Tac1 Regulates Depressive-like Behaviors In Mice

Depression is a major mental illness in hospital setting.However,the underlying mechanism of depression remains unclear.Clinical data showed about 30~40% of patients with major depression disorder developed drug resistance against antidepressants.Therefore,it is important to further study the underlying mechanisms of depression.Substance P belongs to a protein family which is encoded by the Tac1 gene and is widely expressed in the central and peripheral nervous systems.Substance P is involved in multiple biological processes: pain perception,pressure regulation,body temperature regulation,cardiovascular regulation,exercise coordination and gastrointestinal function.Additionally,substance P was reported in the regulation of depression,but the underlying mechanisms was not fully understood.In this study,we first evaluated the expression of Tac1 gene in adult mouse brain by Real-time PCR and found that Tac1 gene was expressed in multiple brain regions and highly expressed in striatum.In the striatum,Tac1 gene mainly encodes substance P.By constructing Tac1-cre;Ai9 mice,the expression of substance P in the striatum was further confirmed.By carrying out Chronic Social Defeat Stress(CSDS)experiment,we found that there was no significant change in the level of substance P mRNA in the striatum of depression-sensitive mice,while substance P expression level was increased in depression-resistant mice.These results suggested that substance P in the striatum was involved in the regulation of depression.To study the role of substance P in depression,we silenced the Tac1 gene in the lateral shell and medial shell of the nucleus accumbens by stereotactic injection.We found that the body weight of the mice in the lateral shell was significantly decreased,but the smell and feeding behavior of the mice did not change,which may be due to depression caused by the weight loss of the mice.Next,we evaluated the animal's depression-like behavior through the sucrose preference experiment;the elevated cross maze experiment and the light and dark field experiment.Results from such studies showed that the sugar consumption rate of the mice in the side shell group was significantly reduced,indicating that the decrease of substance P level in the side shell brain area of the nucleus accumbens could lead to the depression-like behavior.The motility time was significantly reduced in the open arm of the elevated cross maze and in the light field,indicating that the decrease of substance P level in the nucleus accumbens lateral shell region can cause anxiety-like behavior in mice.The results show that the occurrence of depression-like behavior in mice is closely related to the change of substance P level in the lateral shell of the nucleus accumbens,which is helpful for us to further study the pathogenesis of depression.