Correlation Of Resistin In Learning And Memory Impairment Induced By Chronic Stress

Objective:Stress is an individual’s nervous non-specific response to internal and external environmental stimuli.Short-term moderate stress is harmless to individuals,but long-term exposure to stress stimuli will have harmful effects on brain structure and function.Chronic stress is the main risk factor affecting many human diseases in modern society.The brain is the main target organ of chronic stress.After chronic stress,different brain regions,such as the hippocampus,prefrontal cortex,and amygdala,have functional impairments and morphological changes.There is evidence that long-term exposure to stress can affect learning and memory,decision-making,and emotional responses,and may even induce pathological processes such as depression and Alzheimer’s disease.Therefore,understanding the effects and mechanisms of stress on learning and memory is of great significance for reducing the negative effects of stress,and for understanding the occurrence of neurodegenerative diseases such as Alzheimer’s disease.Chronic stress mainly acts on the hypothalamic-pituitary-adrenal axis to release glucocorticoids,cortisol in mammals and corticosterone in rodents.Corticosterone has a much higher affinity for mineralocorticoid receptors than glucocorticoid receptors,and only binds to glucocorticoid receptors when corticosterone levels are elevated,such as chronic stress.Mitochondria are the key target of intracellular glucocorticoid signal transduction,and it is the key to coping with and adapting to stress.Mitochondria provide a large amount of energy needed to meet the stress response and are especially important for the brain.Resistin is a cysteine-rich polypeptide hormone secreted by fat cells.Resistin plays a key role in insulin resistance,various metabolic,inflammatory and autoimmune diseases,but its function in the nervous system is still controversial.Our previous studies have found that the injection of resistin into the lateral ventricle can inhibit the differentiation of neural stem cells and transplanted neural stem cells into astrocytes in the subventricular zone of the mouse brain.In vitro studies have shown that resistin affects astrocytes by acting on TLR4 receptors.Glial cells differentiate,which in turn changes the permeability of the blood-brain barrier.In addition,we found that in the differentiation system of neural stem cells to astrocytes,resistin reduces the mitochondrial membrane potential of the cells,and JC-1 changes from a polymerized state to a monomer,producing green fluorescence.Further reveal that resistin may affect the function of cell mitochondria.The normal function of the brain depends on the coupling of nerves and blood vessels,that is,the neural activity rapidly increases the local blood flow to meet the transient changes in the local brain energy demand.We speculate that resistin may affect the glucose uptake of astrocytes,cause changes in cerebral blood flow,and ultimately reduce neuronal responsiveness.We analyzed the changes in cerebral blood flow regulated by resistin and the impairment of learning and memory caused by chronic stress.Methods: 1.Firstly,male C57/BL6 mice aged 6-8 weeks were used to prepare a 21-day chronic restraint stress model.Afterwards,test the mouse body weight,blood sugar,corticosterone and other indicators to identify whether the model is successfully prepared.2.Perform Y maze and new object recognition experiments on mice under chronic restraint stress for 21 days to detect whether the model mice have learning and memory impairment.3.ELISA method is used to detect NF-L in serum to verify the learning and memory impairment of model mice from the molecular level.4.ELISA method was used to detect the expression level of resistin in serum and four parts of brain tissues including prefrontal cortex,hypothalamus,hippocampus and striatum,and analyze its correlation with the changes in learning and memory of model mice.5.The paraffin sections of the hippocampus were prepared to detect which cells secreted resistin.6.Resistin was injected into the lateral ventricle of male C57/BL6 mice aged 6-8weeks,and the cerebral blood flow was detected by laser speckle blood flow imaging.Results: 1.During the preparation of the 21 d model,the weight of the experimental group mice increased slowly,but the rate of increase was significantly lower than that of the control group.The blood glucose of the experimental group mice was significantly higher than that of the control group.2.Compared with the control group,the learning and memory ability of the experimental group mice was significantly reduced.3.The content of serum NF-L in experimental group was significantly higher than that in control group.4.The level of resistin in the serum of chronic restraint stress mice was significantly increased,and the expression of resistin in the hippocampus and hypothalamus was significantly higher,but there was no significant difference in the levels of leptin and adiponectin in the supernatant of the hippocampus of the experimental group and the control group;and Compared with the control group,there was no significant difference in the expression of resistin in the prefrontal cortex and striatum of the experimental group.The changes in learning and memory caused by chronic restraint stress are negatively correlated with resistin levels in serum and hippocampus.5.Paraffin sections of hippocampus showed that resistin was expressed in some glial fibrillary acidic protein-positive astrocytes.6.Preliminary experimental results showed that the average cerebral blood perfusion blood volume of mice injected with different concentrations of resistin into the lateral ventricle decreased significantly.After the preparation of the model,it was detected that the average blood volume of the cerebral blood perfusion of the mice decreased significantly.Compared with the control group,the cerebral blood flow of the experimental group decreased more significantly.It is suggested that chronic stress may cause changes in the expression of resistin and lead to changes in cerebral blood flow,causing learning and memory disorders.Conclusion: Chronic stress-induced reduction in learning and memory ability of mice is positively correlated with serum resistin levels;injection of resistin into the lateral ventricle can reduce cerebral blood perfusion in mice.