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
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
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
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
Neurological disorders are amongst the most widely studied human aliments.Yet,they are also one of the most poorly understood.Although most of these disorders are polygenic,genotype still plays an important role in th...Neurological disorders are amongst the most widely studied human aliments.Yet,they are also one of the most poorly understood.Although most of these disorders are polygenic,genotype still plays an important role in their etiologies.For example,in schizophrenia and autism spectrum disorders,there is a 40-60%concordance rate in monozygotic twins,with 60-90%heritability（Burmeister et al.,2008）.However,the mechanisms by which multiple genes and their genomic variations influence the phenotypes of the disorders remain to be understood. The complexities of the disorders are tur- ther compounded by the individual rarity of the genomic variations and their variable penetrance （Cook and Scherer, 2008）. Thus, conventional disease modeling, such as gene knockout in cells or in animals, to attain the desired disease genotype may not be the most suitable platform for tackling most neurological disorders.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
Deep brain stimulation surgery has been performed in various movement disorders and psychiatric diseases.However,electrical stimulation may unexpectedly affect other types of adjacent neurons outside of the target are...Deep brain stimulation surgery has been performed in various movement disorders and psychiatric diseases.However,electrical stimulation may unexpectedly affect other types of adjacent neurons outside of the target area.Recently,optogenetics has provided the opportunity to modulate specific target neurons.Since this novel technique can individually control specific neurons in freely moving animals,it could be proposed to restore neural circuit function to related diseases,such as affective disorders,Huntington’s disease(HD),and Parkinson’s disease(PD).Herein,we discuss how optogenetics works as a treatment for Parkinson’s disease and other neural circuit dysfunctions.展开更多
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
Epilepsy,a common neurological disorder,is characterized by recurrent seizures that can lead to cognitive,psychological,and neurobiological consequences.The pathogenesis of epilepsy involves neuronal dysfunction at th...Epilepsy,a common neurological disorder,is characterized by recurrent seizures that can lead to cognitive,psychological,and neurobiological consequences.The pathogenesis of epilepsy involves neuronal dysfunction at the molecular,cellular,and neural circuit levels.Abnormal molecular signaling pathways or dysfunction of specific cell types can lead to epilepsy by disrupting the normal functioning of neural circuits.The continuous emergence of new technologies and the rapid advancement of existing ones have facilitated the discovery and comprehensive understanding of the neural circuit mechanisms underlying epilepsy.Therefore,this review aims to investigate the current understanding of the neural circuit mechanisms in epilepsy based on various technologies,including electroencephalography,magnetic resonance imaging,optogenetics,chemogenetics,deep brain stimulation,and brain-computer interfaces.Additionally,this review discusses these mechanisms from three perspectives:structural,synaptic,and transmitter circuits.The findings reveal that the neural circuit mechanisms of epilepsy encompass information transmission among different structures,interactions within the same structure,and the maintenance of homeostasis at the cellular,synaptic,and neurotransmitter levels.These findings offer new insights for investigating the pathophysiological mechanisms of epilepsy and enhancing its clinical diagnosis and treatment.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
Optogenetic has been widely applied in various pathogenesis investigations of neuropathic diseases since its accurate and targeted regulation of neuronal activity.However,due to the mismatch between the soft tissues a...Optogenetic has been widely applied in various pathogenesis investigations of neuropathic diseases since its accurate and targeted regulation of neuronal activity.However,due to the mismatch between the soft tissues and the optical waveguide,the long-term neural regulation within soft tissue(such as brain and spinal cord)by implantable optical fibers is a large challenge.Herein,we designed a modulus selfadaptive hydrogel optical fiber(MSHOF)with tunable mechanical properties(Young’modulus was tunable in the range of 0.32-10.56MPa)and low light attenuation(0.12-0.21 dB/cm,472nm laser light),which adapts to light transmission under soft tissues.These advantages of MSHOF can ensure the effectiveness of optogenetic stimulation meanwhile safeguarding the safety of the brain/materials interaction interface.In addition,this work provides more design possibilities of MSHOF for photogenetic stimuli and has significant application prospects in photomedical therapy.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
