Excitotoxicity is a process observed in many disease states by which an excessive synaptic excitation causes neuronal death, and is thought to be triggered by the extracellular accumulation of the excitatory neurotran...Excitotoxicity is a process observed in many disease states by which an excessive synaptic excitation causes neuronal death, and is thought to be triggered by the extracellular accumulation of the excitatory neurotransmitter glutamate, which binds and activates ionotropic N-methyl-D-aspartate glutamatergic receptors （NMDARs） in the brain. Normally, NMDARs mediate calcium entry into the cell to regulate physiological processes such as synaptic plasticity and memory,展开更多
The pleiotropic functions of circulating high density lipoprotein（HDL） on peripheral vascular health are well established. HDL plays a pivotal role in reverse cholesterol transport and is also known to suppress infl...The pleiotropic functions of circulating high density lipoprotein（HDL） on peripheral vascular health are well established. HDL plays a pivotal role in reverse cholesterol transport and is also known to suppress inflammation,endothelial activation and apoptosis in peripheral vessels. Although not expressed in the central nervous system, HDL has nevertheless emerged as a potential resilience factor for dementia in multiple epidemiological studies. Animal model data specifically support a role for HDL in attenuating the accumulation of P-amyloid within cerebral vessels concomitant with reduced neuroinflammation and improved cognitive performance. As the vascular contributions to dementia are increasingly appreciated, this review seeks to summarize recent literature focused on the vasoprotective properties of HDL that may extend to cerebral vessels, discuss potential roles of HDL in dementia relative to brainderived lipoproteins, identify gaps in current knowledge, and highlight new opportunities for research and discovery.展开更多
N-methyl-D-aspartate glutamate receptors(NMDARs)play crucial roles in the pathogenesis of neuronal injuries following a stroke insult;therefore,a plethora of preclinical studies focus on better understanding functions...N-methyl-D-aspartate glutamate receptors(NMDARs)play crucial roles in the pathogenesis of neuronal injuries following a stroke insult;therefore,a plethora of preclinical studies focus on better understanding functions of NMDARs and their associated signaling pathways.Over the past decades,NMDARs have been found to exert dual effects in neuronal deaths signaling and neuronal survival signaling during cerebral ischemia.Moreover,many complex intracellular signaling pathways downstream of NMDAR activation have been elucidated,which provide novel targets for developing much-needed neuro-protectants for patients with stroke.In this review,we will discuss the recent progress in understanding the underlying mechanisms of stroke related to NMDAR activation and the potential therapeutic strategies based on these discoveries.展开更多
Glaucoma is a chronic neurodegener-ative disorder characterized by progressive damage and loss of retinal ganglion cells （RGCs）. It is considered one of the leading causes of irreversible blindness in the olde...Glaucoma is a chronic neurodegener-ative disorder characterized by progressive damage and loss of retinal ganglion cells （RGCs）. It is considered one of the leading causes of irreversible blindness in the older population. There are estimates that glaucoma will affect 80 million individuals worldwide by the end of this de-cade, and yet we are still not able to identify the signals and the mechanisms that trigger this neurodegenerative disease. Various hypotheses have been generated to ad-dress the causes of the progressive RGC death that char-acterizes the disease. Age and increased intraocular pres-sure （IOP） have been established as the main risk factors for the development of glaucoma. Recent studies have identifed additional factors that play a role in the patho-genesis of this complex multifactorial disease, including infammation, oxidative stress, vascular dysregulation, disrupted axonal transport of neurotrophic factors, and the release of neurotoxic agents such as glutamate, nitric oxide and free radicals. The currently approved therapies for glaucoma that seek to reduce IOP, including medica-tions, laser treatment, and surgery, are unable to reliably stop RGC loss and functional impairment. Considering the signifcant personal, medical and socio-economic im-pacts of glaucoma as a leading cause of blindness, there is a pressing need for new innovative treatment strategies. Here we focus on the role of neuroinfammation in glau-coma and the opportunities that new fndings in this area have for the development of future therapeutics.展开更多
At a time of unprecedented need and despite significant advances in understanding brain function and related diseases,the drug pipeline for treatment of mental ill-health is failing[1,2].The reasons are many,including...At a time of unprecedented need and despite significant advances in understanding brain function and related diseases,the drug pipeline for treatment of mental ill-health is failing[1,2].The reasons are many,including the unparalleled complexity of the central nervous system(CNS)itself,a lack of interdisciplinary research collaborations,increased drug development costs,and higher risk of clinical failure of CNS drugs compared with other areas of drug development[3–6].It is now widely recognized that individual dimensions of mental ill health arise from altered neural processes within specific brain circuits that may be shared across diagnostic categories[7,8].The inclusion of cognitive and social processes is particularly appropriate because cognitive dysfunction is of paramount importance to the understanding and treatment of many psychiatric disorders[9].This issue is further compounded by the lack of adequate medication to reverse cognitive and social deficits.With respect to neurodevelopmental disorders that give rise to early onset of a spectrum of symptoms related to schizophrenia,attention deficit hyperactivity disorder,autism spectrum disorders(ASD)to name but a few,the need to discover effective treatment options is particularly urgent.展开更多
