·Optogenetics is a new and rapidly evolving gene and neuroengineering technology that allows optical control of specific populations of neurons without affecting other neurons in the brain at high temporal and sp...·Optogenetics is a new and rapidly evolving gene and neuroengineering technology that allows optical control of specific populations of neurons without affecting other neurons in the brain at high temporal and spatial resolution. By heterologous expression of the light-sensitive membrane proteins, cell type-specific depolarization or hyperpolarization can be optically induced on a millisecond time scale. Optogenetics has the higher selectivity and specificity compared to traditional electrophysiological techniques and pharmaceutical methods. It has been a novel promising tool for medical research. Because of easy handling, high temporal and spatial precision, optogenetics has been applied to many aspects of nervous system research, such as tactual neural circuit, visual neural circuit, auditory neural circuit and olfactory neural circuit, as well as research of some neurological diseases. The review highlights the recent advances of optogenetics in medical study.展开更多
The anterolateral motor cortex of rodents is an important motor auxiliary area,and its function is similar to that of the premotor area in humans.Activation and inhibition of the contralesional anterolateral motor cor...The anterolateral motor cortex of rodents is an important motor auxiliary area,and its function is similar to that of the premotor area in humans.Activation and inhibition of the contralesional anterolateral motor cortex(cALM)have been shown to have direct effects on motor behavior.However,the significance of cALM activation and inhibition in the treatment of stroke remains unclear.This study investigated the role of optogenetic cALM stimulation in a mouse model of cerebral stroke.The results showed that 21-day optogenetic cALM inhibition,but not activation,improved neurological function.In addition,optogenetic cALM stimulation substantially altered dendritic structural reorganization and dendritic spine plasticity,as optogenetic cALM inhibition resulted in increased dendritic length,number of dendritic spines,and number of perforated synapses,whereas optogenetic activation led to an increase in the number of multiple synapse boutons and the number of dendritic intersections.Furthermore,RNA-seq analysis showed that multiple biological processes regulated by the cALM were upregulated immediately after optogenetic cALM inhibition,and that several immediate-early genes(including cFOS,Erg1,and Sema3f)were expressed at higher levels after optogenetic inhibition than after optogenetic activation.These results were confirmed by quantitative reverse transcription-polymerase chain reaction.Finally,immunofluorescence analysis showed that the c-FOS signal in layer V of the primary motor cortex in the ischemic hemisphere was higher after optogenetic cALM activation than it was after optogenetic cALM inhibition.Taken together,these findings suggest that optogenetic cALM stimulation promotes neural reorganization in the primary motor cortex of the ischemic hemisphere,and that optogenetic cALM inhibition and activation have different effects on neural plasticity.The study was approved by the Experimental Animal Ethics Committee of Fudan University(approval No.201802173 S)on March 3,2018.展开更多
Ion channels present in the plasma membrane are responsible for integration and propagation of electric signals,which transmit information in nerve cells.Malfunction of these ion channels leads to many neurological di...Ion channels present in the plasma membrane are responsible for integration and propagation of electric signals,which transmit information in nerve cells.Malfunction of these ion channels leads to many neurological diseases.Recently,optogenetic technology has gained a lot of attention for the manipulation of neuronal circuits.Optogenetics is a neuromodulation approach that has been developed to control neuronal functions and activities using light.The lanthanide-doped upconversion nanoparticles(UCNPs)absorb low energy photons in near-infrared(NIR) window and emit high energy photons in the visible spectrum region via nonlinear processes.In the last few decades,UCNPs have gained great attention in various bio-medical applications such as bio-imaging,drug delivery and optogenetics.The near-infrared illumination is considered more suitable for optogenetics application,due to its lower degree of light attenuation and higher tissue penetration compared to visible light.Therefore,UCNPs have been considered as the new promising candidates for optogenetics applications.Upconversion nanoparticlemediated optogenetic systems provide a great opportunity to manipulate the ion channel in deep tissue.Herein,we summarize the upconversion photoluminescence in lanthanide doped nanomaterials and its mechanisms and several approaches adopted to tune emission color or enhance upconversion efficiency.Recent advances of lanthanide-doped UCNPs design strategy and their mechanism are reviewed.Then,we discuss the neural circuitry modulation using upconversion nanoparticles mediated optogenetics.Moreover,the future perspectives towards optogenetics are also included.展开更多
