Ketogenic diet （KD） is a high fat, low protein, low carbohydrate diet. Its antiepileptic effect is certain but the underlying mechanism is unknown. Mossy fiber sprouting in the inner molecular layer of the dentate g...Ketogenic diet （KD） is a high fat, low protein, low carbohydrate diet. Its antiepileptic effect is certain but the underlying mechanism is unknown. Mossy fiber sprouting in the inner molecular layer of the dentate gyrus causes the synaptic reorganization in the hippocampus, which is an important cause of temporal lobe epilepsy in animals and humans. It is also essential to the genesis and development of epilepsy. As the predominant excitatory neurotransmitter in the central nervous system, glutamate plays a role in synaptic reorganization and development of epilepsy.展开更多
Background:Anterior thalamic nuclei(ATN)deep brain stimulation(DBS)is an effective method of controlling epilepsy,especially temporal lobe epilepsy.Mossy fiber sprouting(MFS)plays an indispensable role in the pathogen...Background:Anterior thalamic nuclei(ATN)deep brain stimulation(DBS)is an effective method of controlling epilepsy,especially temporal lobe epilepsy.Mossy fiber sprouting(MFS)plays an indispensable role in the pathogenesis and progression of epilepsy,but the effect of ATN-DBS on MFS in the chronic stage of epilepsy and the potential underlying mechanisms are unknown.This study aimed to investigate the effect of ATN-DBS on MFS,as well as potential signaling pathways by a kainic acid(KA)-induced epileptic model.Methods:Twenty-four rhesus monkeys were randomly assigned to control,epilepsy(EP),EP-sham-DBS,and EP-DBS groups.KA was injected to establish the chronic epileptic model.The left ATN was implanted with a DBS lead and stimulated for 8 weeks.Enzyme-linked immunosorbent assay,Western blotting,and immunofluorescence staining were used to evaluate MFS and levels of potential molecular mediators in the hippocampus.One-way analysis of variance,followed by the Tukeypost hoc correction,was used to analyze the statistical significance of differences among multiple groups.Results:ATN-DBS is found to significantly reduce seizure frequency in the chronic stage of epilepsy.The number of ectopic granule cells was reduced in monkeys that received ATN stimulation(P<0.0001).Levels of 3′,5′-cyclic adenosine monophosphate(cAMP)and protein kinase A(PKA)in the hippocampus,together with Akt phosphorylation,were noticeably reduced in monkeys that received ATN stimulation(P=0.0030 andP=0.0001,respectively).ATN-DBS also significantly reduced MFS scores in the hippocampal dentate gyrus and CA3 sub-regions(allP<0.0001).Conclusion:ATN-DBS is shown to down-regulate the cAMP/PKA signaling pathway and Akt phosphorylation and to reduce the number of ectopic granule cells,which may be associated with the reduced MFS in chronic epilepsy.The study provides further insights into the mechanism by which ATN-DBS reduces epileptic seizures.展开更多
Axonal regeneration and ifber regrowth is limited in the adult central nervous system, but re-search over the last decades has revealed a high intrinsic capacity of brain and spinal cord circuits to adapt and reorgani...Axonal regeneration and ifber regrowth is limited in the adult central nervous system, but re-search over the last decades has revealed a high intrinsic capacity of brain and spinal cord circuits to adapt and reorganize after smaller injuries or denervation. Short-distance ifber growth and synaptic rewiring was found in cortex, brain stem and spinal cord and could be associated with restoration of sensorimotor functions that were impaired by the injury. Such processes of struc-tural plasticity were initially observed in the corticospinal system following spinal cord injury or stroke, but recent studies showed an equally high potential for structural and functional reorganization in reticulospinal, rubrospinal or propriospinal projections. Here we review the lesion-induced plastic changes in the propriospinal pathways, and we argue that they represent a key mechanism triggering sensorimotor recovery upon incomplete spinal cord injury. The for-mation or strengthening of spinal detour pathways bypassing supraspinal commands around the lesion site to the denervated spinal cord were identiifed as prominent neural substrate inducing substantial motor recovery in different species from mice to primates. Indications for the exis-tence of propriospinal bypasses were also found in humans after cortical stroke. It is mandatory for current research to dissect the biological mechanisms underlying spinal circuit remodeling and to investigate how these processes can be stimulated in an optimal way by therapeutic inter-ventions （e.g., ifber-growth enhancing interventions, rehabilitation）. This knowledge will clear the way for the development of novel strategies targeting the remarkable plastic potential of pro-priospinal circuits to maximize functional recovery after spinal cord injury.展开更多
文摘Ketogenic diet （KD） is a high fat, low protein, low carbohydrate diet. Its antiepileptic effect is certain but the underlying mechanism is unknown. Mossy fiber sprouting in the inner molecular layer of the dentate gyrus causes the synaptic reorganization in the hippocampus, which is an important cause of temporal lobe epilepsy in animals and humans. It is also essential to the genesis and development of epilepsy. As the predominant excitatory neurotransmitter in the central nervous system, glutamate plays a role in synaptic reorganization and development of epilepsy.
