Dataset Information

Computational modeling of opioid-induced synaptic plasticity in hippocampus.

ABSTRACT: According to a broad range of research, opioids consumption can lead to pathological memory formation. Experimental observations suggested that hippocampal glutamatergic synapses play an indispensable role in forming such a pathological memory. It has been suggested that memory formation at the synaptic level is developed through LTP induction. Here, we attempt to computationally indicate how morphine induces pathological LTP at hippocampal CA3-CA1 synapses. Then, based on simulations, we will suggest how one can prevent this type of pathological LTP. To this purpose, a detailed computational model is presented, which consists of one pyramidal neuron and one interneuron both from CA3, one CA1 pyramidal neuron, and one astrocyte. Based on experimental findings morphine affects the hippocampal neurons in three primary ways: 1) disinhibitory mechanism of interneurons in CA3, 2) enhancement of NMDARs current by ? Opioid Receptor (?OR) activation and 3) by attenuation of astrocytic glutamate reuptake ability. By utilizing these effects, simulations were implemented. Our results indicate that morphine can induce LTP by all aforementioned possible mechanisms. Based on our simulation results, attenuation of pathologic LTP achieved mainly by stimulation of astrocytic glutamate transporters, down-regulation of the astrocytic metabotropic glutamate receptors (mGlurs) or by applying NMDAR's antagonist. Based on our observations, we suggest that astrocyte has a dominant role in forming addiction-related memories. This finding may help researchers in exploring drug actions for preventing relapse.

SUBMITTER: Borjkhani M

PROVIDER: S-EPMC5841814 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Computational modeling of opioid-induced synaptic plasticity in hippocampus.

Borjkhani Mehdi M Bahrami Fariba F Janahmadi Mahyar M

PloS one 20180307 3

According to a broad range of research, opioids consumption can lead to pathological memory formation. Experimental observations suggested that hippocampal glutamatergic synapses play an indispensable role in forming such a pathological memory. It has been suggested that memory formation at the synaptic level is developed through LTP induction. Here, we attempt to computationally indicate how morphine induces pathological LTP at hippocampal CA3-CA1 synapses. Then, based on simulations, we will s ...[more]

PMID: 29513763

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Project description:Exercise facilitates hippocampal neurogenesis and neuroplasticity that in turn, promotes cognitive function. Our previous studies have demonstrated that in male mice, voluntary exercise enables hippocampus-dependent learning in conditions that are normally subthreshold for long-term memory formation in sedentary animals. Such cognitive enhancement can be maintained long after exercise has ceased and can be re-engaged by a subsequent subthreshold exercise session, suggesting exercise-induced benefits are temporally dynamic. In females, the extent to which the benefits of exercise can be maintained and the mechanisms underlying this maintenance have yet to be defined. Here, we examined the exercise parameters required to initiate and maintain the benefits of exercise in female C57BL/6J mice. Using a subthreshold version of the hippocampus-dependent task called object-location memory (OLM) task, we show that 14d of voluntary exercise enables learning under subthreshold acquisition conditions in female mice. Following the initial exercise, a 7d sedentary delay results in diminished performance, which can be re-facilitated when animals receive 2d of reactivating exercise following the sedentary delay. Assessment of estrous cycle reveals enhanced wheel running activity during the estrus phase relative to the diestrus phase, whereas estrous phase on training or test had no effect on OLM performance. Utilizing the same exercise parameters, we demonstrate that 14d of exercise enhances long-term potentiation (LTP) in the CA1 region of the hippocampus, an effect that persists throughout the sedentary delay and following the reactivating exercise session. Previous studies have proposed exercise-induced BDNF upregulation as the mechanism underlying exercise-mediated benefits on synaptic plasticity and cognition. However, our assessment of hippocampal Bdnf mRNA expression following memory retrieval reveals no difference between exercise conditions and control, suggesting that persistent Bdnf upregulation may not be required for maintenance of exercise-induced benefits. Together, our data indicate that 14d of voluntary exercise can initiate long-lasting benefits on neuroplasticity and cognitive function in female mice, establishing the first evidence on the temporal endurance of exercise-induced benefits in females.

Project description:Modified constraint-induced movement therapy is an effective treatment for neurological and motor impairments in patients with stroke by increasing the use of their affected limb and limiting the contralateral limb. However, the molecular mechanism underlying its efficacy remains unclear. In this study, a middle cerebral artery occlusion (MCAO) rat model was produced by the suture method. Rats received modified constraint-induced movement therapy 1 hour a day for 14 consecutive days, starting from the 7th day after middle cerebral artery occlusion. Day 1 of treatment lasted for 10 minutes at 2 r/min, day 2 for 20 minutes at 2 r/min, and from day 3 onward for 20 minutes at 4 r/min. CatWalk gait analysis, adhesive removal test, and Y-maze test were used to investigate motor function, sensory function as well as cognitive function in rodent animals from the 1st day before MCAO to the 21st day after MCAO. On the 21st day after MCAO, the neurotransmitter receptor-related genes from both contralateral and ipsilateral hippocampi were tested by micro-array and then verified by western blot assay. The glutamate related receptor was shown by transmission electron microscopy and the glutamate content was determined by high-performance liquid chromatography. The results of behavior tests showed that modified constraint-induced movement therapy promoted motor and sensory functional recovery in the middle cerebral artery-occluded rats, but had no effect on cognitive function. The modified constraint-induced movement therapy upregulated the expression of glutamate ionotropic receptor AMPA type subunit 3 (Gria3) in the hippocampus and downregulated the expression of the beta3-adrenergic receptor gene Adrb3 and arginine vasopressin receptor 1A, Avpr1a in the middle cerebral artery-occluded rats. In the ipsilateral hippocampus, only Adra2a was downregulated, and there was no significant change in Gria3. Transmission electron microscopy revealed a denser distribution the more distribution of postsynaptic glutamate receptor 2/3, which is an ?-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor, within 240 nm of the postsynaptic density in the contralateral cornu ammonis 3 region. The size and distribution of the synaptic vesicles within 100 nm of the presynaptic active zone were unchanged. Western blot analysis showed that modified constraint-induced movement therapy also increased the expression of glutamate receptor 2/3 and brain-derived neurotrophic factor in the hippocampus of rats with middle cerebral artery occlusion, but had no effect on Synapsin I levels. Besides, we also found modified constraint-induced movement therapy effectively reduced glutamate content in the contralateral hippocampus. This study demonstrated that modified constraint-induced movement therapy is an effective rehabilitation therapy in middle cerebral artery-occluded rats, and suggests that these positive effects occur via the upregulation of the postsynaptic membrane ?-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor expression. This study was approved by the Institutional Animal Care and Use Committee of Fudan University, China (approval No. 201802173S) on March 3, 2018.

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Computational modeling of opioid-induced synaptic plasticity in hippocampus.

Publications

Computational modeling of opioid-induced synaptic plasticity in hippocampus.

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