Pain is an unpleasant sensory and emotional experience associated with,or resembling that associated with,actual or potential tissue damage.The processing of pain involves complicated modulation at the levels of the p...Pain is an unpleasant sensory and emotional experience associated with,or resembling that associated with,actual or potential tissue damage.The processing of pain involves complicated modulation at the levels of the periphery,spinal cord,and brain.The pathogenesis of chronic pain is still not fully understood,which makes the clinical treatment challenging.Optogenetics,which combines optical and genetic technologies,can precisely intervene in the activity of specific groups of neurons and elements of the related circuits.Taking advantage of optogenetics,researchers have achieved a body of new findings that shed light on the cellular and circuit mechanisms of pain transmission,pain modulation,and chronic pain both in the periphery and the central nervous system.In this review,we summarize recent findings in pain research using optogenetic approaches and discuss their significance in understanding the pathogenesis of chronic pain.展开更多
Cognitive impairment is the most common complication in patients with temporal lobe epilepsy with hippocampal scle rosis.There is no effective treatment for cognitive impairment.Medial septum cholinergic neurons have ...Cognitive impairment is the most common complication in patients with temporal lobe epilepsy with hippocampal scle rosis.There is no effective treatment for cognitive impairment.Medial septum cholinergic neurons have been reported to be a potential target for controlling epileptic seizures in tempo ral lobe epile psy.However,their role in the cognitive impairment of temporal lobe epilepsy remains unclear.In this study,we found that patients with temporal lobe epile psy with hippocampal sclerosis had a low memory quotient and severe impairment in verbal memory,but had no impairment in nonverbal memory.The cognitive impairment was slightly correlated with reduced medial septum volume and medial septum-hippocampus tra cts measured by diffusion tensor imaging.In a mouse model of chronic temporal lobe epilepsy induced by kainic acid,the number of medial septum choline rgic neurons was reduced and acetylcholine release was reduced in the hippocampus.Furthermore,selective apoptosis of medial septum cholinergic neurons mimicked the cognitive deficits in epileptic mice,and activation of medial septum cholinergic neurons enhanced hippocampal acetylcholine release and restored cognitive function in both kainic acid-and kindling-induced epile psy models.These res ults suggest that activation of medial septum cholinergic neurons reduces cognitive deficits in temporal lobe epilepsy by increasing acetylcholine release via projections to the hippocampus.展开更多
Generating diverse motor behaviors critical for survival is a challenge that confronts the central nervous system(CNS)of all animals.During movement execution,the CNS performs complex calculations to control a large n...Generating diverse motor behaviors critical for survival is a challenge that confronts the central nervous system(CNS)of all animals.During movement execution,the CNS performs complex calculations to control a large number of neuromusculoskeletal elements.The theory of modular motor control proposes that spinal interneurons are organized in discrete modules that can be linearly combined to generate a variety of behavioral patterns.These modules have been previously represented as stimulus-evoked force fields(FFs)comprising isometric limb-endpoint forces across workspace locations.Here,we ask whether FFs elicited by different stimulations indeed represent the most elementary units of motor control or are themselves the combination of a limited number of even more fundamental motor modules.To probe for potentially more elementary modules,we optogenetically stimulated the lumbosacral spinal cord of intact and spinalized Thy1-ChR2 transgenic mice(n=21),eliciting FFs from as many single stimulation loci as possible(20-70 loci per mouse)at minimally necessary power.We found that the resulting varieties of FFs defied simple categorization with just a few clusters.We used gradient descent to further decompose the FFs into their underlying basic force fields(BFFs),whose linear combination explained FF variability.Across mice,we identified 4-5 BFFs with partially localizable but overlapping representations along the spinal cord.The BFFs were structured and topographically distributed in such a way that a rostral-to-caudal traveling wave of activity across the lumbosacral spinal cord may generate a swing-to-stance gait cycle.These BFFs may represent more rudimentary submodules that can be flexibly merged to produce a library of motor modules for building different motor behaviors.展开更多
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
