Optogenetics has revolutionized the field of neuroscience by enabling precise control of neural activity through light-sensitive proteins known as opsins.This review article discusses the fundamental principles of opt...Optogenetics has revolutionized the field of neuroscience by enabling precise control of neural activity through light-sensitive proteins known as opsins.This review article discusses the fundamental principles of optogenetics,including the activation of both excitatory and inhibitory opsins,as well as the development of optogenetic models that utilize recombinant viral vectors.A considerable portion of the article addresses the limitations of optogenetic tools and explores strategies to overcome these challenges.These strategies include the use of adeno-associated viruses,cell-specific promoters,modified opsins,and methodologies such as bioluminescent optogenetics.The application of viral recombinant vectors,particularly adeno-associated viruses,is emerging as a promising avenue for clinical use in delivering opsins to target cells.This trend indicates the potential for creating tools that offer greater flexibility and accuracy in opsin delivery.The adaptations of these viral vectors provide advantages in optogenetic studies by allowing for the restricted expression of opsins through cell-specific promoters and various viral serotypes.The article also examines different cellular targets for optogenetics,including neurons,astrocytes,microglia,and Schwann cells.Utilizing specific promoters for opsin expression in these cells is essential for achieving precise and efficient stimulation.Research has demonstrated that optogenetic stimulation of both neurons and glial cells-particularly the distinct phenotypes of microglia,astrocytes,and Schwann cells-can have therapeutic effects in neurological diseases.Glial cells are increasingly recognized as important targets for the treatment of these disorders.Furthermore,the article emphasizes the emerging field of bioluminescent optogenetics,which combines optogenetic principles with bioluminescent proteins to visualize and manipulate neural activity in real time.By integrating molecular genetics techniques with bioluminescence,researchers have developed methods to monitor neuronal activity efficiently and less invasively,enhancing our understanding of central nervous system function and the mechanisms of plasticity in neurological disorders beyond traditional neurobiological methods.Evidence has shown that optogenetic modulation can enhance motor axon regeneration,achieve complete sensory reinnervation,and accelerate the recovery of neuromuscular function.This approach also induces complex patterns of coordinated motor neuron activity and promotes neural reorganization.Optogenetic approaches hold immense potential for therapeutic interventions in the central nervous system.They enable precise control of neural circuits and may offer new treatments for neurological disorders,particularly spinal cord injuries,peripheral nerve injuries,and other neurodegenerative diseases.展开更多
The hippocampus is the brain structure that is responsible for the formation of learning memories.Sleep disorders leading to cognitive impairment are strongly associated with the hippocampus.Phototherapy offers a new ...The hippocampus is the brain structure that is responsible for the formation of learning memories.Sleep disorders leading to cognitive impairment are strongly associated with the hippocampus.Phototherapy offers a new physical therapy for the treatment of sleep disorders,with the advantages of being noninvasive and having few side effects.However,the mechanism by which phototherapy improves cognitive impairment caused by sleep disorders remains unclear.In this study,we used phototherapy combined with optogenetic technology to investigate the effect of noninvasive phototherapy on cognitive functions in sleep-deprived mice.Our results suggest that phototherapy might improve cognitive functions in sleep-deprived mice by modulating the hippocampus.Our study expands the research progress on noninvasive phototherapy for the treatment of sleep disorders.展开更多
Depression is a multifaceted disorder with a largely unresolved etiology influenced by a complex interplay of pathogenic factors.Despite decades of research,it remains a major condition that significantly diminishes p...Depression is a multifaceted disorder with a largely unresolved etiology influenced by a complex interplay of pathogenic factors.Despite decades of research,it remains a major condition that significantly diminishes patients’quality of life.Advances in optogenetics have introduced a powerful tool for exploring the neural mechanisms underlying depression.By selectively expressing optogenes in specific cell types in mice,researchers can study the roles of these cells through targeted light stimulation,offering new insights into central nervous system disorders.The use of viral vectors to express opsins in distinct neuronal subtypes enables precise activation or inhibition of these neurons via light.When combined with behavioral,morphological,and electrophysiological analyses,optogenetics provides an invaluable approach to investigating the neural mechanisms of psychiatric conditions.This review synthesizes current research on the application of optogenetics to understand the mechanisms of depression.This study aims to enhance our knowledge of optogenetic strategies for regulating depression and advancing antidepressant research.展开更多
