Pub Date : 2024-05-24DOI: 10.1038/s41583-024-00823-z
Marcel S. Woo, Jan Broder Engler, Manuel A. Friese
Chronic low-grade inflammation and neuronal deregulation are two components of a smoldering disease activity that drives the progression of disability in people with multiple sclerosis (MS). Although several therapies exist to dampen the acute inflammation that drives MS relapses, therapeutic options to halt chronic disability progression are a major unmet clinical need. The development of such therapies is hindered by our limited understanding of the neuron-intrinsic determinants of resilience or vulnerability to inflammation. In this Review, we provide a neuron-centric overview of recent advances in deciphering neuronal response patterns that drive the pathology of MS. We describe the inflammatory CNS environment that initiates neurotoxicity by imposing ion imbalance, excitotoxicity and oxidative stress, and by direct neuro-immune interactions, which collectively lead to mitochondrial dysfunction and epigenetic dysregulation. The neuronal demise is further amplified by breakdown of neuronal transport, accumulation of cytosolic proteins and activation of cell death pathways. Continuous neuronal damage perpetuates CNS inflammation by activating surrounding glia cells and by directly exerting toxicity on neighbouring neurons. Further, we explore strategies to overcome neuronal deregulation in MS and compile a selection of neuronal actuators shown to impact neurodegeneration in preclinical studies. We conclude by discussing the therapeutic potential of targeting such neuronal actuators in MS, including some that have already been tested in interventional clinical trials. Slowing neurodegeneration is the most pressing clinical need for multiple sclerosis (MS). In this Review, Woo, Engler and Friese provide a neuron-centric view on inflammation-induced neurodegeneration in MS and discuss key pathways and molecules that can be therapeutically targeted.
{"title":"The neuropathobiology of multiple sclerosis","authors":"Marcel S. Woo, Jan Broder Engler, Manuel A. Friese","doi":"10.1038/s41583-024-00823-z","DOIUrl":"10.1038/s41583-024-00823-z","url":null,"abstract":"Chronic low-grade inflammation and neuronal deregulation are two components of a smoldering disease activity that drives the progression of disability in people with multiple sclerosis (MS). Although several therapies exist to dampen the acute inflammation that drives MS relapses, therapeutic options to halt chronic disability progression are a major unmet clinical need. The development of such therapies is hindered by our limited understanding of the neuron-intrinsic determinants of resilience or vulnerability to inflammation. In this Review, we provide a neuron-centric overview of recent advances in deciphering neuronal response patterns that drive the pathology of MS. We describe the inflammatory CNS environment that initiates neurotoxicity by imposing ion imbalance, excitotoxicity and oxidative stress, and by direct neuro-immune interactions, which collectively lead to mitochondrial dysfunction and epigenetic dysregulation. The neuronal demise is further amplified by breakdown of neuronal transport, accumulation of cytosolic proteins and activation of cell death pathways. Continuous neuronal damage perpetuates CNS inflammation by activating surrounding glia cells and by directly exerting toxicity on neighbouring neurons. Further, we explore strategies to overcome neuronal deregulation in MS and compile a selection of neuronal actuators shown to impact neurodegeneration in preclinical studies. We conclude by discussing the therapeutic potential of targeting such neuronal actuators in MS, including some that have already been tested in interventional clinical trials. Slowing neurodegeneration is the most pressing clinical need for multiple sclerosis (MS). In this Review, Woo, Engler and Friese provide a neuron-centric view on inflammation-induced neurodegeneration in MS and discuss key pathways and molecules that can be therapeutically targeted.","PeriodicalId":49142,"journal":{"name":"Nature Reviews Neuroscience","volume":"25 7","pages":"493-513"},"PeriodicalIF":28.7,"publicationDate":"2024-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141092104","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-23DOI: 10.1038/s41583-024-00824-y
Michelle W. Wu, Nazim Kourdougli, Carlos Portera-Cailliau
Mammalian cortical networks are active before synaptogenesis begins in earnest, before neuronal migration is complete, and well before an animal opens its eyes and begins to actively explore its surroundings. This early activity undergoes several transformations during development. The most important of these is a transition from episodic synchronous network events, which are necessary for patterning the neocortex into functionally related modules, to desynchronized activity that is computationally more powerful and efficient. Network desynchronization is perhaps the most dramatic and abrupt developmental event in an otherwise slow and gradual process of brain maturation. In this Review, we summarize what is known about the phenomenology of developmental synchronous activity in the rodent neocortex and speculate on the mechanisms that drive its eventual desynchronization. We argue that desynchronization of network activity is a fundamental step through which the cortex transitions from passive, bottom–up detection of sensory stimuli to active sensory processing with top–down modulation. At early developmental stages, spontaneous activity in the mammalian cortex is characterized by the occurrence of highly synchronous network events. Portera-Cailliau and colleagues describe these activity patterns, their underlying mechanisms and function, and their transition to the desynchronized activity observed in adult individuals.