Spinal cord injury is a severe neurological disorder;however,current treatment methods often fail to restore nerve function effectively.Spinal cord stimulation via electrical signals is a promising therapeutic modalit...Spinal cord injury is a severe neurological disorder;however,current treatment methods often fail to restore nerve function effectively.Spinal cord stimulation via electrical signals is a promising therapeutic modality for spinal cord injury.Based on similar principles,this review aims to explore the potential of optical and acoustic neuromodulation techniques,emphasizing their benefits in the context of spinal cord injury.Photoacoustic imaging,renowned for its noninvasive nature,high-resolution capabilities,and cost-effectiveness,is well recognized for its role in early diagnosis,dynamic monitoring,and surgical guidance in stem cell therapies for spinal cord injury.Moreover,photoacoustodynamic therapy offers multiple pathways for tissue regeneration.Optogenetics and sonogenetics use genetic engineering to achieve precise neuronal activation,while photoacoustoelectric therapy leverages photovoltaic materials for electrical modulation of the nervous system,introducing an innovative paradigm for nerve system disorder management.Collectively,these advancements represent a transformative shift in the diagnosis and treatment of spinal cord injury,with the potential to significantly enhance nerve function remodeling and improve patient outcomes.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
Dear Editor,It is now well established that optogenetic stimulation can achieve precise intervention and modulate the activity of local neurons or neural circuits in the brain.Although this technique holds promise for...Dear Editor,It is now well established that optogenetic stimulation can achieve precise intervention and modulate the activity of local neurons or neural circuits in the brain.Although this technique holds promise for clinical therapy for neurological and psychiatric disorders,it requires the expression of lightsensitive proteins(such as channel rhodopsin)or photoactivatable chemicals(such as caged neurotransmitters)in the targeted brain regions[1].展开更多
Background:The development of ketamine-like rapid antidepressants holds promise for enhancing the therapeutic efficacy of depression,but the underlying cellular and molecular mechanisms remain unclear.Implicated in de...Background:The development of ketamine-like rapid antidepressants holds promise for enhancing the therapeutic efficacy of depression,but the underlying cellular and molecular mechanisms remain unclear.Implicated in depression regulation,the neuropeptide pituitary adenylate cyclase-activating polypeptide(PACAP)is investigated here to examine its role in mediating the rapid antidepressant response.Methods:The onset of antidepressant response was assessed through depression-related behavioral paradigms.The signaling mechanism of PACAP in the hippocampal dentate gyrus(DG)was evaluated by utilizing site-directed gene knockdown,pharmacological interventions,or optogenetic manipulations.Overall,446 mice were used for behavioral and molecular signaling testing.Mice were divided into control or experimental groups randomly in each experiment,and the experimental manipulations included:chronic paroxetine treatments(4 d,9 d,14 d)or a single treatment of ketamine;social defeat or lipopolysaccharides-injection induced depression models;different doses of PACAP(0.4 ng/site,2 ng/site,4 ng/site;microinjected into the hippocampal DG);pharmacological intra-DG interventions(CALM and PACAP6-38);intra-DG viral-mediated PACAP RNAi;and opotogenetics using channelrhodopsins 2(ChR2)or endoplasmic natronomonas halorhodopsine 3.0(eNpHR3.0).Behavioral paradigms included novelty suppressed feeding test,tail suspension test,forced swimming test,and sucrose preference test.Western blotting,ELISA,or quantitative real-time PCR(RT-PCR)analysis were used to detect the expressions of proteins/peptides or genes in the hippocampus.Results:Chronic administration of the slow-onset antidepressant paroxetine resulted in an increase in hippocampal PACAP expression,and intra-DG blockade of PACAP attenuated the onset of the antidepressant response.The levels of hippocampal PACAP expression were reduced in both two distinct depression animal models and intra-DG knockdown of PACAP induced depression-like behaviors.Conversely,a single infusion of PACAP into the DG region produced a rapid and sustained antidepressant response in both normal and chronically stressed mice.Optogenetic intra-DG excitation of PACAP-expressing neurons instantly elicited antidepressant responses,while optogenetic inhibition induced depression-like behaviors.The longer optogenetic excitation/inhibition elicited the more sustained antidepressant/depression-like responses.Intra-DG PACAP infusion immediately facilitated the signaling for rapid antidepressant response by inhibiting calcium/calmodulin-dependent protein kinaseⅡ(CaM KⅡ)-eukaryotic elongation factor 2(eEF2)and activating the mammalian target of rapamycin(mTOR).Pre-activation of CaMKⅡsignaling within the DG blunted PACAP-induced rapid antidepressant response as well as eEF2-mTOR-brain-derived neurotrophic factor(BDNF)signaling.Finally,acute ketamine treatment upregulated hippocampal PACAP expression,whereas intraDG blockade of PACAP signaling attenuated ketamine’s rapid antidepressant response.Conclusions:Activation of hippocampal PACAP signaling induces a rapid antidepressant response through the regulation of CaMKⅡinhibition-governed eEF2-mTOR-BDNF signaling.展开更多