This study is based on wireless optogenetic technology,utilizing the CRY2/CIB1 photosensitive system to achieve spatiotemporal control of PD-L1 expression.In vitro experiments showed that the surface PD-L1 positivity ...This study is based on wireless optogenetic technology,utilizing the CRY2/CIB1 photosensitive system to achieve spatiotemporal control of PD-L1 expression.In vitro experiments showed that the surface PD-L1 positivity rate of cells increased from 28.6±3.1%to 67.3±5.4%(P<0.001).In animal experiments,the terminal tumor volume in the light exposure group was 450±90 mm3,with a tumor inhibition rate of approximately 49.4%(P<0.001),and the median survival was extended to 32 days(compared to 24 days in the control group,P=0.004).Immunological tests revealed a significant increase in CD8+T cell infiltration(112±18 vs 52±10 cells/HPF,P<0.01),a 30%decrease in the proportion of Tregs(P<0.05),and an increase in the M1/M2 macrophage ratio to 1.8.The results suggest that the wireless optogenetic system can not only precisely regulate PD-L1 but also remodel the tumor immune microenvironment,providing a new approach for precise immunotherapy of GBM.展开更多
Clinical experiments have proven that the pedunculopontine nucleus(PPN)plays a crucial role in the modulation of beta oscillations in Parkinson’s disease(PD).Here,we propose a new computational framework by introduci...Clinical experiments have proven that the pedunculopontine nucleus(PPN)plays a crucial role in the modulation of beta oscillations in Parkinson’s disease(PD).Here,we propose a new computational framework by introducing the PPN and related synaptic connections to the classic basal ganglia-thalamo-cortical model.Fascinatingly,the improved model can not only simulate the basic saturated and beta activities mentioned in previous studies but also produce the normal alpha rhythm that is much closer to physiological phenomena.Specifically,the results show that Parkinsonian oscillation activities can be controlled and modulated by the connection strength between the PPN and the globus pallidus internal nucleus(GPi)and the subthalamic nucleus(STN),supporting the fact that PPN is overinhibited in PD.Meanwhile,the internal mechanism underlying these state transitions is further explained from the perspective of dynamics.Additionally,both deep brain stimulation(DBS)and optogenetic technology are considered effective in terms of abnormal oscillations.Especially when a low-frequency DBS is added to the PPN,beta oscillations can be suppressed,but it is excited again as the DBS’s frequency gradually increases to a larger value.These results coincide with the experimental results that low-frequency stimulation of the PPN is effective,and verify the rationality of the model.Furthermore,we show that optogenetic stimulation of the globus pallidus external(GPe)expressing excitatory channelrhodopsin(ChR2)can effectively inhibit beta oscillations,whereas exciting the STN and PPN has a limited effect.These results are consistent with experimental reports suggesting that the symptoms of PD’s movement disorder can be alleviated under the GPe-ChR2,but not STN-ChR2,situation.Although the functional role of the PPN and the feasibility of optogenetic stimulation remain to be clinically explored,the results obtained help us understand the mechanisms of beta oscillations in PD.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
Inflammatory processes are an integral part of the stress response and are likely to result from a programmed adaptation that is vital to the organism＇s survival and well-being.The whole inflammatory response is medi...Inflammatory processes are an integral part of the stress response and are likely to result from a programmed adaptation that is vital to the organism＇s survival and well-being.The whole inflammatory response is mediated by largely overlapping circuits in the limbic forebrain,hypothalamus and brainstem,but is also under the control of the neuroendocrine and autonomic nervous systems.Genetically predisposed individuals who fail to tune the respective contributions of the two systems in accordance with stressor modality and intensity after adverse experiences can be at risk for stress-related psychiatric disorders and cardiovascular diseases.Altered glucocorticoid（GC） homeostasis due to GC resistance leads to the failure of neural and negative feedback regulation of the hypothalamic-pituitary-adrenal axis during chronic inflammation,and this might be the mechanism underlying the ensuing brain and heart diseases and the high prevalence of co-morbidity between the two systems.By the combined use of light and genetically-encoded lightsensitive proteins,optogenetics allows cell-type-specific,fast（millisecond-scale） control of precisely defined events in biological systems.This method is an important breakthrough to explore the causality between neural activity patterns and behavioral profiles relevant to anxiety,depression,autism and schizophrenia.Optogenetics also helps to understand the ＂inflammatory dialogue＂,the inflammatory processes in psychiatric disorders and cardiovascular diseases,shared by heart and brain in the context of stress.展开更多