The superior colliculus(SC),one of the most well-characterized midbrain sensorimotor structures where visual,auditory,and somatosensory information are integrated to initiate motor commands,is highly conserved across ...The superior colliculus(SC),one of the most well-characterized midbrain sensorimotor structures where visual,auditory,and somatosensory information are integrated to initiate motor commands,is highly conserved across vertebrate evolution.Moreover,cell-type-specific SC neurons integrate afferent signals within local networks to generate defined output related to innate and cognitive behaviors.This review focuses on the recent progress in understanding of phenotypic diversity amongst SC neurons and their intrinsic circuits and long-projection targets.We further describe relevant neural circuits and specific cell types in relation to behavioral outputs and cognitive functions.The systematic delineation of SC organization,cell types,and neural connections is further put into context across species as these depend upon laminar architecture.Moreover,we focus on SC neural circuitry involving saccadic eye movement,and cognitive and innate behaviors.Overall,the review provides insight into SC functioning and represents a basis for further understanding of the pathology associated with SC dysfunction.展开更多
Neurodegeneration of Parkinson’s disease(PD)starts in an insidious manner,30–50%of dopaminergic neurons have been lost in the substantia nigra before clinical diagnosis.Prodromal stage of the disease,during which th...Neurodegeneration of Parkinson’s disease(PD)starts in an insidious manner,30–50%of dopaminergic neurons have been lost in the substantia nigra before clinical diagnosis.Prodromal stage of the disease,during which the disease pathology has started but is insufficient to result in clinical manifestations,offers a valuable window for disease-modifying therapies.The most focused underlying mechanisms linking the pathological pattern and clinical characteristics of prodromal PD are the prion hypothesis of alpha-synuclein and the selective vulnerability of neurons.In this review,we consider the two potential portals,the vagus nerve and the olfactory bulb,through which abnormal alpha-synuclein can access the brain.We review the clinical,pathological and neuroimaging evidence of the parasympathetic nervous system and the olfactory system in the neurodegenerative process and using the two systems as models to discuss the internal homogeneity and heterogeneity of the prodromal stage of PD,including both the clustering and subtyping of symptoms and signs.Finally,we offer some suggestions on future directions for imaging studies in prodromal Parkinson’s disease.展开更多
文摘Excitotoxicity is a process observed in many disease states by which an excessive synaptic excitation causes neuronal death, and is thought to be triggered by the extracellular accumulation of the excitatory neurotransmitter glutamate, which binds and activates ionotropic N-methyl-D-aspartate glutamatergic receptors （NMDARs） in the brain. Normally, NMDARs mediate calcium entry into the cell to regulate physiological processes such as synaptic plasticity and memory,
文摘The pleiotropic functions of circulating high density lipoprotein（HDL） on peripheral vascular health are well established. HDL plays a pivotal role in reverse cholesterol transport and is also known to suppress inflammation,endothelial activation and apoptosis in peripheral vessels. Although not expressed in the central nervous system, HDL has nevertheless emerged as a potential resilience factor for dementia in multiple epidemiological studies. Animal model data specifically support a role for HDL in attenuating the accumulation of P-amyloid within cerebral vessels concomitant with reduced neuroinflammation and improved cognitive performance. As the vascular contributions to dementia are increasingly appreciated, this review seeks to summarize recent literature focused on the vasoprotective properties of HDL that may extend to cerebral vessels, discuss potential roles of HDL in dementia relative to brainderived lipoproteins, identify gaps in current knowledge, and highlight new opportunities for research and discovery.
文摘N-methyl-D-aspartate glutamate receptors(NMDARs)play crucial roles in the pathogenesis of neuronal injuries following a stroke insult;therefore,a plethora of preclinical studies focus on better understanding functions of NMDARs and their associated signaling pathways.Over the past decades,NMDARs have been found to exert dual effects in neuronal deaths signaling and neuronal survival signaling during cerebral ischemia.Moreover,many complex intracellular signaling pathways downstream of NMDAR activation have been elucidated,which provide novel targets for developing much-needed neuro-protectants for patients with stroke.In this review,we will discuss the recent progress in understanding the underlying mechanisms of stroke related to NMDAR activation and the potential therapeutic strategies based on these discoveries.