Limb loss and spinal cord injury are two debilitating conditions that continue to grow in prevalence. Prosthetic limbs and limb reanimation present two ways of providing affected individuals with means to interact in ...Limb loss and spinal cord injury are two debilitating conditions that continue to grow in prevalence. Prosthetic limbs and limb reanimation present two ways of providing affected individuals with means to interact in the world. These techniques are both dependent on a robust interface with the peripheral nerve. Current methods for interfacing with the peripheral nerve tend to suffer from low specificity, high latency and insufficient robustness for a chronic implant. An optical peripheral nerve interface may solve some of these problems by decreasing invasiveness and providing single axon specificity. In order to implement such an interface three elements are required:(1) a transducer capable of translating light into a neural stimulus or translating neural activity into changes in fluorescence,(2) a means for delivering said transducer and(3) a microscope for providing the stimulus light and detecting the fluorescence change. There are continued improvements in both genetically encoded calcium and voltage indicators as well as new optogenetic actuators for stimulation. Similarly, improvements in specificity of viral vectors continue to improve expression in the axons of the peripheral nerve. Our work has recently shown that it is possible to virally transduce axons of the peripheral nerve for recording from small fibers. The improvements of these components make an optical peripheral nerve interface a rapidly approaching alternative to current methods.展开更多
Peristalsis is widely seen in nature, as this pumping action is important in digestive systems for conveying sustenance to every corner of the body. In this paper, we propose a muscle-powered tubular micro pump that p...Peristalsis is widely seen in nature, as this pumping action is important in digestive systems for conveying sustenance to every corner of the body. In this paper, we propose a muscle-powered tubular micro pump that provides peristaltic transport. We utilized Drosophila melanogaster larvae that express channelrhodopsin-2 (ChR2) on the cell membrane of skeletal muscles to obtain light-responsive muscle tissues. The larvae were forced to contract with blue light stimulation. While changing the speed of the propagating light stimulation, we observed displacement on the surface of the contractile muscle tissues. We obtained peristaltic pumps from the larvae by dissecting them into tubular structures. The average inner diameter of the tubular structures was about 400 lm and the average outer diameter was about 750 lm. Contractions of this tubular structure could be controlled with the same blue light stimulation. To make the inner flow visible, we placed microbeads into the peristaltic pump, and thus determined that the pump could transport microbeads at a speed of 120 lm-s1.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
Dynamic protein-protein interactions are essential for proper cell functioning.Homointeraction events—physical interactions between the same type of proteins—represent a pivotal subset of protein-protein interaction...Dynamic protein-protein interactions are essential for proper cell functioning.Homointeraction events—physical interactions between the same type of proteins—represent a pivotal subset of protein-protein interactions that are widely exploited in activating intracellular signaling pathways.Capacities of modulating protein-protein interactions with spatial and temporal resolution are greatly desired to decipher the dynamic nature of signal transduction mechanisms.The emerging optogenetic technology,based on genetically encoded light-sensitive proteins,provides promising opportunities to dissect the highly complex signaling networks with unmatched specificity and spatiotemporal precision.Here we review recent achievements in the development of optogenetic tools enabling light-inducible protein-protein homo-interactions and their applications in optical activation of signaling pathways.展开更多
Numerous clinical and research applications necessitate the ability to interface with peripheral nerve fibers to read and control relevant neural pathways. Visceral organ modulation and rehabilitative prosthesis are t...Numerous clinical and research applications necessitate the ability to interface with peripheral nerve fibers to read and control relevant neural pathways. Visceral organ modulation and rehabilitative prosthesis are two areas which could benefit greatly from improved neural interfacing approaches. Therapeutic neural interfacing, or ‘bioelectronic medicine', has potential to affect a broad range of disorders given that all the major organs of the viscera are neurally innervated. However, a better understanding of the neural pathways that underlie function and a means to precisely interface with these fibers are required. Existing peripheral nerve interfaces, consisting primarily of electrode-based designs, are unsuited for highly specific(individual axon) communication and/or are invasive to the tissue. Our laboratory has explored an optogenetic approach by which optically sensitive reporters and actuators are targeted to specific cell(axon) types. The nature of such an approach is laid out in this short perspective, along with associated technologies and challenges.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
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
