Treadmill Exercise Interferes With The Occurrence Of Stress-depressive Behaviors And The Changes Of Dendritic Spines And Kalirin-7 In The Brain Area Of ​​the Emotional Circuit

Depression is the most widespread type of mental disorder.It has high morbidity,high recurrence rate and high perniciousness.It is predicted to be world’s first leading cause of illness by 2030.Depression is considered as an interaction disorder among multiple brain regions of mood circuit,including prefrontal cortex,hippocampus,nucleus accumbens,amygdala and etc.The prefrontal cortex belongs to the cortical advanced emotional center and has function such as decision-making.The hippocampus also belongs to the advanced emotional center.The nucleus accumbens is the core region regulating anhedonia.The amygdala is the brain region which affects anxiety-like behaviors.The neuroplastic hypothesis of depression suggests that alterations in the morphology and function of dendritic spines in the nervous system are the causes of depression.Chronic unpredictable mild stress(CUMS)is a classical animal depression model,which intimitates stress in human daily life.It can induce depression-like behaviors of animals and these behaviors can also be reversed by antidepressants.It has been found that chronic stress leads to decrease in the dendritic spine density of pyramidal neurons in the medial prefrontal cortex and hippocampal CA3,as well as increase in the dendritic spine density of medium spiny neurons of nucleus accumbens and neurons of basolateral amygdala.Kalirin-7 can interact with Rho,a small G protein,which is an important regulating protein of dendritic spine density and morphology.But current antidepressants do not work for up to 30%of patients,so there is an urgent need for studies about new approaches to treat depression.In recent years,studies have found exercise can alleviate depression,but the underlined mechanism still remains largely unclear.Studies of neuroplasticity in exercise against depression are rare as well.So the related research is of great significance.This study intends to investigate whether treadmill exercise could reverse CUMS-induced depression-like behaviors,alterations in dendritic spines and Kalinin-7 in mood circuit brain regions.Adult male SD rats were divided into 4 groups.They are control,CUMS,exercise and CUMS+exercise.Sucrose preference and open field tests were used to measure depression-like behaviors.Golgi staining is used to analyse the dendritic spine density and morphology(stubby,thin and mushroom spines)of neurons in the target brain regions,including apical dendrite of the hippocampal CA3 and the medial prefrontal cortex(anterior cingulate cortex,prelimbic cortex and infralimbic cortex)pyramidal neurons,and medium spiny neurons of nucleus accumbens(core and shell)and neurons of basolateral amygdala.Western blot was used to analyse the expression of Kalirin-7 in the target brain regions,including the medial prefrontal cortex,hippocampus,nucleus accumbens and amygdala.The results showed that CUMS-induced depression-like behaviors in rats,accompanied with decrease in the dendritic spine density of pyramidal neurons apical dendrites in the hippocampal CA3 and medial prefrontal cortex and its three sub-regions,as well as increase the dendritic spine density in neurons of amygadala and nucleus accumbens and its two sub-regions.And exercise reverses CUMS-induced depression-like behaviors and alterations in dendritic spine density in brain regions and subregions of mood circuit.In addition,except the dendritic spine density alteration in the infralimbic cortex,which is mainly caused by mushroom dendritic spines,the alterations in dendritic spine density in other brain regions and sub-regions are mainly caused by stubby and thin dendritic spines.CUMS reduced Kalirin-7 expression of medial prefrontal cortex and hippocampal,increased Kalirin-7 expression of nucleus accumbens and amygdala.However,exercise only reversed the decrease in Kalirin-7 in the medial prefrontal cortex.The exercise anti-depression process may base on alterations in neural plasticity in mood circuit brain regions.Exercise and CUMS may first affect the cortical advanced center,such as medial prefrontal cortex and hippocampus and then project to the subcortical lower-level instinct behavioral center which includes nucleus accumbens and amygdala,then cause alterations in depression-like behaviors.Kalirin-7 may play a major role in the medial prefrontal cortex during alterations in neuroplasticity in exercise reversing depression.This research finds the alterations in dendritic spine density in mood circuit brain regions and Kalirin-7 decrease in medial prefrontal cortex induced by CUMS were reversed by treadmill exercise,and accompanied with the reverse of depressive-like behaviors.In addition,the reversive of dendritic spine density induced by treadmill exercise was mainly due to unmnature dendritic spines.It provides important information for potential antidepressant target and future study of brain regions interaction of depression.