The basal ganglia(BG) act as a cohesive functional unit that regulates motor function,habit formation,and reward/addictive behaviors. However,it is still not well understood how the BG maintains wakefulness and suppre...The basal ganglia(BG) act as a cohesive functional unit that regulates motor function,habit formation,and reward/addictive behaviors. However,it is still not well understood how the BG maintains wakefulness and suppresses sleep to achieve al these fundamental functions until genetical y engineered systems developed these years. Significant research efforts have recently been directed at developing genetic-molecular tools to achieve reversible and cell-type specific in vivo silencing or activation of neurons in behaving animals. Optogenetic tools can be used both to specifically activate or inhibit neurons of interest and identify functional synaptic connectivity between specific neuronal populations,both in vivo and in brain slices. Another recently developed system by Roth and colleagues permits the selective and ″remote″ manipulation(activation and silencing) of neuronal activity via all 3 major GPCR signaling pathways(G_i,G_s and G_q). These so-called ″ designer receptors exclusively activated by designer drugs″(DREADD) involve mutant GPCRs that do not respond to their endogenous ligands but are responsive to otherwise inert biological compounds. Recently,we demonstrated the essential roles and the neural pathways of the neurons expressing adenosine A_(2A) receptors or dopamine D_1 receptors in the BG for sleep-wake regulation using the genetically engineered systems including optogenetics and DREADD. We proposed a plausible model in which the caudate-putamen and the nucleus accumbens integrates behavioral processes with sleep/wakefulness through adenosine and dopamine receptors.展开更多
Temporal lobe epilepsy(TLE) is a common type of epilepsy and is not well controlled by current treatments.The frequent failure to treat TLE may be due to our lack of precise cellular/circuit mechanisms underlying TLE....Temporal lobe epilepsy(TLE) is a common type of epilepsy and is not well controlled by current treatments.The frequent failure to treat TLE may be due to our lack of precise cellular/circuit mechanisms underlying TLE.The early series of our studies have proved the success of low-frequency stimulation treatment for epilepsy,which was mainly depending on the stimulation target,the stimulation frequency and stimulation time(the therapeutic-window phenomenon).Now,by using optogenetics,viral tracing,multiple-channel EEG analysis,imaging,electrophysiology and pharmacology strategies,we are continued to investigate the circuit mechanism of therapeutic deep brain stimulation,and found that entorhinal principal neurons mediate antiepileptic ″ glutamatergic-GABAergic″ neuronal circuit for brain stimulation treatments of epilepsy.Meanwhile,we are currently focusing on the interplay of inhibitory and excitatory network in the key input/output regions of the hippocampus that related to the generation of in TLE.Specially,we found that depolarized GABAergic signaling in subicular microcircuit mediates generalized seizures in TLE and a direct septal cholinergic circuit attenuates TLE through driving hippocampal somatostatin inhibition.These findings may be of therapeutic interest in understanding the pathological neuronal circuitry in TLE and further the development of novel therapeutic approaches or drug targets.展开更多
OBJECTIVE Temporal lobe epilepsy(TLE)is one of the most common types of human epilepsy,and they are often resistant to current treatments.METHODS By using optogenetic,electrophysiological,imaging and pharmacology stra...OBJECTIVE Temporal lobe epilepsy(TLE)is one of the most common types of human epilepsy,and they are often resistant to current treatments.METHODS By using optogenetic,electrophysiological,imaging and pharmacology strategies,we aimed toinvestigate the underlying circuit mechanism of TLE and tried to developthe novel and efficient approach to control epilepsy.RESULTS(1)Using micro PET and multichannel EEG recording,we found an abnormal neural network,characterized by early hypometabolism and after discharge spread,during the epileptogenensis of TLE.(2)Deep brain stimulation,especially low frequency stimulation,targeted the epileptic focus and the areas outside of the focus(critical regions for seizure spread),such as the piriform cortex,cerebellum,entorhinal cortex or subiculum,reduced seizure severity in TLE.Its anti-epileptic effect is time-window dependent and polarity dependent,which shows a promising strategy for treating epileptic seizures.(3)Using an optogenetic strategy,we demonstrated that excitatory projection from entorhinal cortex to hippocampus instructs the brain-stimulation treatments of epilepsy.(4)Our data from both the clinical and experimental studies further demonstrated that a disinhibitory GABAergic neuronmediated microcircuit in the subiculum contributes to secondary generalized seizures in TLE.(5)Finally,based on abnormal synchronization of the electrical activity in epileptic circuit,we developed electroresponsive hydrogel nanoparticles modified with angiopep-2 to facilitate the delivery of the antiepileptic drug phenytoin sodium,which greatly improves the therapeutic index.CONCLUSION Our findings may update the current view of epileptic neuronal networks and suggest possible promising ways for epilepsy treatment.展开更多
