Pub Date : 2024-09-01Epub Date: 2024-08-07DOI: 10.1152/jn.00071.2024
Sanjna Kumari, Rishikesh Narayanan
Complex systems are neither fully determined nor completely random. Biological complex systems, including single neurons, manifest intermediate regimes of randomness that recruit integration of specific combinations of functionally specialized subsystems. Such emergence of biological function provides the substrate for the expression of degeneracy, the ability of disparate combinations of subsystems to yield similar function. Here, we present evidence for the expression of degeneracy in morphologically realistic models of dentate gyrus granule cells (GCs) through functional integration of disparate ion-channel combinations. We performed a 45-parameter randomized search spanning 16 active and passive ion channels, each biophysically constrained by their gating kinetics and localization profiles, to search for valid GC models. Valid models were those that satisfied 17 sub- and suprathreshold cellular-scale electrophysiological measurements from rat GCs. A vast majority (>99%) of the 15,000 random models were not electrophysiologically valid, demonstrating that arbitrarily random ion-channel combinations would not yield GC functions. The 141 valid models (0.94% of 15,000) manifested heterogeneities in and cross-dependencies across local and propagating electrophysiological measurements, which matched with their respective biological counterparts. Importantly, these valid models were widespread throughout the parametric space and manifested weak cross-dependencies across different parameters. These observations together showed that GC physiology could neither be obtained by entirely random ion-channel combinations nor is there an entirely determined single parametric combination that satisfied all constraints. The complexity, the heterogeneities in measurement and parametric spaces, and degeneracy associated with GC physiology should be rigorously accounted for while assessing GCs and their robustness under physiological and pathological conditions.NEW & NOTEWORTHY A recent study from our laboratory had demonstrated pronounced heterogeneities in a set of 17 electrophysiological measurements obtained from a large population of rat hippocampal granule cells. Here, we demonstrate the manifestation of ion-channel degeneracy in a heterogeneous population of morphologically realistic conductance-based granule cell models that were validated against these measurements and their cross-dependencies. Our analyses show that single neurons are complex entities whose functions emerge through intricate interactions among several functionally specialized subsystems.
{"title":"Ion-channel degeneracy and heterogeneities in the emergence of signature physiological characteristics of dentate gyrus granule cells.","authors":"Sanjna Kumari, Rishikesh Narayanan","doi":"10.1152/jn.00071.2024","DOIUrl":"10.1152/jn.00071.2024","url":null,"abstract":"<p><p>Complex systems are neither fully determined nor completely random. Biological complex systems, including single neurons, manifest intermediate regimes of randomness that recruit integration of specific combinations of functionally specialized subsystems. Such emergence of biological function provides the substrate for the expression of degeneracy, the ability of disparate combinations of subsystems to yield similar function. Here, we present evidence for the expression of degeneracy in morphologically realistic models of dentate gyrus granule cells (GCs) through functional integration of disparate ion-channel combinations. We performed a 45-parameter randomized search spanning 16 active and passive ion channels, each biophysically constrained by their gating kinetics and localization profiles, to search for valid GC models. Valid models were those that satisfied 17 sub- and suprathreshold cellular-scale electrophysiological measurements from rat GCs. A vast majority (>99%) of the 15,000 random models were not electrophysiologically valid, demonstrating that arbitrarily random ion-channel combinations would not yield GC functions. The 141 valid models (0.94% of 15,000) manifested heterogeneities in and cross-dependencies across local and propagating electrophysiological measurements, which matched with their respective biological counterparts. Importantly, these valid models were widespread throughout the parametric space and manifested weak cross-dependencies across different parameters. These observations together showed that GC physiology could neither be obtained by entirely random ion-channel combinations nor is there an entirely determined single parametric combination that satisfied all constraints. The complexity, the heterogeneities in measurement and parametric spaces, and degeneracy associated with GC physiology should be rigorously accounted for while assessing GCs and their robustness under physiological and pathological conditions.<b>NEW & NOTEWORTHY</b> A recent study from our laboratory had demonstrated pronounced heterogeneities in a set of 17 electrophysiological measurements obtained from a large population of rat hippocampal granule cells. Here, we demonstrate the manifestation of ion-channel degeneracy in a heterogeneous population of morphologically realistic conductance-based granule cell models that were validated against these measurements and their cross-dependencies. Our analyses show that single neurons are complex entities whose functions emerge through intricate interactions among several functionally specialized subsystems.</p>","PeriodicalId":16563,"journal":{"name":"Journal of neurophysiology","volume":null,"pages":null},"PeriodicalIF":2.1,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141902065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-01Epub Date: 2024-07-11DOI: 10.1152/jn.00045.2024