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 suppress...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 all these fundamental functions until genetically engineered systems developed these years.We focused on the adenosine A2A and dopamine D1 Receptors(R)in the BG and obtained following 4 findings:①Nucleus accumbens(NAc)dopamine D1R-expressing neurons are essential in controlling wakefulness and are involved in physiological arousal via the lateral hypothalamus and midbrain circuits;②The rostromedial tegmental nucleus(RMTg),also called the GABAergic tail of the ventral tegmental area,projects to the midbrain dopaminergic system and other regions.Our findings reveal an essential role of the RMTg in the promotion of non-rapid eye movement(non-REM,NREM)sleep and homeostatic regulation;③Opposite to the D1R in the NAc,A2AR made a prominent contribution to sleep control associated with motivation.④Striatal adenosine A2AR neurons control active-period sleep via parvalbumin neurons in external globus pallidus.Taken together,we proposed a plausible model in which the caudate-putamen and NAc integrate behavioral processes with sleep/wakefulness through adenosine and dopamine receptors.The impacts of the BG in physiological sleep and insomnia will be discussed.展开更多
Neuromodulation represents a cutting edge class of both invasive and non-invasive therapeutic methods which alter the activity of neurons.Currently,several different techniques have been developed-or are currently bei...Neuromodulation represents a cutting edge class of both invasive and non-invasive therapeutic methods which alter the activity of neurons.Currently,several different techniques have been developed-or are currently being investigated–to treat a wide variety of neurological and neuropsychiatric disorders.Recently,in vivo and in vitro studies have revealed that neuromodulation can also induce myelination,meaning that it could hold potential as a therapy for various demyelinating diseases including multiple sclerosis and progressive multifocal leukencepalopathy.These findings come on the heels of a paradigm shift in the view of myelin's role within the nervous system from a static structure to an active co-regulator of central nervous system plasticity and participant in neuron-mediated modulation.In the present review,we highlight several of the recent findings regarding the role of neural activity in altering myelination including several soluble and contact-dependent factors that seem to mediate neural activitydependent myelination.We also highlight several considerations for neuromodulatory techniques,including the need for further research into spatiotemporal precision,dosage,and the safety and efficacy of transcranial focused ultrasound stimulation,an emerging neuromodulation technology.As the field of neuromodulation continues to evolve,it could potentially bring forth methods for the treatment of demyelinating diseases,and as such,further investigation into the mechanisms of neuron-dependent myelination as well as neuro-imaging modalities that can monitor myelination activity is warranted.展开更多
Manipulating and real-time monitoring of neuronal activities with cell-type specificity and precise spatiotemporal resolution during animal behavior are fundamental technologies for exploring the functional connectivi...Manipulating and real-time monitoring of neuronal activities with cell-type specificity and precise spatiotemporal resolution during animal behavior are fundamental technologies for exploring the functional connectivity, information transmission, and physiological functions of neural circuits in vivo. However, current techniques for optogenetic stimulation and neuronal activity recording mostly operate independently. Here, we report an all-fiber-transmission photometry system for simultaneous optogenetic manipulation and multi-color recording of neuronal activities and the neurotransmitter release in a freely moving animal. We have designed and manufactured a wavelength-independent multi-branch fiber bundle to enable simultaneous optogenetic manipulation and multi-color recording at different wavelengths. Further, we combine a laser of narrow linewidth with the lock-in amplification method to suppress the optogenetic stimulation-induced artifacts and channel crosstalk. We show that the collection efficiency of our system outperforms a traditional epi-fluorescence system. Further, we demonstrate successful recording of dynamic dopamine(DA) responses to unexpected rewards in the nucleus accumbens(NAc) in a freely moving mouse. We also show simultaneous dual-color recording of neuronal Ca2+ signals and DA dynamics in the NAc upon delivering an unexpected reward and the simultaneous optogenetic activating at dopaminergic terminals in the same location. Thus, our multi-function fiber photometry system provides a compatible, efficient, and flexible solution for neuroscientists to study neural circuits and neurological diseases.展开更多
基金National Natural Sciences Foundation of China (No.81070749)Chongqing Science and Technology Project,China (No.CSTC,2010AB5118)
文摘·Optogenetics is a new and rapidly evolving gene and neuroengineering technology that allows optical control of specific populations of neurons without affecting other neurons in the brain at high temporal and spatial resolution. By heterologous expression of the light-sensitive membrane proteins, cell type-specific depolarization or hyperpolarization can be optically induced on a millisecond time scale. Optogenetics has the higher selectivity and specificity compared to traditional electrophysiological techniques and pharmaceutical methods. It has been a novel promising tool for medical research. Because of easy handling, high temporal and spatial precision, optogenetics has been applied to many aspects of nervous system research, such as tactual neural circuit, visual neural circuit, auditory neural circuit and olfactory neural circuit, as well as research of some neurological diseases. The review highlights the recent advances of optogenetics in medical study.