OBJECTIVE Temporal lobe epilepsy(TLE) is one of the most common types of human epilepsy,and they are often resistant to current treatments. METHODS By using optogenetic,electrophysiological,imaging and pharmacology st...OBJECTIVE Temporal lobe epilepsy(TLE) is one of the most common types of human epilepsy,and they are often resistant to current treatments. METHODS By using optogenetic,electrophysiological,imaging and pharmacology strategies,we aimed toinvestigate the underlying circuit mechanism of TLE and tried to developthe novel and efficient approach to control epilepsy. RESULTS(1) Deep brain stimulation,especially low frequency stimulation,targeted the epileptic focus and the areas outside of the focus(critical regions for seizure spread),such as entorhinal cortex or subiculum,reduced seizure severity in TLE. Its anti-epileptic effect is time-window dependent and polarity dependent,which shows a promising strategy for treating epileptic seizures.(2) Using an optogenetic strategy,we demonstrated that excitatory projection from entorhinal cortex to hippocampus instructs the brain-stimulation treatments of epilepsy.(3) Our data from both the clinical and experimental studies further demonstrated that a disinhibitory GABAergic neuron-mediated microcircuit in the subiculum contributes to secondary generalized seizures in TLE.(4) Finally,based on abnormal synchronization of the electrical activity in epileptic circuit,we developed electro-responsive hydrogel nanoparticles modified with angiopep-2to facilitate the delivery of the antiepileptic drug phenytoin sodium,which greatly improves the therapeutic index. CONCLUSION Our findings may update the current view of epileptic neuronal networks and suggest possible promising ways for epilepsy treatment.展开更多
Optical-neural stimulation,which encompasses cutting-edge techniques such as optogenetics and infrared neurostimulation,employs distinct mechanisms to modulate brain function and behavior.These advanced neuromodulatio...Optical-neural stimulation,which encompasses cutting-edge techniques such as optogenetics and infrared neurostimulation,employs distinct mechanisms to modulate brain function and behavior.These advanced neuromodulation techniques offer accurate manipulation of targeted areas,even selectively modulating specific neurons,in the brain.This makes it possible to investigate the cause-and-effect connections between neural activity and behavior,allowing for a better comprehension of the intricate brain dynamics towards complex environments.Non-human primates serve as an essential animal model for investigating these complex functions in brain research,bridging the gap between the basic research and clinical applications.One of the earliest optical studies utilizing optogenetic neuromodulation in monkeys was conducted in 2009.Since then,the optical-neural stimulations have been effectively applied in non-human primates.This review summarises recent research that employed optogenetics or infrared neurostimulation techniques to regulate brain function and behavior in non-human primates.The current state of optical-neural stimulations discussed here demonstrates their efficacy in advancing the understanding of brain systems.Nevertheless,there are still challenges that need to be addressed before they can fully achieve their potential.展开更多
OBJECTIVE Chronic cerebral hy⁃poperfusion can lead to progressive demyelin⁃ation and ischemic vascular dementia,yet there are no effective treatments.METHODS Magnetic resonance imaging was employed in patients with wh...OBJECTIVE Chronic cerebral hy⁃poperfusion can lead to progressive demyelin⁃ation and ischemic vascular dementia,yet there are no effective treatments.METHODS Magnetic resonance imaging was employed in patients with white matter damage,and optogenetics and skin stroking were exerted to activate glutamater⁃gic neurons in the somatosensory cortex in a clas⁃sical mouse model of ischemia vascular dementia.RESULTS White matter damage was correlated with disrupted cortical structure from MRI results.In a mouse model,activating glutamatergic neu⁃rons in the somatosensory cortex promotes prolif⁃eration of OPCs and remyelination to rescue cog⁃nitive impairment after chronic cerebral hypoper⁃fusion.Such therapeutic action was limited to stimulation with moderate intensity at the upper layers of the cortex,but was achieved over a wide time window after ischemia.Mechanistically,enhanced glutamatergic neuron-OPC functional synaptic connections are required for protection from activation of cortical glutamatergic neurons.Finally,skin stroking activation of the somatosen⁃sory cortex,an easier approach for clinical trans⁃lation,promoted OPC proliferation and remyelin⁃ation as well as cognitive recovery after cerebral hypoperfusion.CONCLUSION Activation of gluta⁃matergic neurons in the somatosensory cortex may serve as novel approaches for treating isch⁃emic vascular dementia through precise modula⁃tion of glutamatergic neuron-OPC circuits.展开更多
