Role And Mechanism Of Chronic Footshock Stress In Transient Global Ischemia-induced Spatial Learning And Memory Impairment In Mice

Depression is the most common neuropsychiatric disease in modern society and its incidence is increasing year by year.The main clinical manifestation is a state of low mood,significantly and persistently,often accompanied by slow thinking,decreased willingness and cognitive impairment,etc.,and its pathogenesis is closely related to many aspects,such as physical,psychological and social environment.Depression can affect people's thoughts,behaviors,personality traits and perception of the surrounding environment,even suicidal tendencies in severe cases,and bring the heavy burdens to families and society.Transient global ischemia(TGI)is a transient cerebral ischemia caused by temporary decrease or interruption of the blood supply to the carotid or vertebrobasilar system.It is characterized by sudden,transient,and reversible neurological dysfunction.TGI attacks often last for a few minutes,and symptoms usually recover completely within a short period of time(<60 minutes),with rare neurological deficits.However,the TGI attacks are repetitive,affecting the life and work of patients and weakening their social adaptability seriously.In addition,the recurrent TGI can lead to emotional disorders such as anxiety and depression,and can cause cerebrovascular diseases(such as ischemic stroke)in severe cases,increasing the burden on families and society.Depression and transient global ischemia represent the most common psychological and neurological diseases,respectively,and are tightly associated.Numerous studies have shown that cerebral ischemia is a risk factor for the onset of depression and can aggravate the clinical phenotype associated with depression.However,the effects of depression on cerebral ischemic attacks have been limited to recent epidemiological studies,and no relevant experimental studies have been reported.In the mouse models of cerebral ischemia,tTGI preferentially causes spatial learning/memory impairment and hippocampal neuron loss(especially in the dorsal CA1 region)depending on the duration of ischaemic time,which is positively correlated with the degree of hippocampal damage.Therefore,to illustrate the connection between depression and TGI,we studied the neurological function and structural abnormalities caused by TGI attacks under the condition of CFS(Chronic footshock stress-a depression modeling method,can cause depression-like phenotype in mice)by detecting the spatial learning/memory ability and the number of pyramidal neurons in CA1 area.In our study,C57BL/6J mice were used as the main experimental materials and research objects,using animal models,viral tracing,electrophysiological recording,chemogenetics,behavioral testing and other research techniques,to explore the role and mechanism of chronic footshock stress on spatial learning and memory impairment induced by transient global ischemiaOur studies demonstrated that the time threshold for the occurrence of significant spatial learning and memory impairment and loss of pyramidal neurons in the CA1region after stimulation of TGI in C57BL/6J mice is between 10-20 min;CFS can increase the susceptibility of mice to TGI-10min,aggravating the damage of spatial learning and memory in mice and the loss of pyramidal neurons in CA1 area;the direct projections from LC-tyrosine hydroxylase positive(TH~+)neurons to dorsal CA1 area were decreased in CFS-mice,suggesting that the Th:LC-CA1 circuit may be involved in depression associated neurological damage induced by ischaemia;specific inhibition of Th:LC-CA1 projection loop by chemogenetics can aggravate the TGI-induced spatial learning and memory impairment and the loss of pyramidal neurons in CA1;on the contrary,by chemogenetic activation of the Th:LC-CA1projection loop,the process of neuropathic damage caused by TGI stimulation after CFS modeling can be saved.Therefore,our experimental results demonstrated that the Th:LC-CA1 projection loop plays an important role in CFS aggravating TGI-induced neurological function and structural damage.Taken together,we found that depression can elevate the susceptibility of hippocampus to ischemic stimulation in mice,aggravating the spatial learning/memory impairment in mice and the loss of pyramidal neurons in CA1 area induced by TGI;the Th:LC-CA1 projection loop is involved in the neuropathophysiological process of depression-related neurological damage induced by ischemia.Our findings provide a potential intervention for preventing neurological damage caused by depression-related cerebral ischemic attacks.