{"title":"Network state transitions during cortical development","authors":"Michelle W. Wu, Nazim Kourdougli, Carlos Portera-Cailliau","doi":"10.1038/s41583-024-00824-y","DOIUrl":"10.1038/s41583-024-00824-y","url":null,"abstract":"Mammalian cortical networks are active before synaptogenesis begins in earnest, before neuronal migration is complete, and well before an animal opens its eyes and begins to actively explore its surroundings. This early activity undergoes several transformations during development. The most important of these is a transition from episodic synchronous network events, which are necessary for patterning the neocortex into functionally related modules, to desynchronized activity that is computationally more powerful and efficient. Network desynchronization is perhaps the most dramatic and abrupt developmental event in an otherwise slow and gradual process of brain maturation. In this Review, we summarize what is known about the phenomenology of developmental synchronous activity in the rodent neocortex and speculate on the mechanisms that drive its eventual desynchronization. We argue that desynchronization of network activity is a fundamental step through which the cortex transitions from passive, bottom–up detection of sensory stimuli to active sensory processing with top–down modulation. At early developmental stages, spontaneous activity in the mammalian cortex is characterized by the occurrence of highly synchronous network events. Portera-Cailliau and colleagues describe these activity patterns, their underlying mechanisms and function, and their transition to the desynchronized activity observed in adult individuals.","PeriodicalId":49142,"journal":{"name":"Nature Reviews Neuroscience","volume":"25 8","pages":"535-552"},"PeriodicalIF":28.7,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141087762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-15DOI: 10.1038/s41583-024-00826-w
Maria Papatriantafyllou
{"title":"Mapping the social memory network","authors":"Maria Papatriantafyllou","doi":"10.1038/s41583-024-00826-w","DOIUrl":"10.1038/s41583-024-00826-w","url":null,"abstract":"","PeriodicalId":49142,"journal":{"name":"Nature Reviews Neuroscience","volume":"25 7","pages":"449-449"},"PeriodicalIF":28.7,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140925014","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-14DOI: 10.1038/s41583-024-00819-9
Alexander B. Silva, Kaylo T. Littlejohn, Jessie R. Liu, David A. Moses, Edward F. Chang
Loss of speech after paralysis is devastating, but circumventing motor-pathway injury by directly decoding speech from intact cortical activity has the potential to restore natural communication and self-expression. Recent discoveries have defined how key features of speech production are facilitated by the coordinated activity of vocal-tract articulatory and motor-planning cortical representations. In this Review, we highlight such progress and how it has led to successful speech decoding, first in individuals implanted with intracranial electrodes for clinical epilepsy monitoring and subsequently in individuals with paralysis as part of early feasibility clinical trials to restore speech. We discuss high-spatiotemporal-resolution neural interfaces and the adaptation of state-of-the-art speech computational algorithms that have driven rapid and substantial progress in decoding neural activity into text, audible speech, and facial movements. Although restoring natural speech is a long-term goal, speech neuroprostheses already have performance levels that surpass communication rates offered by current assistive-communication technology. Given this accelerated rate of progress in the field, we propose key evaluation metrics for speed and accuracy, among others, to help standardize across studies. We finish by highlighting several directions to more fully explore the multidimensional feature space of speech and language, which will continue to accelerate progress towards a clinically viable speech neuroprosthesis. A clinically viable speech neuroprosthesis could restore natural speech to individuals with vocal-tract paralysis. In this Review, Silva et al. discuss rapid progress in neural interfaces and computational algorithms for decoding speech from cortical activity and propose evaluation metrics to help standardize speech neuroprostheses.
