Study On The Role Of Medial-prefrontal Cortex Agglutinin Agrin In Depression-like Behaviors In Mice

Major depressive disorder(MDD)is a mental illness with a high incidence and high disability rate.The pathogenesis of depression involves biological,psychological,environmental and other factors,and its pathological mechanism has not been fully defined,but a single neurotransmitter system disorder is not enough to explain the occurrence of depression.At present,the neural circuit involved in regulating the function of multiple brain regions and neurotransmitter system has become one of the focus of the pathogenesis of depression research.medial prefrontal cortex(mPFC),as a higher level brain region regulating emotion,cognition and decision making,not only receives information input from different brain regions,but also integrates information to other cortical and subcortical regions.Studies have shown that mPFC plays an important role in the pathogenesis of a variety of neuropsychiatric disorders,including anxiety disorders,depression,schizophrenia,Parkinson’s disease,and Alzheimer’s disease.An in-depth study of the changes of mPFC neural circuits and their molecular mechanisms during the occurrence of these neuropsychiatric diseases will be helpful for the prevention and treatment of these neuropsychiatric diseases.The development of the nervous system is very complex.It involves nerve induction,formation of neural circuits,polarity establishment and migration of nerve cells.In these processes,the interaction between cells is very important.These interactions can be broadly divided into two types.One relies on direct contact between cells and works by binding ligands to receptors on the cell surface.The other mediates interactions between cells by secreting soluble proteins such as cytokines,adhesion molecules,proteoglycans and hormones.Among them,proteoglycan is widely distributed in the central nervous system and plays an important role in promoting the indirect interconnections between cells during the development of the nervous system,such as participating in the development of the nervous system,synaptic formation,brain aging,repair after brain injury and affecting the growth of synapses.Agrin is a kind of extracellular matrix protein(ECM)protein with heparan sulfate proteoglycan(HSPG)as the core.A large number of studies have confirmed that Agrin not only plays an important role in skeletal muscle development,neuromuscular joint formation,hematopoietic,inflammation and other processes,but also plays an important role in the repair of the central nervous system after injury.However,the specific mechanism of Agrin in the central nervous system is still unclear.Previous studies have shown that agglutinin Agrin level in serum of patients with major depression is significantly increased,and agglutinin Agrin content in serum of patients with depression is positively correlated with the severity of depression,suggesting that Agrin level increase is correlated with the onset of depression.This topic mainly explores the role of mPFC Agrin in the pathogenesis of depression and the related mechanism.In this study,we make use of C57BL/6J mice to build a chronic unpredictability stress(CUS)model to explore the change of the agglomerin Agrin level in mPFC induced by chronic stress exposure in depressed mice.The result shows that compared with the control group,The expression level of agglutinin Agrin in mPFC in stressed group was significantly increased.Then,immunofluorescence staining was used to detect the expression pattern of Agrin in different nerve cells in multiple brain regions of mice.The results showed that agglutinin Agrin was highly expressed in cortex,hippocampus and amygdala,and Agrin was mainly expressed in neurons,but hardly expressed in astrocytes and microglia.By injecting exogenous Agrin protein into mouse mPFC through cannula implantation,we found that exogenous Agrin injection induced depression-like behavior in mice.Finally,we injected Cre virus to lower Agrin in mPFC of Agrin floxed mice,and the results showed that lower Agrin in mPFC resulted in a certain anti-anxiety behavior in mice.These findings provide us with new clues and evidence to explore the role of agglutinin Agrin in depression.