Chronic pain relief remains an unmet medical need.Current research points to a substantial contribution of glia-neuron interaction in its pathogenesis.Particularly,microglia play a crucial role in the development of c...Chronic pain relief remains an unmet medical need.Current research points to a substantial contribution of glia-neuron interaction in its pathogenesis.Particularly,microglia play a crucial role in the development of chronic pain.To better understand the microglial contribution to chronic pain,specific regional and temporal manipulations of microglia are necessary.Recently,two new approaches have emerged that meet these demands.Chemogenetic tools allow the expression of designer receptors exclusively activated by designer drugs(DREADDs)specifically in microglia.Similarly,optogenetic tools allow for microglial manipulation via the activation of artificially expressed,light-sensitive proteins.Chemo-and optogenetic manipulations of microglia in vivo are powerful in interrogating microglial function in chronic pain.This review summarizes these emerging tools in studying the role of microglia in chronic pain and highlights their potential applications in microglia-related neurological disorders.展开更多
Optogenetics is a newly-introduced technology in the life sciences and is gaining increasing attention.It refers to the combination of optical technologies and genetic methods to control the activity of specific cell ...Optogenetics is a newly-introduced technology in the life sciences and is gaining increasing attention.It refers to the combination of optical technologies and genetic methods to control the activity of specific cell groups in living tissue,during which high-resolution spatial and temporal manipulation of cells is achieved.Optogenetics has been applied to numerous regions,including cerebral cortex,hippocampus,ventral tegmental area,nucleus accumbens,striatum,spinal cord,and retina,and has revealed new directions of research in neuroscience and the treatment of related diseases.Since optogenetic tools are controllable at high spatial and temporal resolution,we discuss its applications in these regions in detail and the recent understanding of higher brain functions,such as reward-seeking,learning and memory,and sleep.Further,the possibilities of improved utility of this newly-emerging technology are discussed.We intend to provide a paradigm of the latest advances in neuroscience using optogenetics.展开更多
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 ...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
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
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
In vito fber photometry is a powerful technique to analyze the dy namics of population neurons during fiunctional study of neuroscience.Here,we introduced a detailed protocol for fiber photometry-based calciun reordin...In vito fber photometry is a powerful technique to analyze the dy namics of population neurons during fiunctional study of neuroscience.Here,we introduced a detailed protocol for fiber photometry-based calciun reording in freely moving mice,covering from virus injection,fiber stub insertion,optogenetical stimulation to data procurement and analysis.Furthemnore,we applied this protocol to explore neuronal activity of mice latenal-posterior(LP)thalaric nucleus in response to optogenetical stimulation of primary visual cortex(V1)neurons,and explore axon clusters activity of optogenetically evoked V1 neurons.Final confirmation of virus-based protein expression in V1 and precise fber insertion indicated that the surgery procedure of this protocol is reliable for functional calcium recording.The scripts for data analysis and some tips in our protocol are provided in details.Together,this protocol is simple,low-cost,and effective for neuronal activity detection by fiber photometry,which will hep neuroscience researchers to carry out fiunctional and behavioral study in vivo.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
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 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
Disorders of gastrointestinal(GI)motility are associated with various symptoms such as nausea,vomiting,and constipation.However,the underlying causes of impaired GI motility remainunclear,which has led to variation in...Disorders of gastrointestinal(GI)motility are associated with various symptoms such as nausea,vomiting,and constipation.However,the underlying causes of impaired GI motility remainunclear,which has led to variation in the efficacy of therapies to treat GI dysfunction.Optoge-netics is a novel approach through which target cells can be precisely controlled by light and hasshown great potential in GI motility research.Here,we summarized recent studies of GI motilitypatterns utilizing optogenetic devices and focused on the ability of opsins,which are geneticallyexpressed in different types of cells in the gut,to regulate the excitability of target cells.We hopethat our review of recent findings regarding optogenetic control of GI cells broadens the scope ofapplication for optogenetics in GI motility studies.展开更多