Optogenetics,a technique that employs light for neuromodulation,has revolutionized the study of neural mechanisms and the treatment of neurological disorders due to its high spatiotemporal resolution and cell-type spe...Optogenetics,a technique that employs light for neuromodulation,has revolutionized the study of neural mechanisms and the treatment of neurological disorders due to its high spatiotemporal resolution and cell-type specificity.However,visible light,particularly blue and green light,commonly used in conventional optogenetics,has limited penetration in biological tissue.This limitation necessitates the implantation of optical fibers for light delivery,especially in deep brain regions,leading to tissue damage and experimental constraints.To overcome these challenges,the use of orange-red and infrared light with greater tissue penetration has emerged as a promising approach for tetherless optical neuromodulation.In this review,we provide an overview of the development and applications of tetherless optical neuromodulation methods with long wavelengths.We first discuss the exploration of orange-red wavelength-responsive rhodopsins and their performance in tetherless optical neuromodulation.Then,we summarize two novel tetherless neuromodulation methods using near-infrared light:upconversion nanoparticle-mediated optogenetics and photothermal neuromodulation.In addition,we discuss recent advances in mid-infrared optical neuromodulation.展开更多
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 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.
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Neurological disorders are amongst the most widely studied human aliments.Yet,they are also one of the most poorly understood.Although most of these disorders are polygenic,genotype still plays an important role in their etiologies.For example,in schizophrenia and autism spectrum disorders,there is a 40-60%concordance rate in monozygotic twins,with 60-90%heritability（Burmeister et al.,2008）.However,the mechanisms by which multiple genes and their genomic variations influence the phenotypes of the disorders remain to be understood. The complexities of the disorders are tur- ther compounded by the individual rarity of the genomic variations and their variable penetrance （Cook and Scherer, 2008）. Thus, conventional disease modeling, such as gene knockout in cells or in animals, to attain the desired disease genotype may not be the most suitable platform for tackling most neurological disorders.
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supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute,funded by the Ministry of Health&Welfare,Republic of Korea(grant number HI16C2188)funded by an Asan Life Science Institute Grant(grant number 17‐241)from the Asan Medical Center,Seoul,Republic of Korea.
文摘Deep brain stimulation surgery has been performed in various movement disorders and psychiatric diseases.However,electrical stimulation may unexpectedly affect other types of adjacent neurons outside of the target area.Recently,optogenetics has provided the opportunity to modulate specific target neurons.Since this novel technique can individually control specific neurons in freely moving animals,it could be proposed to restore neural circuit function to related diseases,such as affective disorders,Huntington’s disease(HD),and Parkinson’s disease(PD).Herein,we discuss how optogenetics works as a treatment for Parkinson’s disease and other neural circuit dysfunctions.
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 Basic Research Programs of Science and Technology Commission Foundation of Shanxi Province,No.20210302123486(to WJ).
文摘Epilepsy,a common neurological disorder,is characterized by recurrent seizures that can lead to cognitive,psychological,and neurobiological consequences.The pathogenesis of epilepsy involves neuronal dysfunction at the molecular,cellular,and neural circuit levels.Abnormal molecular signaling pathways or dysfunction of specific cell types can lead to epilepsy by disrupting the normal functioning of neural circuits.The continuous emergence of new technologies and the rapid advancement of existing ones have facilitated the discovery and comprehensive understanding of the neural circuit mechanisms underlying epilepsy.Therefore,this review aims to investigate the current understanding of the neural circuit mechanisms in epilepsy based on various technologies,including electroencephalography,magnetic resonance imaging,optogenetics,chemogenetics,deep brain stimulation,and brain-computer interfaces.Additionally,this review discusses these mechanisms from three perspectives:structural,synaptic,and transmitter circuits.The findings reveal that the neural circuit mechanisms of epilepsy encompass information transmission among different structures,interactions within the same structure,and the maintenance of homeostasis at the cellular,synaptic,and neurotransmitter levels.These findings offer new insights for investigating the pathophysiological mechanisms of epilepsy and enhancing its clinical diagnosis and treatment.
