons are involved in the regulation of PTSD.•MS and MHb are connected through glutamatergic neural pathways.•MS-MHb glutamatergic pathway is involved in modulating behavior.•MS-MHb glutamatergic pathway is involved in the regulation of cardiac function.