Binte Zehra, Nesrin Mohamed, Ahmad Farhat, Gilles Bru-Mercier, Dharana Satsangi, Richa Tambi, Rihana Kamarudheen, Muhammad Kumail, Reem Khalil, Mauro Pessia, Maria Cristina D'Adamo, Bakhrom K Berdiev, Mohammed Uddin
Generation of human induced pluripotent stem cells (iPSCs) through reprogramming was a transformational change in the field of regenerative medicine that led to new possibilities for drug discovery and cell replacement therapy. Several protocols have been established to differentiate hiPSCs into neuronal lineages. However, low differentiation efficiency is one of the major drawbacks of these approaches. Here, we compared the efficiency of two methods of neuronal differentiation from iPSCs cultured in two different culture media, StemFlex Medium (SFM) and Essential 8 Medium (E8M). The results indicated that iPSCs cultured in E8M efficiently generated different types of neurons in a shorter time and without the growth of undifferentiated nonneuronal cells in the culture as compared with those generated from iPSCs in SFM. Furthermore, these neurons were validated as functional units immunocytochemically by confirming the expression of mature neuronal markers (i.e., NeuN, β tubulin, and Synapsin I) and whole cell patch-clamp recordings. Long-read single-cell RNA sequencing confirms the presence of upper and deep layer cortical layer excitatory and inhibitory neuronal subtypes in addition to small populations of GABAergic neurons in day 30 neuronal cultures. Pathway analysis indicated that our protocol triggers the signaling transcriptional networks important for the process of neuronal differentiation in vivo.NEW & NOTEWORTHY Low differentiation efficiency is one of the major drawbacks of the existing protocols to differentiate iPSCs into neuronal lineages. Here, we present time-efficient and robust approach of neuronal differentiation leading to the generation of functional brain units, cortical layer neurons. We found iPSCs cultured in Essential 8 media (E8M) resulted in neuronal differentiation without the signs of growth of spontaneously differentiated cells in culture at any point in 35 days compared with Stemflex media (SFM).
{"title":"Integrative analysis of long isoform sequencing and functional data identifies distinct cortical layer neuronal subtypes derived from human iPSCs.","authors":"Binte Zehra, Nesrin Mohamed, Ahmad Farhat, Gilles Bru-Mercier, Dharana Satsangi, Richa Tambi, Rihana Kamarudheen, Muhammad Kumail, Reem Khalil, Mauro Pessia, Maria Cristina D'Adamo, Bakhrom K Berdiev, Mohammed Uddin","doi":"10.1152/jn.00045.2024","DOIUrl":"10.1152/jn.00045.2024","url":null,"abstract":"<p><p>Generation of human induced pluripotent stem cells (iPSCs) through reprogramming was a transformational change in the field of regenerative medicine that led to new possibilities for drug discovery and cell replacement therapy. Several protocols have been established to differentiate hiPSCs into neuronal lineages. However, low differentiation efficiency is one of the major drawbacks of these approaches. Here, we compared the efficiency of two methods of neuronal differentiation from iPSCs cultured in two different culture media, StemFlex Medium (SFM) and Essential 8 Medium (E8M). The results indicated that iPSCs cultured in E8M efficiently generated different types of neurons in a shorter time and without the growth of undifferentiated nonneuronal cells in the culture as compared with those generated from iPSCs in SFM. Furthermore, these neurons were validated as functional units immunocytochemically by confirming the expression of mature neuronal markers (i.e., NeuN, β tubulin, and Synapsin I) and whole cell patch-clamp recordings. Long-read single-cell RNA sequencing confirms the presence of upper and deep layer cortical layer excitatory and inhibitory neuronal subtypes in addition to small populations of GABAergic neurons in day 30 neuronal cultures. Pathway analysis indicated that our protocol triggers the signaling transcriptional networks important for the process of neuronal differentiation <i>in vivo</i>.<b>NEW & NOTEWORTHY</b> Low differentiation efficiency is one of the major drawbacks of the existing protocols to differentiate iPSCs into neuronal lineages. Here, we present time-efficient and robust approach of neuronal differentiation leading to the generation of functional brain units, cortical layer neurons. We found iPSCs cultured in Essential 8 media (E8M) resulted in neuronal differentiation without the signs of growth of spontaneously differentiated cells in culture at any point in 35 days compared with Stemflex media (SFM).</p>","PeriodicalId":16563,"journal":{"name":"Journal of neurophysiology","volume":null,"pages":null},"PeriodicalIF":2.1,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141580009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-01Epub Date: 2024-07-17DOI: 10.1152/jn.00431.2023
Xin Sienna Yu, Huiying Zhu, Lisa Griffin
