The Role Of Hypothalamic Plasticity In Restraint Stress Changing HPA Axis Reactivity And Behavioral Manifestations

Background:Stress is physiological and psychological responses of human body to external stimulus,and thus leading to endocrine and behavioral changes. Hypothalamus-pituitaryadrenal(HPA) axis plays an important role in it,however, it still remains unclear about the regulation mechanism of HPA axis excitability. It has been found that hypothalamic plasticity changes play a crucial role in HPA axis excitability.The study of hypothalamic plasticity for prevention secondary damage of stress has important value.Neuroplasticity changes mainly refers to nerve cells changes resulting from various external or internal stimuli factor and neuroendocrine response, divided into structural plasticity and functional plasticity.Brain-derived neurotrophic factor(BDNF) and growth-associated protein(GAP-43)are considered to be molecular markers of neural plasticity. And they are related with regeneration and proliferation of nerve cell. they can be used to mark and quantify the degree and scope of plasticity in the hypothala mus. Functional Plasticity can enhance the synaptic transmission efficiency and action potential. That act as long-term potentiation of synaptic transmission LTP), the opposite is called long-term depression(LTD). The glutamate α—amino—3—hydroxy—5— methyl—4— isoxazole propionic acid(AMPA) receptor Glu R2 subunit and N- methyl-D- aspartate(NMDA) receptor NR2 B subunit Play a central role in regulating LTP / LTD,can be used to mark the functional plasticity.In the study,I successfully established restraint stress model of rats.I used behavioral experiments 、 enzyme-linked immunosorbent assay(ELISA) method 、 immuno histochemistry and Western blotting(WB) experiment,and research the affects after restraint stress to rat behavior 、 plasma concentrations of corticotropin-releasing hormone(CRH)、hypothalamus morphology、marker protein of neuronal structural plasticity and function plasticity.And to research the intervention affects of corticotropin-releasing hormone type 1 receptor(CRH1R) specific blocker CP-154526.Thereby it maybe clarify the correlation among hypothalamic plasticity after restraint stress、HPA axis excitability and the behavioral changes.results:1. In behavioral experiments,after chronic restraint stress,the general condition of rats showed reduced activity、reduced resistance、delayed response of pure、loss of appetite、weight gain slowed.In the open-field test, rats after 7 days of restraint stress exhibited increase of spanning lattice times,standing times and the modification times,and showing the manic state. After chronic restraint stress,rats exhibited decrease of spanning lattice times,standing times and the modification times,and showing the depressed state.In the forced swiming test and tail suspension test in rats with chronic restraint stress increased immobility time.The rate of sugar preferences in rats with chronic restraint stress is decreased,that reflecting the lack of pleasure in rats. The CP-154526 can greatly increase the amount of weight gain in rats with chronic restraint stress,and improve the stress behavioral and psychological symptoms in chronic stress rats. We recognize the therapeutic effect of CP-154526 in adverse reactions of stress. chronic restraint stress can increase CRH concentration in the serum,leads to increase excitability of HPA axis.CP-154526 can antagonize the effect of CRH,reducing the activity of the HPA axis.2. The hematoxylin-eosin(HE) staining results showed chronic restraint stress can cause hypothalamic cell structure being changed greatly.Compared with the control group,the hypothalamic cell body from chronic restraint stres rats had clear boundary,bigger nuclear staining,clear nuclear membrane,single nucleolus. Cell membrane and nuclear membrane of chronic restraint stress group all are integrity and clear. Structural plasticity of hypothalamus after chronic stress was occurred. Chronic restraint stress also up-regulation of expression of brain derived neurotrophic factor brain derived neurotrophic factor(BDNF) and Growth Associated Protein 43(GAP-43) protein in hypothalamus,and cause NR2 B subunit expression enhancing in hypothalamus,but GluR2 subunit expression was decrease. CP-154526 can retardant the upregulation expression of BDNF、GAP-43 protein and NR2 B subunit in hypothalamus after stress,also can retardant the downregulation expression of GluR2 subunit in hypothalamus after stress.Conclusions:The expression of BDNF and GAP-43 in hypothalamus after stress increased,and BDNF and GAP-43 participation in structural plasticity. NMDA receptor NR2 B subunit increased and AMPA receptor subunit Glu R2 reduced, resulting in LTP / LTD changed, at last cause functional plasticity. Hypothalamic plasticity changes are related with increasing activity of the HPA axis and behavioral changes. Hypothalamic plasticity induced increasing activity of HPA axis and induced depression-like behavior. The CP-154526 antagonistic hypothalamic plasticity by blocking CRH1 R,further inhibiting the activity increase of the HPA axis and improve depressive symptoms.At last CP-154526 reverse the pathological process of chronic stress,to antagonize the effects of stress.