{"title":"The speech neuroprosthesis","authors":"Alexander B. Silva, Kaylo T. Littlejohn, Jessie R. Liu, David A. Moses, Edward F. Chang","doi":"10.1038/s41583-024-00819-9","DOIUrl":"10.1038/s41583-024-00819-9","url":null,"abstract":"Loss of speech after paralysis is devastating, but circumventing motor-pathway injury by directly decoding speech from intact cortical activity has the potential to restore natural communication and self-expression. Recent discoveries have defined how key features of speech production are facilitated by the coordinated activity of vocal-tract articulatory and motor-planning cortical representations. In this Review, we highlight such progress and how it has led to successful speech decoding, first in individuals implanted with intracranial electrodes for clinical epilepsy monitoring and subsequently in individuals with paralysis as part of early feasibility clinical trials to restore speech. We discuss high-spatiotemporal-resolution neural interfaces and the adaptation of state-of-the-art speech computational algorithms that have driven rapid and substantial progress in decoding neural activity into text, audible speech, and facial movements. Although restoring natural speech is a long-term goal, speech neuroprostheses already have performance levels that surpass communication rates offered by current assistive-communication technology. Given this accelerated rate of progress in the field, we propose key evaluation metrics for speed and accuracy, among others, to help standardize across studies. We finish by highlighting several directions to more fully explore the multidimensional feature space of speech and language, which will continue to accelerate progress towards a clinically viable speech neuroprosthesis. A clinically viable speech neuroprosthesis could restore natural speech to individuals with vocal-tract paralysis. In this Review, Silva et al. discuss rapid progress in neural interfaces and computational algorithms for decoding speech from cortical activity and propose evaluation metrics to help standardize speech neuroprostheses.","PeriodicalId":49142,"journal":{"name":"Nature Reviews Neuroscience","volume":"25 7","pages":"473-492"},"PeriodicalIF":28.7,"publicationDate":"2024-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140921175","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-08DOI: 10.1038/s41583-024-00825-x
Tina T. Liu
In this Journal Club, Tina Liu describes a 1988 paper that revealed the capacity of the sensory cortex for functional reorganization
在本期期刊俱乐部中，Tina Liu 介绍了 1988 年的一篇论文，该论文揭示了感觉皮层的功能重组能力
{"title":"Unravelling nature and nurture in cortical (re)organization","authors":"Tina T. Liu","doi":"10.1038/s41583-024-00825-x","DOIUrl":"10.1038/s41583-024-00825-x","url":null,"abstract":"In this Journal Club, Tina Liu describes a 1988 paper that revealed the capacity of the sensory cortex for functional reorganization","PeriodicalId":49142,"journal":{"name":"Nature Reviews Neuroscience","volume":"25 7","pages":"451-451"},"PeriodicalIF":28.7,"publicationDate":"2024-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140892200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-07DOI: 10.1038/s41583-024-00817-x
André A. Fenton
The representation of distinct spaces by hippocampal place cells has been linked to changes in their place fields (the locations in the environment where the place cells discharge strongly), a phenomenon that has been termed ‘remapping’. Remapping has been assumed to be accompanied by the reorganization of subsecond cofiring relationships among the place cells, potentially maximizing hippocampal information coding capacity. However, several observations challenge this standard view. For example, place cells exhibit mixed selectivity, encode non-positional variables, can have multiple place fields and exhibit unreliable discharge in fixed environments. Furthermore, recent evidence suggests that, when measured at subsecond timescales, the moment-to-moment cofiring of a pair of cells in one environment is remarkably similar in another environment, despite remapping. Here, I propose that remapping is a misnomer for the changes in place fields across environments and suggest instead that internally organized manifold representations of hippocampal activity are actively registered to different environments to enable navigation, promote memory and organize knowledge. The location-specific firing of hippocampal place cells changes when an animal enters a new environment, a phenomenon known as ‘remapping’. In this Perspective, André A. Fenton challenges standard models of place cell remapping and proposes a key role for the ‘re-registration’ of internally organized place cell population dynamics in the encoding of distinct environments.