Neuromuscular fatigue induces superior migration of the humeral head in individuals with subacromial pain. This has been attributed to weakness of rotator cuff muscles and overactive deltoid muscles. Investigation of common inputs to motoneuron pools of the rotator cuff and deltoid muscles offers valuable insight into the underlying mechanisms of neuromuscular control deficits associated with subacromial pain. This study aims to investigate intermuscular coherence across the rotator cuff and deltoid muscles during a sustained submaximal isometric fatiguing contraction in individuals with and without subacromial pain. Twenty symptomatic and 18 asymptomatic young adults participated in this study. Surface electromyogram (EMG) was recorded from the middle deltoid (MD) and infraspinatus (IS). Intramuscular EMG was recorded with fine-wire electrodes in the supraspinatus (SS). Participants performed an isometric fatiguing contraction of 30° scaption at 25% maximum voluntary contraction (MVC) until endurance limit. Pooled coherence of muscle pairs (SS-IS, SS-MD, IS-MD) in the 2-5 Hz (delta), 5-15 Hz (alpha), and 15-35 Hz (beta) frequency bands during the initial and final 30 s of the fatigue task were compared. SS-IS and SS-MD delta-band coherence increased with fatigue in the asymptomatic group but not the symptomatic group. In the alpha and beta bands, SS-IS and SS-MD coherence increased with fatigue in both groups. IS-MD beta-band coherence was greater in the symptomatic than the asymptomatic group. Individuals with subacromial pain failed to increase common drive across rotator cuff and deltoid muscles and have altered control strategies during neuromuscular fatigue. This may contribute to glenohumeral joint instability and subacromial pain experienced by these individuals.NEW & NOTEWORTHY Through the computation of shared neural drive across glenohumeral muscles, this study reveals that individuals with subacromial pain were unable to increase shared neural drive within the rotator cuff and across the supraspinatus and deltoid muscles during neuromuscular fatigue induced by sustained isometric contraction. These deficits in common drive across the shoulder muscles likely contribute to the joint instability and pain experienced by these individuals.
{"title":"Fatigue-related changes in intermuscular electromyographic coherence across rotator cuff and deltoid muscles in individuals with and without subacromial pain.","authors":"Xin Sienna Yu, Huiying Zhu, Lisa Griffin","doi":"10.1152/jn.00431.2023","DOIUrl":"10.1152/jn.00431.2023","url":null,"abstract":"<p><p>Neuromuscular fatigue induces superior migration of the humeral head in individuals with subacromial pain. This has been attributed to weakness of rotator cuff muscles and overactive deltoid muscles. Investigation of common inputs to motoneuron pools of the rotator cuff and deltoid muscles offers valuable insight into the underlying mechanisms of neuromuscular control deficits associated with subacromial pain. This study aims to investigate intermuscular coherence across the rotator cuff and deltoid muscles during a sustained submaximal isometric fatiguing contraction in individuals with and without subacromial pain. Twenty symptomatic and 18 asymptomatic young adults participated in this study. Surface electromyogram (EMG) was recorded from the middle deltoid (MD) and infraspinatus (IS). Intramuscular EMG was recorded with fine-wire electrodes in the supraspinatus (SS). Participants performed an isometric fatiguing contraction of 30° scaption at 25% maximum voluntary contraction (MVC) until endurance limit. Pooled coherence of muscle pairs (SS-IS, SS-MD, IS-MD) in the 2-5 Hz (delta), 5-15 Hz (alpha), and 15-35 Hz (beta) frequency bands during the initial and final 30 s of the fatigue task were compared. SS-IS and SS-MD delta-band coherence increased with fatigue in the asymptomatic group but not the symptomatic group. In the alpha and beta bands, SS-IS and SS-MD coherence increased with fatigue in both groups. IS-MD beta-band coherence was greater in the symptomatic than the asymptomatic group. Individuals with subacromial pain failed to increase common drive across rotator cuff and deltoid muscles and have altered control strategies during neuromuscular fatigue. This may contribute to glenohumeral joint instability and subacromial pain experienced by these individuals.<b>NEW & NOTEWORTHY</b> Through the computation of shared neural drive across glenohumeral muscles, this study reveals that individuals with subacromial pain were unable to increase shared neural drive within the rotator cuff and across the supraspinatus and deltoid muscles during neuromuscular fatigue induced by sustained isometric contraction. These deficits in common drive across the shoulder muscles likely contribute to the joint instability and pain experienced by these individuals.</p>","PeriodicalId":16563,"journal":{"name":"Journal of neurophysiology","volume":null,"pages":null},"PeriodicalIF":2.1,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141626990","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-01Epub Date: 2024-07-10DOI: 10.1152/jn.00320.2022
Pietro Mazzoni, Mwiza Ushe, John R Younce, Scott A Norris, Tamara Hershey, Morvarid Karimi, Samer D Tabbal, Joel S Perlmutter