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.
基金supported by the National Key Research and Development Program of China(Nos.2021YFA1201302 and 2021YFA1201300)the National Natural Science Foundation of China(Nos.52303033,52173029)+1 种基金Shanghai Sailing Program(No.23YF1400400)the Natural Science Foundation of Shanghai(No.21ZR1400500).
文摘Optogenetic has been widely applied in various pathogenesis investigations of neuropathic diseases since its accurate and targeted regulation of neuronal activity.However,due to the mismatch between the soft tissues and the optical waveguide,the long-term neural regulation within soft tissue(such as brain and spinal cord)by implantable optical fibers is a large challenge.Herein,we designed a modulus selfadaptive hydrogel optical fiber(MSHOF)with tunable mechanical properties(Young’modulus was tunable in the range of 0.32-10.56MPa)and low light attenuation(0.12-0.21 dB/cm,472nm laser light),which adapts to light transmission under soft tissues.These advantages of MSHOF can ensure the effectiveness of optogenetic stimulation meanwhile safeguarding the safety of the brain/materials interaction interface.In addition,this work provides more design possibilities of MSHOF for photogenetic stimuli and has significant application prospects in photomedical therapy.
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 Key R&D Program of China,No.2023YFC2509700the Beijing Natural Science Foundation-Haidian Original Innovation Joint Fund,No.L232141the Research and Application of Clinical Characteristic Diagnosis and Treatment Program,No.Z221100007422019(all to WD)。
文摘Spinal cord injury is a severe neurological disorder;however,current treatment methods often fail to restore nerve function effectively.Spinal cord stimulation via electrical signals is a promising therapeutic modality for spinal cord injury.Based on similar principles,this review aims to explore the potential of optical and acoustic neuromodulation techniques,emphasizing their benefits in the context of spinal cord injury.Photoacoustic imaging,renowned for its noninvasive nature,high-resolution capabilities,and cost-effectiveness,is well recognized for its role in early diagnosis,dynamic monitoring,and surgical guidance in stem cell therapies for spinal cord injury.Moreover,photoacoustodynamic therapy offers multiple pathways for tissue regeneration.Optogenetics and sonogenetics use genetic engineering to achieve precise neuronal activation,while photoacoustoelectric therapy leverages photovoltaic materials for electrical modulation of the nervous system,introducing an innovative paradigm for nerve system disorder management.Collectively,these advancements represent a transformative shift in the diagnosis and treatment of spinal cord injury,with the potential to significantly enhance nerve function remodeling and improve patient outcomes.
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supported by grants from the Key Strategic Science and Technology Cooperation Project of the Ministry of Science and Technology of China(2023YFE0206800)the National Natural Science Foundation of China(81625006,31820103005,32200620,32170976,81971874)+1 种基金Zhejiang Province Natural Science Foundation of China(LZ24C090003 and LY21C090003)the Peak Discipline Cultivation Program of Zhejiang University School of Basic Medicine.
文摘Dear Editor,It is now well established that optogenetic stimulation can achieve precise intervention and modulate the activity of local neurons or neural circuits in the brain.Although this technique holds promise for clinical therapy for neurological and psychiatric disorders,it requires the expression of lightsensitive proteins(such as channel rhodopsin)or photoactivatable chemicals(such as caged neurotransmitters)in the targeted brain regions[1].