The size of the blind population in 2015 was estimated to be approximately 36 million（Bourne et al.,2017）.According to the predictions by Bourne and co-workers,the number of the visually impaired is expected to reac...The size of the blind population in 2015 was estimated to be approximately 36 million（Bourne et al.,2017）.According to the predictions by Bourne and co-workers,the number of the visually impaired is expected to reach nearly 100 million by 2050.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
基金supported by a grant from the Russian Science Foundation,No.23-75-10041(to MY)。
文摘Optogenetics has revolutionized the field of neuroscience by enabling precise control of neural activity through light-sensitive proteins known as opsins.This review article discusses the fundamental principles of optogenetics,including the activation of both excitatory and inhibitory opsins,as well as the development of optogenetic models that utilize recombinant viral vectors.A considerable portion of the article addresses the limitations of optogenetic tools and explores strategies to overcome these challenges.These strategies include the use of adeno-associated viruses,cell-specific promoters,modified opsins,and methodologies such as bioluminescent optogenetics.The application of viral recombinant vectors,particularly adeno-associated viruses,is emerging as a promising avenue for clinical use in delivering opsins to target cells.This trend indicates the potential for creating tools that offer greater flexibility and accuracy in opsin delivery.The adaptations of these viral vectors provide advantages in optogenetic studies by allowing for the restricted expression of opsins through cell-specific promoters and various viral serotypes.The article also examines different cellular targets for optogenetics,including neurons,astrocytes,microglia,and Schwann cells.Utilizing specific promoters for opsin expression in these cells is essential for achieving precise and efficient stimulation.Research has demonstrated that optogenetic stimulation of both neurons and glial cells-particularly the distinct phenotypes of microglia,astrocytes,and Schwann cells-can have therapeutic effects in neurological diseases.Glial cells are increasingly recognized as important targets for the treatment of these disorders.Furthermore,the article emphasizes the emerging field of bioluminescent optogenetics,which combines optogenetic principles with bioluminescent proteins to visualize and manipulate neural activity in real time.By integrating molecular genetics techniques with bioluminescence,researchers have developed methods to monitor neuronal activity efficiently and less invasively,enhancing our understanding of central nervous system function and the mechanisms of plasticity in neurological disorders beyond traditional neurobiological methods.Evidence has shown that optogenetic modulation can enhance motor axon regeneration,achieve complete sensory reinnervation,and accelerate the recovery of neuromuscular function.This approach also induces complex patterns of coordinated motor neuron activity and promotes neural reorganization.Optogenetic approaches hold immense potential for therapeutic interventions in the central nervous system.They enable precise control of neural circuits and may offer new treatments for neurological disorders,particularly spinal cord injuries,peripheral nerve injuries,and other neurodegenerative diseases.
基金Supported by the Tianjin Municipal Education Commission Scientic Research Project No.2023YXZD10。
文摘The hippocampus is the brain structure that is responsible for the formation of learning memories.Sleep disorders leading to cognitive impairment are strongly associated with the hippocampus.Phototherapy offers a new physical therapy for the treatment of sleep disorders,with the advantages of being noninvasive and having few side effects.However,the mechanism by which phototherapy improves cognitive impairment caused by sleep disorders remains unclear.In this study,we used phototherapy combined with optogenetic technology to investigate the effect of noninvasive phototherapy on cognitive functions in sleep-deprived mice.Our results suggest that phototherapy might improve cognitive functions in sleep-deprived mice by modulating the hippocampus.Our study expands the research progress on noninvasive phototherapy for the treatment of sleep disorders.
基金funded by the Natural Science Foundation of China(No.82305049).
文摘Depression is a multifaceted disorder with a largely unresolved etiology influenced by a complex interplay of pathogenic factors.Despite decades of research,it remains a major condition that significantly diminishes patients’quality of life.Advances in optogenetics have introduced a powerful tool for exploring the neural mechanisms underlying depression.By selectively expressing optogenes in specific cell types in mice,researchers can study the roles of these cells through targeted light stimulation,offering new insights into central nervous system disorders.The use of viral vectors to express opsins in distinct neuronal subtypes enables precise activation or inhibition of these neurons via light.When combined with behavioral,morphological,and electrophysiological analyses,optogenetics provides an invaluable approach to investigating the neural mechanisms of psychiatric conditions.This review synthesizes current research on the application of optogenetics to understand the mechanisms of depression.This study aims to enhance our knowledge of optogenetic strategies for regulating depression and advancing antidepressant research.