文摘The anterolateral motor cortex of rodents is an important motor auxiliary area,and its function is similar to that of the premotor area in humans.Activation and inhibition of the contralesional anterolateral motor cortex(cALM)have been shown to have direct effects on motor behavior.However,the significance of cALM activation and inhibition in the treatment of stroke remains unclear.This study investigated the role of optogenetic cALM stimulation in a mouse model of cerebral stroke.The results showed that 21-day optogenetic cALM inhibition,but not activation,improved neurological function.In addition,optogenetic cALM stimulation substantially altered dendritic structural reorganization and dendritic spine plasticity,as optogenetic cALM inhibition resulted in increased dendritic length,number of dendritic spines,and number of perforated synapses,whereas optogenetic activation led to an increase in the number of multiple synapse boutons and the number of dendritic intersections.Furthermore,RNA-seq analysis showed that multiple biological processes regulated by the cALM were upregulated immediately after optogenetic cALM inhibition,and that several immediate-early genes(including cFOS,Erg1,and Sema3f)were expressed at higher levels after optogenetic inhibition than after optogenetic activation.These results were confirmed by quantitative reverse transcription-polymerase chain reaction.Finally,immunofluorescence analysis showed that the c-FOS signal in layer V of the primary motor cortex in the ischemic hemisphere was higher after optogenetic cALM activation than it was after optogenetic cALM inhibition.Taken together,these findings suggest that optogenetic cALM stimulation promotes neural reorganization in the primary motor cortex of the ischemic hemisphere,and that optogenetic cALM inhibition and activation have different effects on neural plasticity.The study was approved by the Experimental Animal Ethics Committee of Fudan University(approval No.201802173 S)on March 3,2018.
基金Project supported by the Fonds de recherche du Québec-Nature et technologies(FRQNT)Canada for Merit Scholarship Program for Foreign Students(PBEEE)Fellowship。
文摘Ion channels present in the plasma membrane are responsible for integration and propagation of electric signals,which transmit information in nerve cells.Malfunction of these ion channels leads to many neurological diseases.Recently,optogenetic technology has gained a lot of attention for the manipulation of neuronal circuits.Optogenetics is a neuromodulation approach that has been developed to control neuronal functions and activities using light.The lanthanide-doped upconversion nanoparticles(UCNPs)absorb low energy photons in near-infrared(NIR) window and emit high energy photons in the visible spectrum region via nonlinear processes.In the last few decades,UCNPs have gained great attention in various bio-medical applications such as bio-imaging,drug delivery and optogenetics.The near-infrared illumination is considered more suitable for optogenetics application,due to its lower degree of light attenuation and higher tissue penetration compared to visible light.Therefore,UCNPs have been considered as the new promising candidates for optogenetics applications.Upconversion nanoparticlemediated optogenetic systems provide a great opportunity to manipulate the ion channel in deep tissue.Herein,we summarize the upconversion photoluminescence in lanthanide doped nanomaterials and its mechanisms and several approaches adopted to tune emission color or enhance upconversion efficiency.Recent advances of lanthanide-doped UCNPs design strategy and their mechanism are reviewed.Then,we discuss the neural circuitry modulation using upconversion nanoparticles mediated optogenetics.Moreover,the future perspectives towards optogenetics are also included.
基金supported by grants from the National Natural Science Foundation of China(82073819 and 81872843)Fundamental Research Funds for the Central Universities of China(2021QNA7005).