文摘Glaucoma is a chronic neurodegener-ative disorder characterized by progressive damage and loss of retinal ganglion cells （RGCs）. It is considered one of the leading causes of irreversible blindness in the older population. There are estimates that glaucoma will affect 80 million individuals worldwide by the end of this de-cade, and yet we are still not able to identify the signals and the mechanisms that trigger this neurodegenerative disease. Various hypotheses have been generated to ad-dress the causes of the progressive RGC death that char-acterizes the disease. Age and increased intraocular pres-sure （IOP） have been established as the main risk factors for the development of glaucoma. Recent studies have identifed additional factors that play a role in the patho-genesis of this complex multifactorial disease, including infammation, oxidative stress, vascular dysregulation, disrupted axonal transport of neurotrophic factors, and the release of neurotoxic agents such as glutamate, nitric oxide and free radicals. The currently approved therapies for glaucoma that seek to reduce IOP, including medica-tions, laser treatment, and surgery, are unable to reliably stop RGC loss and functional impairment. Considering the signifcant personal, medical and socio-economic im-pacts of glaucoma as a leading cause of blindness, there is a pressing need for new innovative treatment strategies. Here we focus on the role of neuroinfammation in glau-coma and the opportunities that new fndings in this area have for the development of future therapeutics.
文摘At a time of unprecedented need and despite significant advances in understanding brain function and related diseases,the drug pipeline for treatment of mental ill-health is failing[1,2].The reasons are many,including the unparalleled complexity of the central nervous system(CNS)itself,a lack of interdisciplinary research collaborations,increased drug development costs,and higher risk of clinical failure of CNS drugs compared with other areas of drug development[3–6].It is now widely recognized that individual dimensions of mental ill health arise from altered neural processes within specific brain circuits that may be shared across diagnostic categories[7,8].The inclusion of cognitive and social processes is particularly appropriate because cognitive dysfunction is of paramount importance to the understanding and treatment of many psychiatric disorders[9].This issue is further compounded by the lack of adequate medication to reverse cognitive and social deficits.With respect to neurodevelopmental disorders that give rise to early onset of a spectrum of symptoms related to schizophrenia,attention deficit hyperactivity disorder,autism spectrum disorders(ASD)to name but a few,the need to discover effective treatment options is particularly urgent.
基金This review was supported by the Key-Area Research and Development Program of Guangdong Province(2018B030331001)the National Natural Science Foundation of China(31630031 and 31930047)+3 种基金the Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence Fund(2019025),the Guangdong Provincial Key Laboratory of Brain Connectome and Behavior(2017B030301017)the Chinese Academy of Sciences International Partnership Program(172644KYSB20170004)the CAS President’s International Fellowship for Distinguished Scientists(2021DB0003)the Canadian Institutes of Health Research(#10677).
文摘The superior colliculus(SC),one of the most well-characterized midbrain sensorimotor structures where visual,auditory,and somatosensory information are integrated to initiate motor commands,is highly conserved across vertebrate evolution.Moreover,cell-type-specific SC neurons integrate afferent signals within local networks to generate defined output related to innate and cognitive behaviors.This review focuses on the recent progress in understanding of phenotypic diversity amongst SC neurons and their intrinsic circuits and long-projection targets.We further describe relevant neural circuits and specific cell types in relation to behavioral outputs and cognitive functions.The systematic delineation of SC organization,cell types,and neural connections is further put into context across species as these depend upon laminar architecture.Moreover,we focus on SC neural circuitry involving saccadic eye movement,and cognitive and innate behaviors.Overall,the review provides insight into SC functioning and represents a basis for further understanding of the pathology associated with SC dysfunction.
文摘Neurodegeneration of Parkinson’s disease(PD)starts in an insidious manner,30–50%of dopaminergic neurons have been lost in the substantia nigra before clinical diagnosis.Prodromal stage of the disease,during which the disease pathology has started but is insufficient to result in clinical manifestations,offers a valuable window for disease-modifying therapies.The most focused underlying mechanisms linking the pathological pattern and clinical characteristics of prodromal PD are the prion hypothesis of alpha-synuclein and the selective vulnerability of neurons.In this review,we consider the two potential portals,the vagus nerve and the olfactory bulb,through which abnormal alpha-synuclein can access the brain.We review the clinical,pathological and neuroimaging evidence of the parasympathetic nervous system and the olfactory system in the neurodegenerative process and using the two systems as models to discuss the internal homogeneity and heterogeneity of the prodromal stage of PD,including both the clustering and subtyping of symptoms and signs.Finally,we offer some suggestions on future directions for imaging studies in prodromal Parkinson’s disease.