文摘This study is based on wireless optogenetic technology,utilizing the CRY2/CIB1 photosensitive system to achieve spatiotemporal control of PD-L1 expression.In vitro experiments showed that the surface PD-L1 positivity rate of cells increased from 28.6±3.1%to 67.3±5.4%(P<0.001).In animal experiments,the terminal tumor volume in the light exposure group was 450±90 mm3,with a tumor inhibition rate of approximately 49.4%(P<0.001),and the median survival was extended to 32 days(compared to 24 days in the control group,P=0.004).Immunological tests revealed a significant increase in CD8+T cell infiltration(112±18 vs 52±10 cells/HPF,P<0.01),a 30%decrease in the proportion of Tregs(P<0.05),and an increase in the M1/M2 macrophage ratio to 1.8.The results suggest that the wireless optogenetic system can not only precisely regulate PD-L1 but also remodel the tumor immune microenvironment,providing a new approach for precise immunotherapy of GBM.
基金supported by the National Natural Science Foundation of China(Grant Nos.12072265 and 12372064).
文摘Clinical experiments have proven that the pedunculopontine nucleus(PPN)plays a crucial role in the modulation of beta oscillations in Parkinson’s disease(PD).Here,we propose a new computational framework by introducing the PPN and related synaptic connections to the classic basal ganglia-thalamo-cortical model.Fascinatingly,the improved model can not only simulate the basic saturated and beta activities mentioned in previous studies but also produce the normal alpha rhythm that is much closer to physiological phenomena.Specifically,the results show that Parkinsonian oscillation activities can be controlled and modulated by the connection strength between the PPN and the globus pallidus internal nucleus(GPi)and the subthalamic nucleus(STN),supporting the fact that PPN is overinhibited in PD.Meanwhile,the internal mechanism underlying these state transitions is further explained from the perspective of dynamics.Additionally,both deep brain stimulation(DBS)and optogenetic technology are considered effective in terms of abnormal oscillations.Especially when a low-frequency DBS is added to the PPN,beta oscillations can be suppressed,but it is excited again as the DBS’s frequency gradually increases to a larger value.These results coincide with the experimental results that low-frequency stimulation of the PPN is effective,and verify the rationality of the model.Furthermore,we show that optogenetic stimulation of the globus pallidus external(GPe)expressing excitatory channelrhodopsin(ChR2)can effectively inhibit beta oscillations,whereas exciting the STN and PPN has a limited effect.These results are consistent with experimental reports suggesting that the symptoms of PD’s movement disorder can be alleviated under the GPe-ChR2,but not STN-ChR2,situation.Although the functional role of the PPN and the feasibility of optogenetic stimulation remain to be clinically explored,the results obtained help us understand the mechanisms of beta oscillations in PD.
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supported by the National Natural Science Foundation of China(30970942,91132306)the National Basic Research Development Program(973 program) of China (2010CB529605,2011CB504405)+1 种基金the "Hundred Talents Program" of the Chinese Academy of Sciences,the Guangdong Innovation Research Team Fund for Low-cost Healthcare Technologiesa Shenzhen Governmental Basic Research Grant
文摘Inflammatory processes are an integral part of the stress response and are likely to result from a programmed adaptation that is vital to the organism＇s survival and well-being.The whole inflammatory response is mediated by largely overlapping circuits in the limbic forebrain,hypothalamus and brainstem,but is also under the control of the neuroendocrine and autonomic nervous systems.Genetically predisposed individuals who fail to tune the respective contributions of the two systems in accordance with stressor modality and intensity after adverse experiences can be at risk for stress-related psychiatric disorders and cardiovascular diseases.Altered glucocorticoid（GC） homeostasis due to GC resistance leads to the failure of neural and negative feedback regulation of the hypothalamic-pituitary-adrenal axis during chronic inflammation,and this might be the mechanism underlying the ensuing brain and heart diseases and the high prevalence of co-morbidity between the two systems.By the combined use of light and genetically-encoded lightsensitive proteins,optogenetics allows cell-type-specific,fast（millisecond-scale） control of precisely defined events in biological systems.This method is an important breakthrough to explore the causality between neural activity patterns and behavioral profiles relevant to anxiety,depression,autism and schizophrenia.Optogenetics also helps to understand the ＂inflammatory dialogue＂,the inflammatory processes in psychiatric disorders and cardiovascular diseases,shared by heart and brain in the context of stress.