文摘Pain is an unpleasant sensory and emotional experience associated with,or resembling that associated with,actual or potential tissue damage.The processing of pain involves complicated modulation at the levels of the periphery,spinal cord,and brain.The pathogenesis of chronic pain is still not fully understood,which makes the clinical treatment challenging.Optogenetics,which combines optical and genetic technologies,can precisely intervene in the activity of specific groups of neurons and elements of the related circuits.Taking advantage of optogenetics,researchers have achieved a body of new findings that shed light on the cellular and circuit mechanisms of pain transmission,pain modulation,and chronic pain both in the periphery and the central nervous system.In this review,we summarize recent findings in pain research using optogenetic approaches and discuss their significance in understanding the pathogenesis of chronic pain.
基金National Natural Science Foundation of China,Nos.82003 729 (to Ying W),82022071 (to YiW)Natural Science Foundation of Shandong Province of China,No.ZR2020QH357 (to Ying W)Public Welfare Technology Research Program of Zhejiang Province,No.LGF20H09001 1 (to JF)。
文摘Cognitive impairment is the most common complication in patients with temporal lobe epilepsy with hippocampal scle rosis.There is no effective treatment for cognitive impairment.Medial septum cholinergic neurons have been reported to be a potential target for controlling epileptic seizures in tempo ral lobe epile psy.However,their role in the cognitive impairment of temporal lobe epilepsy remains unclear.In this study,we found that patients with temporal lobe epile psy with hippocampal sclerosis had a low memory quotient and severe impairment in verbal memory,but had no impairment in nonverbal memory.The cognitive impairment was slightly correlated with reduced medial septum volume and medial septum-hippocampus tra cts measured by diffusion tensor imaging.In a mouse model of chronic temporal lobe epilepsy induced by kainic acid,the number of medial septum choline rgic neurons was reduced and acetylcholine release was reduced in the hippocampus.Furthermore,selective apoptosis of medial septum cholinergic neurons mimicked the cognitive deficits in epileptic mice,and activation of medial septum cholinergic neurons enhanced hippocampal acetylcholine release and restored cognitive function in both kainic acid-and kindling-induced epile psy models.These res ults suggest that activation of medial septum cholinergic neurons reduces cognitive deficits in temporal lobe epilepsy by increasing acetylcholine release via projections to the hippocampus.
基金supported by the CUHK Faculty of Medicine Faculty Innovation Award FIA2016/A/04(to V.C.K.C.)Group Research Scheme NL/JW/rc/grs1819/0426/19hc(to V.C.K.C.)The Hong Kong Research Grants Council 24115318,CUHK-R4022-18,14114721,and 14119022(to V.C.K.C)。
文摘Generating diverse motor behaviors critical for survival is a challenge that confronts the central nervous system(CNS)of all animals.During movement execution,the CNS performs complex calculations to control a large number of neuromusculoskeletal elements.The theory of modular motor control proposes that spinal interneurons are organized in discrete modules that can be linearly combined to generate a variety of behavioral patterns.These modules have been previously represented as stimulus-evoked force fields(FFs)comprising isometric limb-endpoint forces across workspace locations.Here,we ask whether FFs elicited by different stimulations indeed represent the most elementary units of motor control or are themselves the combination of a limited number of even more fundamental motor modules.To probe for potentially more elementary modules,we optogenetically stimulated the lumbosacral spinal cord of intact and spinalized Thy1-ChR2 transgenic mice(n=21),eliciting FFs from as many single stimulation loci as possible(20-70 loci per mouse)at minimally necessary power.We found that the resulting varieties of FFs defied simple categorization with just a few clusters.We used gradient descent to further decompose the FFs into their underlying basic force fields(BFFs),whose linear combination explained FF variability.Across mice,we identified 4-5 BFFs with partially localizable but overlapping representations along the spinal cord.The BFFs were structured and topographically distributed in such a way that a rostral-to-caudal traveling wave of activity across the lumbosacral spinal cord may generate a swing-to-stance gait cycle.These BFFs may represent more rudimentary submodules that can be flexibly merged to produce a library of motor modules for building different motor behaviors.