Bradykinesia is a term describing several manifestations of movement disruption caused by Parkinson's disease (PD), including movement slowing, amplitude reduction, and gradual decrease of speed and amplitude over multiple repetitions of the same movement. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves bradykinesia in patients with PD. We examined the effect of DBS on specific components of bradykinesia when applied at two locations within the STN, using signal processing techniques to identify the time course of amplitude and frequency of repeated hand pronation-supination movements performed by participants with and without PD. Stimulation at either location increased movement amplitude, increased frequency, and decreased variability, though not to the range observed in the control group. Amplitude and frequency showed decrement within trials, which was similar in PD and control groups and did not change with DBS. Decrement across trials, by contrast, differed between PD and control groups, and was reduced by stimulation. We conclude that DBS improves specific aspects of movement that are disrupted by PD, whereas it does not affect short-term decrement that could reflect muscular fatigue.NEW & NOTEWORTHY In this study, we examined different components of bradykinesia in patients with Parkinson's disease (PD). We identified different components through signal processing techniques and their response to deep brain stimulation (DBS). We found that some components of bradykinesia respond to stimulation, whereas others do not. This knowledge advances our understanding of brain mechanisms that control movement speed and amplitude.
{"title":"Differential components of bradykinesia in Parkinson's disease revealed by deep brain stimulation.","authors":"Pietro Mazzoni, Mwiza Ushe, John R Younce, Scott A Norris, Tamara Hershey, Morvarid Karimi, Samer D Tabbal, Joel S Perlmutter","doi":"10.1152/jn.00320.2022","DOIUrl":"10.1152/jn.00320.2022","url":null,"abstract":"<p><p>Bradykinesia is a term describing several manifestations of movement disruption caused by Parkinson's disease (PD), including movement slowing, amplitude reduction, and gradual decrease of speed and amplitude over multiple repetitions of the same movement. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves bradykinesia in patients with PD. We examined the effect of DBS on specific components of bradykinesia when applied at two locations within the STN, using signal processing techniques to identify the time course of amplitude and frequency of repeated hand pronation-supination movements performed by participants with and without PD. Stimulation at either location increased movement amplitude, increased frequency, and decreased variability, though not to the range observed in the control group. Amplitude and frequency showed decrement within trials, which was similar in PD and control groups and did not change with DBS. Decrement across trials, by contrast, differed between PD and control groups, and was reduced by stimulation. We conclude that DBS improves specific aspects of movement that are disrupted by PD, whereas it does not affect short-term decrement that could reflect muscular fatigue.<b>NEW & NOTEWORTHY</b> In this study, we examined different components of bradykinesia in patients with Parkinson's disease (PD). We identified different components through signal processing techniques and their response to deep brain stimulation (DBS). We found that some components of bradykinesia respond to stimulation, whereas others do not. This knowledge advances our understanding of brain mechanisms that control movement speed and amplitude.</p>","PeriodicalId":16563,"journal":{"name":"Journal of neurophysiology","volume":null,"pages":null},"PeriodicalIF":2.1,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11427043/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141579961","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-01Epub Date: 2024-08-07DOI: 10.1152/jn.00319.2024
Gil Meir, Amos Katz, Yuliya Berdichevsky, Anat Reiner-Benaim, Itshak Melzer
An unannounced balance loss during walking, i.e., balance perturbation, is a stressful event, which changes the activity of the sympathetic nervous system (SNS). We examined SNS response to unannounced balance perturbation during walking, simulating real-life condition of balance loss. We asked: do laboratory-induced unannounced balance losses during walking cause a sympathetic response, and-if so-does it habituate after a series of perturbations? Thirty-four young adults underwent a series of six successive unannounced balance perturbations while walking on a treadmill. Sympathetic activity was monitored continuously using electrodermal activity and compared before and immediately after each unannounced perturbation. All perturbations elicited a significant increase of electrodermal activity (P < 0.001), indicating a phasic increase in the sympathetic drive. The relative phasic increase of electrodermal activity caused by the first perturbation was significantly higher than the last perturbation (P < 0.05). Three different types of electrodermal activity behavior were observed: steady-level tonic SNS activity, increased SNS activity, and decreased SNS activity. Balance loss during walking triggers phasic SNS response, this response habituates after a series of unannounced balance perturbations. In addition, three distinct patterns of tonic sympathetic activity may imply variations in the ability of the SNS response to habituate across individuals.NEW & NOTEWORTHY Up to date, the literature typically provides information about sympathetic nervous system activity and relatively static balance. We believe that exposing participants to a balance loss during walking, i.e., unexpected perturbation, provides a more ecologically valid situation to measure sympathetic nervous system response; this provides new and vital knowledge that can have a significant impact and understanding of how the SNS responds to a loss of balance in a real-life situation.