文摘The basal ganglia(BG) act as a cohesive functional unit that regulates motor function,habit formation,and reward/addictive behaviors. However,it is still not well understood how the BG maintains wakefulness and suppresses sleep to achieve al these fundamental functions until genetical y engineered systems developed these years. Significant research efforts have recently been directed at developing genetic-molecular tools to achieve reversible and cell-type specific in vivo silencing or activation of neurons in behaving animals. Optogenetic tools can be used both to specifically activate or inhibit neurons of interest and identify functional synaptic connectivity between specific neuronal populations,both in vivo and in brain slices. Another recently developed system by Roth and colleagues permits the selective and ″remote″ manipulation(activation and silencing) of neuronal activity via all 3 major GPCR signaling pathways(G_i,G_s and G_q). These so-called ″ designer receptors exclusively activated by designer drugs″(DREADD) involve mutant GPCRs that do not respond to their endogenous ligands but are responsive to otherwise inert biological compounds. Recently,we demonstrated the essential roles and the neural pathways of the neurons expressing adenosine A_(2A) receptors or dopamine D_1 receptors in the BG for sleep-wake regulation using the genetically engineered systems including optogenetics and DREADD. We proposed a plausible model in which the caudate-putamen and the nucleus accumbens integrates behavioral processes with sleep/wakefulness through adenosine and dopamine receptors.
基金National Natural Science Foundation of China(913322028122100381603084).
文摘Temporal lobe epilepsy(TLE) is a common type of epilepsy and is not well controlled by current treatments.The frequent failure to treat TLE may be due to our lack of precise cellular/circuit mechanisms underlying TLE.The early series of our studies have proved the success of low-frequency stimulation treatment for epilepsy,which was mainly depending on the stimulation target,the stimulation frequency and stimulation time(the therapeutic-window phenomenon).Now,by using optogenetics,viral tracing,multiple-channel EEG analysis,imaging,electrophysiology and pharmacology strategies,we are continued to investigate the circuit mechanism of therapeutic deep brain stimulation,and found that entorhinal principal neurons mediate antiepileptic ″ glutamatergic-GABAergic″ neuronal circuit for brain stimulation treatments of epilepsy.Meanwhile,we are currently focusing on the interplay of inhibitory and excitatory network in the key input/output regions of the hippocampus that related to the generation of in TLE.Specially,we found that depolarized GABAergic signaling in subicular microcircuit mediates generalized seizures in TLE and a direct septal cholinergic circuit attenuates TLE through driving hippocampal somatostatin inhibition.These findings may be of therapeutic interest in understanding the pathological neuronal circuitry in TLE and further the development of novel therapeutic approaches or drug targets.
基金The project supportedp by National Natural Science Foundation of China(91332202,81221003)
文摘OBJECTIVE Temporal lobe epilepsy(TLE)is one of the most common types of human epilepsy,and they are often resistant to current treatments.METHODS By using optogenetic,electrophysiological,imaging and pharmacology strategies,we aimed toinvestigate the underlying circuit mechanism of TLE and tried to developthe novel and efficient approach to control epilepsy.RESULTS(1)Using micro PET and multichannel EEG recording,we found an abnormal neural network,characterized by early hypometabolism and after discharge spread,during the epileptogenensis of TLE.(2)Deep brain stimulation,especially low frequency stimulation,targeted the epileptic focus and the areas outside of the focus(critical regions for seizure spread),such as the piriform cortex,cerebellum,entorhinal cortex or subiculum,reduced seizure severity in TLE.Its anti-epileptic effect is time-window dependent and polarity dependent,which shows a promising strategy for treating epileptic seizures.(3)Using an optogenetic strategy,we demonstrated that excitatory projection from entorhinal cortex to hippocampus instructs the brain-stimulation treatments of epilepsy.(4)Our data from both the clinical and experimental studies further demonstrated that a disinhibitory GABAergic neuronmediated microcircuit in the subiculum contributes to secondary generalized seizures in TLE.(5)Finally,based on abnormal synchronization of the electrical activity in epileptic circuit,we developed electroresponsive hydrogel nanoparticles modified with angiopep-2 to facilitate the delivery of the antiepileptic drug phenytoin sodium,which greatly improves the therapeutic index.CONCLUSION Our findings may update the current view of epileptic neuronal networks and suggest possible promising ways for epilepsy treatment.
