The Effects Of Chronic Stress On The Learning And Memory Abilities Of Rats And The Underlying Mechanisms

Part ? The effects of repeated stress on learning and memory abilities and the underlying mechanism Background: Stress is originally described as a nonspecific response of the body to any demand placed upon it.As a result,the stressor evokes a stress response,which involves the release of hormones such as adrenocorticotropic hormone(ACTH)and glucocorticoid(GC)and other cellular mediators causing downstream reactions.When acute stressors last for a short period of time and the response is efficiently turned on and shut off,the resultingchanges promote the body's attention and adaptability,which resulting in positive effects.But which can also promote pathophysiological processes and even lead to changes in the structure of the brainwhen the body is subjected to chronic or repeated stress and the response is overused or dysregulated.The brain is a maintarget of stress.Animal models show thatstressinduced remodeling of brain architecture.Stress also induced dendritic atrophy and dendritic spines loss.The effects of stress on the brain have long been associated with cognitive impairment and the onset and exacerbation of several neuropsychiatric.So it's important to study the potential mechanisms of stress and find effective treatment to prevent or delay the stress-induced chronic disease.In this study,3-weeks-old rats were exposed to 7-day repeated stress.Behaviors,morphological changes were tested at 24 hrs after stressor cessation to study the mechanism of stress-induced cognitive impairment.Objective: To invesitigate the effects of repeated stress on the learning and memory abilities of rats and the underlying mechanism.Methods: Three-week-old rats were randomly divided into two groups.For repeated restraint stress,rats were placed in air-assessable cylinders for 2hour daily for 7days and the control without any treatment.Behaviors were tested after stressor cessation.To invesitigate the underlying mechanism of impaired learning and memory ability,we performed electrophysiologcal recording of acute brain slices to test LTP and LTD.Golgi staining was used to detect dendritic spine density.Westernblottingwas used to test synaptic-related protein expression.Finally,Ro25-6981 was injected into the CA3 region prior to repeated stress treatment and behavioral changeswere detected by behavior tests.Results: 1.Repeated stress induced cognitive impairments in rats.2.Repeated stress induced hippocampal plasticity deficits in rats.3.Repeated stress decreased the dendritic spine density in hippocampal CA3 region of rats.4.Repeated stress increased synaptic proteins expression in the rat hippocampus and increased the distribution of synaptic proteins on the membrane.5.Repeated stress didn't alter the number of neurons in hippocampus.6.AP-5 blocked repeated stress rats induced by LTD,but failed to reverse the decline of LTP.7.Ro25-6981 blocked the induction of LTD in rats of the repeated stress group;8.Injection of Ro25-6981 in hippocampal CA3 reverses cognitive impairment caused by repeated stress.Conclusion: Repeated stressimpaired dendritic plasticity and inducedcognitive dysfunctionwith increased expression of NMDAR in the hippocampal CA3 region and abnormal aggregation on the membrane.Inhibition of GluN2B-containing NMDAR rescued dendritic plasticity damage and cognitive dysfunction induced by repeated stress,suggesting that repeated stress causes excitotoxicity by activating NMDA receptors and lead to cognitive impairment.Part ? The effects of ELF-EMF amelorates the cognition of 12-month old 3×Tg AD and the underlying mechanismsBackground: Alzheimer's disease(AD)is a progressive neurodegenerative disorder characterized by a decline of cognitive ability.The characteristic neuropathological changes of AD are neurofibrillary tangles,mainly consisted of hyperphosphorylated tau proteins,and senile plaques(SP)formed by extracellular deposits of amyloid-?(A?).Accompanied with AD pathologicalprocess,impaired synaptic function and neuron loss were also observed.Extremely low frequency electromagnetic field(ELF-EMF)is a combination of an electric field and magnetic field with a frequency ranging from 1 Hz to 300 Hz.In recent decades,people have been increasingly exposed to ELF-MF,and therelationship between ELF-MF and health had become research hotspots.ELF-EMF could play a neuroprotective role on Huntington's disease rat model(60 Hz,0.7 m T,4 hours for 21 days),and increased hippocampal long-term potentiation(LTP)in rats.In our previous studies,we found that long-term exposure to ELF-MF(50Hz,500 ?T)played a preventive effect in 3x Tg mice.To explore whether ELF-MF could also ameliorated cognitive deficits and pathyologies in the late AD which had seriously cognitive impairment,12-months-old transgenic mice(3x Tg)were used.Transgenic mice and non-transgenic wild type(WT)mice at 12 months of agewere exposed to 500 ?T of ELF-MF or to the standard environment(SE)for 1 month.We performed behavior test and electrophysiology to evaluate the effect of ELF-MF exposure on cognitive dysfunction in 3×Tg AD mice and explore the underlying molecular mechanisms.Objective: To invesitigate the improved effcts of ELF-MF on learning and memory abilities in 3×Tg AD mice and the underlying molecularmechanisms.Methods: The 12-month-old mice were randomly divided into 4 groups: wild-type mice exposed to the standard environmentgroup(WT-SE),wild-type mice exposed to ELF-MF group(WT-MF),and transgenic mice exposed to the standard environmentgroup(3×Tg-SE),transgenic mice exposed to ELF-MF group(3×Tg-MF),all mice exposed to standard environment or ELF-MFfor one month.After the exposure,we performed behavior test to analysis the cognitive abilities of mice and performed electrophysiology to test long-term potentiation.We detected neuron dendrtic spine densityby Golgi stainning and detected protein expression in hippocampus by western blotting.Immunohistochemistrywas used to detect A? contents in the brain.Results: 1.ELF-MF exposure improved learning and memory abilities in 3×TgAD mice.2.ELF-MF exposure amelioratedhippocampal LTP in 3×Tg AD mice.3.ELF-MF exposure increased 3×Tg AD mice dendritic spine density in hippocampal neurons.4.ELF-MF exposure increased the expression of hippocampal synapse-associated proteins in 3×Tg AD mice.5.ELF-MF exposure reduced A? levels in the brain of 3×Tg AD mice.6.ELF-MF exposure reduced the phosphorylatedlevels of tau in the hippocampus of 3 ×Tg AD mice.Conclusion: ELF-MF exposure rescued the cognitive impairments of 12-month-old AD model mice,enhanced hippocampal synaptic plasticity,and attenuated the pathological process of AD,indicating that ELF-MF exposure has potentialtherapeutic effects on Alzheimer's disease.