{"title":"Sympathetic response following unannounced loss of balance during walking in young adults: laboratory study.","authors":"Gil Meir, Amos Katz, Yuliya Berdichevsky, Anat Reiner-Benaim, Itshak Melzer","doi":"10.1152/jn.00319.2024","DOIUrl":"10.1152/jn.00319.2024","url":null,"abstract":"<p><p>An unannounced balance loss during walking, i.e., balance perturbation, is a stressful event, which changes the activity of the sympathetic nervous system (SNS). We examined SNS response to unannounced balance perturbation during walking, simulating real-life condition of balance loss. We asked: do laboratory-induced unannounced balance losses during walking cause a sympathetic response, and-if so-does it habituate after a series of perturbations? Thirty-four young adults underwent a series of six successive unannounced balance perturbations while walking on a treadmill. Sympathetic activity was monitored continuously using electrodermal activity and compared before and immediately after each unannounced perturbation. All perturbations elicited a significant increase of electrodermal activity (<i>P</i> < 0.001), indicating a phasic increase in the sympathetic drive. The relative phasic increase of electrodermal activity caused by the first perturbation was significantly higher than the last perturbation (<i>P</i> < 0.05). Three different types of electrodermal activity behavior were observed: steady-level tonic SNS activity, increased SNS activity, and decreased SNS activity. Balance loss during walking triggers phasic SNS response, this response habituates after a series of unannounced balance perturbations. In addition, three distinct patterns of tonic sympathetic activity may imply variations in the ability of the SNS response to habituate across individuals.<b>NEW & NOTEWORTHY</b> Up to date, the literature typically provides information about sympathetic nervous system activity and relatively static balance. We believe that exposing participants to a balance loss during walking, i.e., unexpected perturbation, provides a more ecologically valid situation to measure sympathetic nervous system response; this provides new and vital knowledge that can have a significant impact and understanding of how the SNS responds to a loss of balance in a real-life situation.</p>","PeriodicalId":16563,"journal":{"name":"Journal of neurophysiology","volume":null,"pages":null},"PeriodicalIF":2.1,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141897584","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-01Epub Date: 2024-07-25DOI: 10.1152/jn.00230.2024
Obaid U Khurram, Carlos B Mantilla, Gary C Sieck
The diaphragm muscle (DIAm) is the primary inspiratory muscle in mammals. In awake animals, considerable heterogeneity in the electromyographic (EMG) activity of the DIAm reflects varied ventilatory and nonventilatory behaviors. Experiments in awake animals are an essential component to understanding the neuromotor control of breathing, which has especially begun to be appreciated within the last decade. However, insofar as the intent is to study the control of breathing, it is paramount to identify DIAm EMG activity that in fact reflects breathing. Current strategies for doing so in a reproducible, reliable, and efficient fashion are lacking. In the present article, we evaluated DIAm EMG from awake animals using hierarchical clustering across four-dimensional feature space to classify eupneic breathing. Our model, which can be implemented with automated threshold of the clustering dendrogram, successfully identified eupneic breathing with high F1 score (0.92), specificity (0.70), and accuracy (0.88), suggesting that it is a robust and reliable tool for investigating the neural control of breathing.NEW & NOTEWORTHY The heterogeneity of diaphragm muscle (DIAm) activity in awake animals reflects real motor behavior diversity but makes assessments of eupneic breathing challenging. The present article uses an unsupervised machine learning model to identify eupneic breathing amidst a deluge of different DIAm electromyography (EMG) burst patterns in awake rats. This technique offers a scalable and reliable tool that improves efficiency of DIAm EMG analysis and minimizes potential sources of bias.