基金supported by the National Institutes of Health(R01NS088627 and R01NS110825).
文摘Chronic pain relief remains an unmet medical need.Current research points to a substantial contribution of glia-neuron interaction in its pathogenesis.Particularly,microglia play a crucial role in the development of chronic pain.To better understand the microglial contribution to chronic pain,specific regional and temporal manipulations of microglia are necessary.Recently,two new approaches have emerged that meet these demands.Chemogenetic tools allow the expression of designer receptors exclusively activated by designer drugs(DREADDs)specifically in microglia.Similarly,optogenetic tools allow for microglial manipulation via the activation of artificially expressed,light-sensitive proteins.Chemo-and optogenetic manipulations of microglia in vivo are powerful in interrogating microglial function in chronic pain.This review summarizes these emerging tools in studying the role of microglia in chronic pain and highlights their potential applications in microglia-related neurological disorders.
基金supported by the National Basic Research Program of China (2011CB503700)
文摘Optogenetics is a newly-introduced technology in the life sciences and is gaining increasing attention.It refers to the combination of optical technologies and genetic methods to control the activity of specific cell groups in living tissue,during which high-resolution spatial and temporal manipulation of cells is achieved.Optogenetics has been applied to numerous regions,including cerebral cortex,hippocampus,ventral tegmental area,nucleus accumbens,striatum,spinal cord,and retina,and has revealed new directions of research in neuroscience and the treatment of related diseases.Since optogenetic tools are controllable at high spatial and temporal resolution,we discuss its applications in these regions in detail and the recent understanding of higher brain functions,such as reward-seeking,learning and memory,and sleep.Further,the possibilities of improved utility of this newly-emerging technology are discussed.We intend to provide a paradigm of the latest advances in neuroscience using optogenetics.
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.
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.
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supported by the National Natural Science Foundation of China (Grant Nos.31371106 and 91632110)HZAU Independent Innovation Fund (2014BQ019).
文摘In vito fber photometry is a powerful technique to analyze the dy namics of population neurons during fiunctional study of neuroscience.Here,we introduced a detailed protocol for fiber photometry-based calciun reording in freely moving mice,covering from virus injection,fiber stub insertion,optogenetical stimulation to data procurement and analysis.Furthemnore,we applied this protocol to explore neuronal activity of mice latenal-posterior(LP)thalaric nucleus in response to optogenetical stimulation of primary visual cortex(V1)neurons,and explore axon clusters activity of optogenetically evoked V1 neurons.Final confirmation of virus-based protein expression in V1 and precise fber insertion indicated that the surgery procedure of this protocol is reliable for functional calcium recording.The scripts for data analysis and some tips in our protocol are provided in details.Together,this protocol is simple,low-cost,and effective for neuronal activity detection by fiber photometry,which will hep neuroscience researchers to carry out fiunctional and behavioral study in vivo.
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 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 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.
文摘Disorders of gastrointestinal(GI)motility are associated with various symptoms such as nausea,vomiting,and constipation.However,the underlying causes of impaired GI motility remainunclear,which has led to variation in the efficacy of therapies to treat GI dysfunction.Optoge-netics is a novel approach through which target cells can be precisely controlled by light and hasshown great potential in GI motility research.Here,we summarized recent studies of GI motilitypatterns utilizing optogenetic devices and focused on the ability of opsins,which are geneticallyexpressed in different types of cells in the gut,to regulate the excitability of target cells.We hopethat our review of recent findings regarding optogenetic control of GI cells broadens the scope ofapplication for optogenetics in GI motility studies.
基金funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 746526from the National Health and Medical Research Council(RG1063046)
文摘The size of the blind population in 2015 was estimated to be approximately 36 million（Bourne et al.,2017）.According to the predictions by Bourne and co-workers,the number of the visually impaired is expected to reach nearly 100 million by 2050.
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.