基金supported by the National Key Research and Development Program of China(2022YFE0201000)the National Natural Science Foundation of China(82174002,82104416,82204652)the High-Level University Development Program of Guangdong Province,and the Guangzhou Key Science and Technology Research and Development Project(202206010109)。
文摘Background:The development of ketamine-like rapid antidepressants holds promise for enhancing the therapeutic efficacy of depression,but the underlying cellular and molecular mechanisms remain unclear.Implicated in depression regulation,the neuropeptide pituitary adenylate cyclase-activating polypeptide(PACAP)is investigated here to examine its role in mediating the rapid antidepressant response.Methods:The onset of antidepressant response was assessed through depression-related behavioral paradigms.The signaling mechanism of PACAP in the hippocampal dentate gyrus(DG)was evaluated by utilizing site-directed gene knockdown,pharmacological interventions,or optogenetic manipulations.Overall,446 mice were used for behavioral and molecular signaling testing.Mice were divided into control or experimental groups randomly in each experiment,and the experimental manipulations included:chronic paroxetine treatments(4 d,9 d,14 d)or a single treatment of ketamine;social defeat or lipopolysaccharides-injection induced depression models;different doses of PACAP(0.4 ng/site,2 ng/site,4 ng/site;microinjected into the hippocampal DG);pharmacological intra-DG interventions(CALM and PACAP6-38);intra-DG viral-mediated PACAP RNAi;and opotogenetics using channelrhodopsins 2(ChR2)or endoplasmic natronomonas halorhodopsine 3.0(eNpHR3.0).Behavioral paradigms included novelty suppressed feeding test,tail suspension test,forced swimming test,and sucrose preference test.Western blotting,ELISA,or quantitative real-time PCR(RT-PCR)analysis were used to detect the expressions of proteins/peptides or genes in the hippocampus.Results:Chronic administration of the slow-onset antidepressant paroxetine resulted in an increase in hippocampal PACAP expression,and intra-DG blockade of PACAP attenuated the onset of the antidepressant response.The levels of hippocampal PACAP expression were reduced in both two distinct depression animal models and intra-DG knockdown of PACAP induced depression-like behaviors.Conversely,a single infusion of PACAP into the DG region produced a rapid and sustained antidepressant response in both normal and chronically stressed mice.Optogenetic intra-DG excitation of PACAP-expressing neurons instantly elicited antidepressant responses,while optogenetic inhibition induced depression-like behaviors.The longer optogenetic excitation/inhibition elicited the more sustained antidepressant/depression-like responses.Intra-DG PACAP infusion immediately facilitated the signaling for rapid antidepressant response by inhibiting calcium/calmodulin-dependent protein kinaseⅡ(CaM KⅡ)-eukaryotic elongation factor 2(eEF2)and activating the mammalian target of rapamycin(mTOR).Pre-activation of CaMKⅡsignaling within the DG blunted PACAP-induced rapid antidepressant response as well as eEF2-mTOR-brain-derived neurotrophic factor(BDNF)signaling.Finally,acute ketamine treatment upregulated hippocampal PACAP expression,whereas intraDG blockade of PACAP signaling attenuated ketamine’s rapid antidepressant response.Conclusions:Activation of hippocampal PACAP signaling induces a rapid antidepressant response through the regulation of CaMKⅡinhibition-governed eEF2-mTOR-BDNF signaling.
基金supported by China Postdoctoral Science Foundation(2022M723356),"From 0 to 1"Original Innovation Project of the Basic Frontier Scientific Research Program of the Chinese Academy of Sciences(29J20-015-Ⅲ)Chinese Academy of Sciences 100 Talents Project:Research on Task oriented Functional Brain Development of Infants(29J20-052-Ⅲ)Natural Science Basic Research Plan in Shaanxi Province of China(2022JQ544).
文摘Optogenetics,a technique that employs light for neuromodulation,has revolutionized the study of neural mechanisms and the treatment of neurological disorders due to its high spatiotemporal resolution and cell-type specificity.However,visible light,particularly blue and green light,commonly used in conventional optogenetics,has limited penetration in biological tissue.This limitation necessitates the implantation of optical fibers for light delivery,especially in deep brain regions,leading to tissue damage and experimental constraints.To overcome these challenges,the use of orange-red and infrared light with greater tissue penetration has emerged as a promising approach for tetherless optical neuromodulation.In this review,we provide an overview of the development and applications of tetherless optical neuromodulation methods with long wavelengths.We first discuss the exploration of orange-red wavelength-responsive rhodopsins and their performance in tetherless optical neuromodulation.Then,we summarize two novel tetherless neuromodulation methods using near-infrared light:upconversion nanoparticle-mediated optogenetics and photothermal neuromodulation.In addition,we discuss recent advances in mid-infrared optical neuromodulation.