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funded in part by the University of Colorado Medical Scientist Training Program and funds from the NIH SPARC initiative administered through the Office of the Director:1OT2OD023852-01
文摘Limb loss and spinal cord injury are two debilitating conditions that continue to grow in prevalence. Prosthetic limbs and limb reanimation present two ways of providing affected individuals with means to interact in the world. These techniques are both dependent on a robust interface with the peripheral nerve. Current methods for interfacing with the peripheral nerve tend to suffer from low specificity, high latency and insufficient robustness for a chronic implant. An optical peripheral nerve interface may solve some of these problems by decreasing invasiveness and providing single axon specificity. In order to implement such an interface three elements are required:(1) a transducer capable of translating light into a neural stimulus or translating neural activity into changes in fluorescence,(2) a means for delivering said transducer and(3) a microscope for providing the stimulus light and detecting the fluorescence change. There are continued improvements in both genetically encoded calcium and voltage indicators as well as new optogenetic actuators for stimulation. Similarly, improvements in specificity of viral vectors continue to improve expression in the axons of the peripheral nerve. Our work has recently shown that it is possible to virally transduce axons of the peripheral nerve for recording from small fibers. The improvements of these components make an optical peripheral nerve interface a rapidly approaching alternative to current methods.
基金supported by Grant-in-Aid for Japan Society for the Promotion of Science(JSPS)Fellow(17J01742)JSPS,MEXT KAKENHI(21676002,23111705,26249027,and 17H01254)the Industrial Technology Research Grant Program from the New Energy and Industrial Technology Development Organization(NEDO)of Japan
文摘Peristalsis is widely seen in nature, as this pumping action is important in digestive systems for conveying sustenance to every corner of the body. In this paper, we propose a muscle-powered tubular micro pump that provides peristaltic transport. We utilized Drosophila melanogaster larvae that express channelrhodopsin-2 (ChR2) on the cell membrane of skeletal muscles to obtain light-responsive muscle tissues. The larvae were forced to contract with blue light stimulation. While changing the speed of the propagating light stimulation, we observed displacement on the surface of the contractile muscle tissues. We obtained peristaltic pumps from the larvae by dissecting them into tubular structures. The average inner diameter of the tubular structures was about 400 lm and the average outer diameter was about 750 lm. Contractions of this tubular structure could be controlled with the same blue light stimulation. To make the inner flow visible, we placed microbeads into the peristaltic pump, and thus determined that the pump could transport microbeads at a speed of 120 lm-s1.
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supported by a Shun Hing Institute of Advanced Engineering Grant(No.4720247)a General Research Fund/Early Career Scheme(No.24201919)from the Research Grants Council of Hong Kong Special Administrative Region(to LD)。
文摘Dynamic protein-protein interactions are essential for proper cell functioning.Homointeraction events—physical interactions between the same type of proteins—represent a pivotal subset of protein-protein interactions that are widely exploited in activating intracellular signaling pathways.Capacities of modulating protein-protein interactions with spatial and temporal resolution are greatly desired to decipher the dynamic nature of signal transduction mechanisms.The emerging optogenetic technology,based on genetically encoded light-sensitive proteins,provides promising opportunities to dissect the highly complex signaling networks with unmatched specificity and spatiotemporal precision.Here we review recent achievements in the development of optogenetic tools enabling light-inducible protein-protein homo-interactions and their applications in optical activation of signaling pathways.
基金financially supported in part by funds administered through VA Eastern Colorado Health Care System-Denver VA Medical Centerfunds from the NIH SPARC initiative administered through the Office of the Director:1OT2OD023852-01
文摘Numerous clinical and research applications necessitate the ability to interface with peripheral nerve fibers to read and control relevant neural pathways. Visceral organ modulation and rehabilitative prosthesis are two areas which could benefit greatly from improved neural interfacing approaches. Therapeutic neural interfacing, or ‘bioelectronic medicine', has potential to affect a broad range of disorders given that all the major organs of the viscera are neurally innervated. However, a better understanding of the neural pathways that underlie function and a means to precisely interface with these fibers are required. Existing peripheral nerve interfaces, consisting primarily of electrode-based designs, are unsuited for highly specific(individual axon) communication and/or are invasive to the tissue. Our laboratory has explored an optogenetic approach by which optically sensitive reporters and actuators are targeted to specific cell(axon) types. The nature of such an approach is laid out in this short perspective, along with associated technologies and challenges.