基金The project supported by National Natural Science Foundation of China(91332202,81630098)
文摘OBJECTIVE Temporal lobe epilepsy(TLE) is one of the most common types of human epilepsy,and they are often resistant to current treatments. METHODS By using optogenetic,electrophysiological,imaging and pharmacology strategies,we aimed toinvestigate the underlying circuit mechanism of TLE and tried to developthe novel and efficient approach to control epilepsy. RESULTS(1) Deep brain stimulation,especially low frequency stimulation,targeted the epileptic focus and the areas outside of the focus(critical regions for seizure spread),such as entorhinal cortex or subiculum,reduced seizure severity in TLE. Its anti-epileptic effect is time-window dependent and polarity dependent,which shows a promising strategy for treating epileptic seizures.(2) Using an optogenetic strategy,we demonstrated that excitatory projection from entorhinal cortex to hippocampus instructs the brain-stimulation treatments of epilepsy.(3) Our data from both the clinical and experimental studies further demonstrated that a disinhibitory GABAergic neuron-mediated microcircuit in the subiculum contributes to secondary generalized seizures in TLE.(4) Finally,based on abnormal synchronization of the electrical activity in epileptic circuit,we developed electro-responsive hydrogel nanoparticles modified with angiopep-2to facilitate the delivery of the antiepileptic drug phenytoin sodium,which greatly improves the therapeutic index. CONCLUSION Our findings may update the current view of epileptic neuronal networks and suggest possible promising ways for epilepsy treatment.
文摘Optical-neural stimulation,which encompasses cutting-edge techniques such as optogenetics and infrared neurostimulation,employs distinct mechanisms to modulate brain function and behavior.These advanced neuromodulation techniques offer accurate manipulation of targeted areas,even selectively modulating specific neurons,in the brain.This makes it possible to investigate the cause-and-effect connections between neural activity and behavior,allowing for a better comprehension of the intricate brain dynamics towards complex environments.Non-human primates serve as an essential animal model for investigating these complex functions in brain research,bridging the gap between the basic research and clinical applications.One of the earliest optical studies utilizing optogenetic neuromodulation in monkeys was conducted in 2009.Since then,the optical-neural stimulations have been effectively applied in non-human primates.This review summarises recent research that employed optogenetics or infrared neurostimulation techniques to regulate brain function and behavior in non-human primates.The current state of optical-neural stimulations discussed here demonstrates their efficacy in advancing the understanding of brain systems.Nevertheless,there are still challenges that need to be addressed before they can fully achieve their potential.
文摘OBJECTIVE Chronic cerebral hy⁃poperfusion can lead to progressive demyelin⁃ation and ischemic vascular dementia,yet there are no effective treatments.METHODS Magnetic resonance imaging was employed in patients with white matter damage,and optogenetics and skin stroking were exerted to activate glutamater⁃gic neurons in the somatosensory cortex in a clas⁃sical mouse model of ischemia vascular dementia.RESULTS White matter damage was correlated with disrupted cortical structure from MRI results.In a mouse model,activating glutamatergic neu⁃rons in the somatosensory cortex promotes prolif⁃eration of OPCs and remyelination to rescue cog⁃nitive impairment after chronic cerebral hypoper⁃fusion.Such therapeutic action was limited to stimulation with moderate intensity at the upper layers of the cortex,but was achieved over a wide time window after ischemia.Mechanistically,enhanced glutamatergic neuron-OPC functional synaptic connections are required for protection from activation of cortical glutamatergic neurons.Finally,skin stroking activation of the somatosen⁃sory cortex,an easier approach for clinical trans⁃lation,promoted OPC proliferation and remyelin⁃ation as well as cognitive recovery after cerebral hypoperfusion.CONCLUSION Activation of gluta⁃matergic neurons in the somatosensory cortex may serve as novel approaches for treating isch⁃emic vascular dementia through precise modula⁃tion of glutamatergic neuron-OPC circuits.
