| Severe or prolonged stressful life events impair cognitive function by influencing a series of brain regions in a complex manner.The hippocampus,a structure implicated in learning and memory processes,is particularly vulnerable to stressful experiences.Exposure to acute stress consistently disrupts hippocampal-dependent memory retrieval immediately afterward.Extensive studies have demonstrated that elevated glucocorticoid hormones during stress impair memory retrieval by modulating glutamatergic synaptic plasticity at the Schaffer collateral/commissural-CA1 synapses in the hippocampus,likely through inhibiting LTP induction or facilitating LTD.Nevertheless,the magnitude of impairment by glucocorticoids does not match the impact of stress on memory,indicating that multiple neural mechanisms,not limited to the effects of glucocorticoids,may underlie stress-induced impairment of memory retrieval.In addition to glucocorticoid hormones,acute stress also elicits the engagement of various neurotransmitters and neuromodulators,including monoamines,endogenous opioid peptides(EOPs),endocannabinoids,neuropeptide Y,oxytocin,and sex hormones,which interact with glucocorticoid hormones to manipulate responses to stress.Exposure to stress rapidly increases the release of enkephalin,β-endorphin,dynorphin,and nociceptin in brain regions closely related to emotion and cognition.Through activation of the three major opioid receptors that are densely expressed in the central nervous system(μ,δ,and κ),EOPs actively participate in the modulation of a series of cognitive,emotional,cardiovascular,and gastroenterological responses and enable adaptation to stress.However,whether the endogenous opioid system(EOS)plays an essential role in stress-induced impairments of learning and memory remains completely unknown.Therefore,in this experiment,we created animal model that memory retrieval impairment after acute stress(elevated platform,50 min)in C57 mice.On this basis,we studied the function of μ opioid receptor on memory retrieval impairment after acute stress by using stereotactic surgery、behavioral neuroscience、neuropharmacology、molecular biology and situ hybridization technique with RNA Probes.Finally,we proved the mechanism of memory retrieval damage.The main results showed as follow:1.Modeling of memory retrieval impairment after acute stress in two days.Day 1:during 12 trials of water maze training;Day 2:acute stress before MWM probe test trial on memory retrieval.The result showed memory retrieval impairment would be maintained at least 2 hours after acute stress.2.Naloxone intraperitoneal injection 30 min before acute stress completely abolished the memory-retrieval impairment observed in the stressed mice,suggesting that the opioid receptors are required for this memory impairment.Intra-hippocampal infusion of the μ opioid receptor antagonist CTAP(0.5 μg/μl);,but not δ opioid receptor or κ opioid receptor antagonist,completely eliminated the stress-induced impairment of memory retrieval.Further studies showed intra-hippocampal infusion of enkephalin antiserum also eliminated the stress-induced impairment of memory retrieval.It is reasonable to conclude that the acute stress induced impairment of memory retrieval specifically requires activation of μ opioid receptor(binding with enkephalin)in the hippocampus.3.Non-selective μ opioid receptor deletion and selective μ opioid receptor deletion from GABAergic neurons,glutamatergic neurons and astrocytes had been shown by genotypic identification and situ hybridization technique with RNA Probes.4.Non-selective μ opioid receptor deletion and selective μ opioid receptor deletion from GABAergic neurons abolished the stress-induced impairment of memory retrieval.Together with the results of hippocampal microinjection with μ opioid receptor antagonists and agonists,these results definitively reveal the essential role of μ opioid receptor on GABAergic neurons in stress-induced memory impairment.5.When a sub-effective dose of muscimol was microinjected immediately after acute stress,memory retrieval remained unimpaired,suggesting that a small amount of muscimol is able to neutralize the stress-induced depression by properly activating GABAA receptors.whereas the combined muscimol+L-655,708(extrasynaptic GABAAR antagonist)group showed no observable impairment.These data strongly suggest that acute stress inhibits GABA release in the hippocampus CA1 area,decreases post-synaptic inhibitory currents,and causes excitation-inhibition unbalance in the hippocampus,finally impairs memory retrieval.In conclusion,the present study revealed that μ opioid receptor expressed at GABAergic neurons were activated by EOPs(enkephalin)and subsequently GABA release less in the hippocampus CA1 area causing excitation-inhibition unbalance in the hippocampus for stress-induced impairment of memory retrieval.These results provide rationale for understanding the physiological function of endogenous opioid peptide system and effective treatment of learning and memory disorders. |