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.
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 all these fundamental functions until genetically engineered systems developed these years.We focused on the adenosine A2A and dopamine D1 Receptors(R)in the BG and obtained following 4 findings:①Nucleus accumbens(NAc)dopamine D1R-expressing neurons are essential in controlling wakefulness and are involved in physiological arousal via the lateral hypothalamus and midbrain circuits;②The rostromedial tegmental nucleus(RMTg),also called the GABAergic tail of the ventral tegmental area,projects to the midbrain dopaminergic system and other regions.Our findings reveal an essential role of the RMTg in the promotion of non-rapid eye movement(non-REM,NREM)sleep and homeostatic regulation;③Opposite to the D1R in the NAc,A2AR made a prominent contribution to sleep control associated with motivation.④Striatal adenosine A2AR neurons control active-period sleep via parvalbumin neurons in external globus pallidus.Taken together,we proposed a plausible model in which the caudate-putamen and NAc integrate behavioral processes with sleep/wakefulness through adenosine and dopamine receptors.The impacts of the BG in physiological sleep and insomnia will be discussed.
基金the Medical Scientist Training Program(T32GM007250)Predoctoral Training in Molecular Therapeutics Program(T32GM008803)。
文摘Neuromodulation represents a cutting edge class of both invasive and non-invasive therapeutic methods which alter the activity of neurons.Currently,several different techniques have been developed-or are currently being investigated–to treat a wide variety of neurological and neuropsychiatric disorders.Recently,in vivo and in vitro studies have revealed that neuromodulation can also induce myelination,meaning that it could hold potential as a therapy for various demyelinating diseases including multiple sclerosis and progressive multifocal leukencepalopathy.These findings come on the heels of a paradigm shift in the view of myelin's role within the nervous system from a static structure to an active co-regulator of central nervous system plasticity and participant in neuron-mediated modulation.In the present review,we highlight several of the recent findings regarding the role of neural activity in altering myelination including several soluble and contact-dependent factors that seem to mediate neural activitydependent myelination.We also highlight several considerations for neuromodulatory techniques,including the need for further research into spatiotemporal precision,dosage,and the safety and efficacy of transcranial focused ultrasound stimulation,an emerging neuromodulation technology.As the field of neuromodulation continues to evolve,it could potentially bring forth methods for the treatment of demyelinating diseases,and as such,further investigation into the mechanisms of neuron-dependent myelination as well as neuro-imaging modalities that can monitor myelination activity is warranted.
基金supported by Beijing Municipal Governmentsupported by the National Natural Science Foundation of China(Grant Nos.61890952)the Director Fund of WNLO。
文摘Manipulating and real-time monitoring of neuronal activities with cell-type specificity and precise spatiotemporal resolution during animal behavior are fundamental technologies for exploring the functional connectivity, information transmission, and physiological functions of neural circuits in vivo. However, current techniques for optogenetic stimulation and neuronal activity recording mostly operate independently. Here, we report an all-fiber-transmission photometry system for simultaneous optogenetic manipulation and multi-color recording of neuronal activities and the neurotransmitter release in a freely moving animal. We have designed and manufactured a wavelength-independent multi-branch fiber bundle to enable simultaneous optogenetic manipulation and multi-color recording at different wavelengths. Further, we combine a laser of narrow linewidth with the lock-in amplification method to suppress the optogenetic stimulation-induced artifacts and channel crosstalk. We show that the collection efficiency of our system outperforms a traditional epi-fluorescence system. Further, we demonstrate successful recording of dynamic dopamine(DA) responses to unexpected rewards in the nucleus accumbens(NAc) in a freely moving mouse. We also show simultaneous dual-color recording of neuronal Ca2+ signals and DA dynamics in the NAc upon delivering an unexpected reward and the simultaneous optogenetic activating at dopaminergic terminals in the same location. Thus, our multi-function fiber photometry system provides a compatible, efficient, and flexible solution for neuroscientists to study neural circuits and neurological diseases.
