查看更多>>摘要：Animal survival necessitates adaptive behav-iors in volatile environmental contexts.Virtual reality(VR)technology is instrumental to study the neural mechanisms underlying behaviors modulated by environmental con-text by simulating the real world with maximized control of contextual elements.Yet current VR tools for rodents have limited flexibility and performance(e.g.,frame rate)for context-dependent cognitive research.Here,we describe a high-performance VR platform with which to study con-textual behaviors immersed in editable virtual contexts.This platform was assembled from modular hardware and custom-written software with flexibility and upgradability.Using this platform,we trained mice to perform context-dependent cognitive tasks with rules ranging from discrim-ination to delayed-sample-to-match while recording from thousands of hippocampal place cells.By precise manipula-tions of context elements,we found that the context recogni-tion was intact with partial context elements,but impaired by exchanges of context elements.Collectively,our work establishes a configurable VR platform with which to inves-tigate context-dependent cognition with large-scale neural recording.
查看更多>>摘要：Acetylcholine(ACh)is an important neuromod-ulator in various cognitive functions.However,it is unclear how ACh influences neural circuit dynamics by altering cellular properties.Here,we investigated how ACh influ-ences reverberatory activity in cultured neuronal networks.We found that ACh suppressed the occurrence of evoked reverberation at low to moderate doses,but to a much lesser extent at high doses.Moreover,high doses of ACh caused a longer duration of evoked reverberation,and a higher occur-rence of spontaneous activity.With whole-cell recording from single neurons,we found that ACh inhibited excita-tory postsynaptic currents(EPSCs)while elevating neu-ronal firing in a dose-dependent manner.Furthermore,all ACh-induced cellular and network changes were blocked by muscarinic,but not nicotinic receptor antagonists.With computational modeling,we found that simulated changes in EPSCs and the excitability of single cells mimicking the effects of ACh indeed modulated the evoked network reverberation similar to experimental observations.Thus,ACh modulates network dynamics in a biphasic fashion,probably by inhibiting excitatory synaptic transmission and facilitating neuronal excitability through muscarinic signal-ing pathways.
查看更多>>摘要：Diabetic neuropathic pain(DNP)is the most common disabling complication of diabetes.Emerging evi-dence has linked the pathogenesis of DNP to the aberrant sprouting of sensory axons into the epidermal area;however,the underlying molecular events remain poorly understood.Here we found that an axon guidance molecule,Netrin-3(Ntn-3),was expressed in the sensory neurons of mouse dorsal root ganglia(DRGs),and downregulation of Ntn-3 expression was highly correlated with the severity of DNP in a diabetic mouse model.Genetic ablation of Ntn-3 increased the intra-epidermal sprouting of sensory axons and worsened the DNP in diabetic mice.In contrast,the elevation of Ntn-3 levels in DRGs significantly inhibited the intra-epidermal axon sprouting and alleviated DNP in diabetic mice.In con-clusion,our studies identified Ntn-3 as an important regula-tor of DNP pathogenesis by gating the aberrant sprouting of sensory axons,indicating that Ntn-3 is a potential druggable target for DNP treatment.
查看更多>>摘要：The perception of motion is an important func-tion of vision.Neural wiring diagrams for extracting direc-tional information have been obtained by connectome recon-struction.Direction selectivity in Drosophila is thought to originate in T4/T5 neurons through integrating inputs with different temporal filtering properties.Through genetic screening based on synaptic distribution,we isolated a new type of TmY neuron,termed TmY-ds,that form recipro-cal synaptic connections with T4/T5 neurons.Its neurites responded to grating motion along the four cardinal direc-tions and showed a variety of direction selectivity.Intrigu-ingly,its direction selectivity originated from temporal filtering neurons rather than T4/T5.Genetic silencing and activation experiments showed that TmY-ds neurons are functionally upstream of T4/T5.Our results suggest that direction selectivity is generated in a tripartite circuit formed among these three neurons—temporal filtering,TmY-ds,and T4/T5 neurons,in which TmY-ds plays a role in the enhancement of direction selectivity in T4/T5 neurons.