{"title":"Remapping revisited: how the hippocampus represents different spaces","authors":"André A. Fenton","doi":"10.1038/s41583-024-00817-x","DOIUrl":"10.1038/s41583-024-00817-x","url":null,"abstract":"The representation of distinct spaces by hippocampal place cells has been linked to changes in their place fields (the locations in the environment where the place cells discharge strongly), a phenomenon that has been termed ‘remapping’. Remapping has been assumed to be accompanied by the reorganization of subsecond cofiring relationships among the place cells, potentially maximizing hippocampal information coding capacity. However, several observations challenge this standard view. For example, place cells exhibit mixed selectivity, encode non-positional variables, can have multiple place fields and exhibit unreliable discharge in fixed environments. Furthermore, recent evidence suggests that, when measured at subsecond timescales, the moment-to-moment cofiring of a pair of cells in one environment is remarkably similar in another environment, despite remapping. Here, I propose that remapping is a misnomer for the changes in place fields across environments and suggest instead that internally organized manifold representations of hippocampal activity are actively registered to different environments to enable navigation, promote memory and organize knowledge. The location-specific firing of hippocampal place cells changes when an animal enters a new environment, a phenomenon known as ‘remapping’. In this Perspective, André A. Fenton challenges standard models of place cell remapping and proposes a key role for the ‘re-registration’ of internally organized place cell population dynamics in the encoding of distinct environments.","PeriodicalId":49142,"journal":{"name":"Nature Reviews Neuroscience","volume":"25 6","pages":"428-448"},"PeriodicalIF":34.7,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140876936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-02DOI: 10.1038/s41583-024-00821-1
Katherine Whalley
A subset of female mice that show anxiety-related traits seek out a starvation-like state when exposed to repeated stress
表现出焦虑相关特征的一部分雌性小鼠在反复受到压力时会寻求类似饥饿的状态
{"title":"Stress drives seeking of starvation","authors":"Katherine Whalley","doi":"10.1038/s41583-024-00821-1","DOIUrl":"10.1038/s41583-024-00821-1","url":null,"abstract":"A subset of female mice that show anxiety-related traits seek out a starvation-like state when exposed to repeated stress","PeriodicalId":49142,"journal":{"name":"Nature Reviews Neuroscience","volume":"25 7","pages":"449-449"},"PeriodicalIF":28.7,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140819423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-25DOI: 10.1038/s41583-024-00814-0
Ali Choucry, Masanori Nomoto, Kaoru Inokuchi
Memories are thought to be stored in neuronal ensembles referred to as engrams. Studies have suggested that when two memories occur in quick succession, a proportion of their engrams overlap and the memories become linked (in a process known as prospective linking) while maintaining their individual identities. In this Review, we summarize the key principles of memory linking through engram overlap, as revealed by experimental and modelling studies. We describe evidence of the involvement of synaptic memory substrates, spine clustering and non-linear neuronal capacities in prospective linking, and suggest a dynamic somato-synaptic model, in which memories are shared between neurons yet remain separable through distinct dendritic and synaptic allocation patterns. We also bring into focus retrospective linking, in which memories become associated after encoding via offline reactivation, and discuss key temporal and mechanistic differences between prospective and retrospective linking, as well as the potential differences in their cognitive outcomes. Many cognitive functions rely on the ability to link distinct but related memories, while retaining the capacity to recall the individual details of the linked memories. Inokuchi and colleagues describe evidence that memory linking involves engram overlap and discuss the mechanisms that regulate this process.
{"title":"Engram mechanisms of memory linking and identity","authors":"Ali Choucry, Masanori Nomoto, Kaoru Inokuchi","doi":"10.1038/s41583-024-00814-0","DOIUrl":"10.1038/s41583-024-00814-0","url":null,"abstract":"Memories are thought to be stored in neuronal ensembles referred to as engrams. Studies have suggested that when two memories occur in quick succession, a proportion of their engrams overlap and the memories become linked (in a process known as prospective linking) while maintaining their individual identities. In this Review, we summarize the key principles of memory linking through engram overlap, as revealed by experimental and modelling studies. We describe evidence of the involvement of synaptic memory substrates, spine clustering and non-linear neuronal capacities in prospective linking, and suggest a dynamic somato-synaptic model, in which memories are shared between neurons yet remain separable through distinct dendritic and synaptic allocation patterns. We also bring into focus retrospective linking, in which memories become associated after encoding via offline reactivation, and discuss key temporal and mechanistic differences between prospective and retrospective linking, as well as the potential differences in their cognitive outcomes. Many cognitive functions rely on the ability to link distinct but related memories, while retaining the capacity to recall the individual details of the linked memories. Inokuchi and colleagues describe evidence that memory linking involves engram overlap and discuss the mechanisms that regulate this process.","PeriodicalId":49142,"journal":{"name":"Nature Reviews Neuroscience","volume":"25 6","pages":"375-392"},"PeriodicalIF":34.7,"publicationDate":"2024-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140648679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-25DOI: 10.1038/s41583-024-00820-2
Sian Lewis
The main direction of motor skill-specific information between rat primary motor cortex and dorsolateral striatum is shown to switch from cortex-predominant before learning to striatum-predominant after learning.
{"title":"Skill switching","authors":"Sian Lewis","doi":"10.1038/s41583-024-00820-2","DOIUrl":"10.1038/s41583-024-00820-2","url":null,"abstract":"The main direction of motor skill-specific information between rat primary motor cortex and dorsolateral striatum is shown to switch from cortex-predominant before learning to striatum-predominant after learning.","PeriodicalId":49142,"journal":{"name":"Nature Reviews Neuroscience","volume":"25 6","pages":"373-373"},"PeriodicalIF":34.7,"publicationDate":"2024-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140642266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：