基金National Nature Science Foundation of China(Nos.81671104,81701268,61761166004,and 81830033)Beijing Municipal Administration of Hospitals’Ascent Plan(No.DFL20150503)+1 种基金Capital Health Research and Development of Special(No.2018-2-1076)China Postdoctoral Science Foundation(No.2018T110120)。
文摘Background:Anterior thalamic nuclei(ATN)deep brain stimulation(DBS)is an effective method of controlling epilepsy,especially temporal lobe epilepsy.Mossy fiber sprouting(MFS)plays an indispensable role in the pathogenesis and progression of epilepsy,but the effect of ATN-DBS on MFS in the chronic stage of epilepsy and the potential underlying mechanisms are unknown.This study aimed to investigate the effect of ATN-DBS on MFS,as well as potential signaling pathways by a kainic acid(KA)-induced epileptic model.Methods:Twenty-four rhesus monkeys were randomly assigned to control,epilepsy(EP),EP-sham-DBS,and EP-DBS groups.KA was injected to establish the chronic epileptic model.The left ATN was implanted with a DBS lead and stimulated for 8 weeks.Enzyme-linked immunosorbent assay,Western blotting,and immunofluorescence staining were used to evaluate MFS and levels of potential molecular mediators in the hippocampus.One-way analysis of variance,followed by the Tukeypost hoc correction,was used to analyze the statistical significance of differences among multiple groups.Results:ATN-DBS is found to significantly reduce seizure frequency in the chronic stage of epilepsy.The number of ectopic granule cells was reduced in monkeys that received ATN stimulation(P<0.0001).Levels of 3′,5′-cyclic adenosine monophosphate(cAMP)and protein kinase A(PKA)in the hippocampus,together with Akt phosphorylation,were noticeably reduced in monkeys that received ATN stimulation(P=0.0030 andP=0.0001,respectively).ATN-DBS also significantly reduced MFS scores in the hippocampal dentate gyrus and CA3 sub-regions(allP<0.0001).Conclusion:ATN-DBS is shown to down-regulate the cAMP/PKA signaling pathway and Akt phosphorylation and to reduce the number of ectopic granule cells,which may be associated with the reduced MFS in chronic epilepsy.The study provides further insights into the mechanism by which ATN-DBS reduces epileptic seizures.
文摘Axonal regeneration and ifber regrowth is limited in the adult central nervous system, but re-search over the last decades has revealed a high intrinsic capacity of brain and spinal cord circuits to adapt and reorganize after smaller injuries or denervation. Short-distance ifber growth and synaptic rewiring was found in cortex, brain stem and spinal cord and could be associated with restoration of sensorimotor functions that were impaired by the injury. Such processes of struc-tural plasticity were initially observed in the corticospinal system following spinal cord injury or stroke, but recent studies showed an equally high potential for structural and functional reorganization in reticulospinal, rubrospinal or propriospinal projections. Here we review the lesion-induced plastic changes in the propriospinal pathways, and we argue that they represent a key mechanism triggering sensorimotor recovery upon incomplete spinal cord injury. The for-mation or strengthening of spinal detour pathways bypassing supraspinal commands around the lesion site to the denervated spinal cord were identiifed as prominent neural substrate inducing substantial motor recovery in different species from mice to primates. Indications for the exis-tence of propriospinal bypasses were also found in humans after cortical stroke. It is mandatory for current research to dissect the biological mechanisms underlying spinal circuit remodeling and to investigate how these processes can be stimulated in an optimal way by therapeutic inter-ventions （e.g., ifber-growth enhancing interventions, rehabilitation）. This knowledge will clear the way for the development of novel strategies targeting the remarkable plastic potential of pro-priospinal circuits to maximize functional recovery after spinal cord injury.