查看更多>>摘要：The thalamocortical(TC)circuit is closely asso-ciated with pain processing.The hyperpolarization-activated cyclic nucleotide-gated(HCN)2 channel is predominantly expressed in the ventral posterolateral thalamus(VPL)that has been shown to mediate neuropathic pain.However,the role of VPL HCN2 in modulating TC circuit activity is largely unknown.Here,by using optogenetics,neuronal trac-ing,electrophysiological recordings,and virus knockdown strategies,we showed that the activation of VPL TC neurons potentiates excitatory synaptic transmission to the hindlimb region of the primary somatosensory cortex(S1HL)as well as mechanical hypersensitivity following spared nerve injury(SNI)-induced neuropathic pain in mice.Either pharmaco-logical blockade or virus knockdown of HCN2(shRNA-Hcn2)in the VPL was sufficient to alleviate SNI-induced hyperalgesia.Moreover,shRNA-Hcn2 decreased the excit-ability of TC neurons and synaptic transmission of the VPL-S1HL circuit.Together,our studies provide a novel mechanism by which HCN2 enhances the excitability of the TC circuit to facilitate neuropathic pain.
查看更多>>摘要：Itch is an unpleasant sensation that provokes the desire to scratch.While acute itch serves as a protec-tive system to warn the body of external irritating agents,chronic itch is a debilitating but poorly-treated clinical dis-ease leading to repetitive scratching and skin lesions.How-ever,the neural mechanisms underlying the pathophysiol-ogy of chronic itch remain mysterious.Here,we identified a cell type-dependent role of the anterior cingulate cortex(ACC)in controlling chronic itch-related excessive scratch-ing behaviors in mice.Moreover,we delineated a neural circuit originating from excitatory neurons of the ACC to the ventral tegmental area(VTA)that was critically involved in chronic itch.Furthermore,we demonstrate that the ACCĺVTA circuit also selectively modulated histaminergic acute itch.Finally,the ACC neurons were shown to predomi-nantly innervate the non-dopaminergic neurons of the VTA.Taken together,our findings uncover a cortex-midbrain cir-cuit for chronic itch-evoked scratching behaviors and shed novel insights on therapeutic intervention.
查看更多>>摘要：Predatory hunting is an important type of innate behavior evolutionarily conserved across the animal king-dom.It is typically composed of a set of sequential actions,including prey search,pursuit,attack,and consumption.This behavior is subject to control by the nervous system.Early studies used toads as a model to probe the neuroethology of hunting,which led to the proposal of a sensory-triggered release mechanism for hunting actions.More recent stud-ies have used genetically-trackable zebrafish and rodents and have made breakthrough discoveries in the neuroethol-ogy and neurocircuits underlying this behavior.Here,we review the sophisticated neurocircuitry involved in hunting and summarize the detailed mechanism for the circuitry to encode various aspects of hunting neuroethology,including sensory processing,sensorimotor transformation,motiva-tion,and sequential encoding of hunting actions.We also discuss the overlapping brain circuits for hunting and feed-ing and point out the limitations of current studies.We pro-pose that hunting is an ideal behavioral paradigm in which to study the neuroethology of motivated behaviors,which may shed new light on epidemic disorders,including binge-eating,obesity,and obsessive-compulsive disorders.
查看更多>>摘要：Parkinson's disease(PD)is a common neuro-degenerative disorder caused by the loss of dopamine neu-rons in the substantia nigra and the formation of Lewy bod-ies,which are mainly composed of alpha-synuclein fibrils.Alpha-synuclein plays a vital role in the neuroinflamma-tion mediated by the nucleotide-binding oligomerization domain-,leucine-rich repeat-,and pyrin domain-containing protein 3(NLRP3)inflammasome in PD.A better under-standing of the NLRP3 inflammasome-mediated neuroin-flammation and the related mitochondrial impairment during PD progression may facilitate the development of promis-ing therapies for PD.This review focuses on the molecular mechanisms underlying NLRP3 inflammasome activation,comprising priming and protein complex assembly,as well as the role of mitochondrial impairment and its subsequent inflammatory effects on the progression of neurodegenera-tion in PD.In addition,the therapeutic strategies targeting the NLRP3 inflammasome for PD treatment are discussed,including the inhibitors of NLRP3 inflammatory pathways,mitochondria-focused treatments,microRNAs,and other therapeutic compounds.
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