膈肌(DIAm)是哺乳动物特有的肌肉,也是参与呼吸的主要肌肉。在清醒的动物中,DIAm 肌电图(EMG)活动的相当大的异质性反映了不同的换气和非换气行为。清醒动物的实验是了解呼吸的神经运动控制的重要组成部分;因此,最重要的是明确识别实际上反映呼吸的 DIAm 肌电图活动。目前还缺乏以可重复、可靠和高效的方式实现这一目标的策略。本研究利用机器学习评估清醒大鼠的 DIAm EMG,使用四维特征空间的分层聚类来对舒张期呼吸进行分类。我们的模型可以通过聚类树枝图的自动阈值来实现,它以较高的 F1 分数(0.92)、特异性(0.70)和准确性(0.88)成功地识别出了通气呼吸,表明它是研究呼吸神经控制的一种稳健可靠的工具。
{"title":"Identification of eupneic breathing using machine learning.","authors":"Obaid U Khurram, Carlos B Mantilla, Gary C Sieck","doi":"10.1152/jn.00230.2024","DOIUrl":"10.1152/jn.00230.2024","url":null,"abstract":"<p><p>The diaphragm muscle (DIAm) is the primary inspiratory muscle in mammals. In awake animals, considerable heterogeneity in the electromyographic (EMG) activity of the DIAm reflects varied ventilatory and nonventilatory behaviors. Experiments in awake animals are an essential component to understanding the neuromotor control of breathing, which has especially begun to be appreciated within the last decade. However, insofar as the intent is to study the control of breathing, it is paramount to identify DIAm EMG activity that in fact reflects breathing. Current strategies for doing so in a reproducible, reliable, and efficient fashion are lacking. In the present article, we evaluated DIAm EMG from awake animals using hierarchical clustering across four-dimensional feature space to classify eupneic breathing. Our model, which can be implemented with automated threshold of the clustering dendrogram, successfully identified eupneic breathing with high F1 score (0.92), specificity (0.70), and accuracy (0.88), suggesting that it is a robust and reliable tool for investigating the neural control of breathing.<b>NEW & NOTEWORTHY</b> The heterogeneity of diaphragm muscle (DIAm) activity in awake animals reflects real motor behavior diversity but makes assessments of eupneic breathing challenging. The present article uses an unsupervised machine learning model to identify eupneic breathing amidst a deluge of different DIAm electromyography (EMG) burst patterns in awake rats. This technique offers a scalable and reliable tool that improves efficiency of DIAm EMG analysis and minimizes potential sources of bias.</p>","PeriodicalId":16563,"journal":{"name":"Journal of neurophysiology","volume":null,"pages":null},"PeriodicalIF":2.1,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11427058/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141759204","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-01DOI: 10.1152/jn.00193.2023_COR
{"title":"Corrigendum for Vreven et al., volume 132, 2024, p. 226-239.","authors":"","doi":"10.1152/jn.00193.2023_COR","DOIUrl":"https://doi.org/10.1152/jn.00193.2023_COR","url":null,"abstract":"","PeriodicalId":16563,"journal":{"name":"Journal of neurophysiology","volume":null,"pages":null},"PeriodicalIF":2.1,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142108360","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-01Epub Date: 2024-06-26DOI: 10.1152/jn.00079.2024
Yi Wang, Juan Du, Youfang Hu, Sufen Zhang
Sensorimotor deficits following stroke remain a major cause of disability, but little is known about the specific pathological mechanisms. Exploring the pathological mechanisms and identifying potential therapeutic targets to promote functional rehabilitation after stroke are essential. CXCL10, also known as interferon-γ-inducible protein 10 (IP-10), plays an important role in multiple brain disorders by mediating synaptic plasticity, yet its role in stroke is still unclear. In this study, mice were subjected to photothrombotic (PT) stroke, and sensorimotor deficits were determined by the ladder walking tests, tape removal tests, and rotarod tests. The density of dendritic spines and synaptic plasticity was determined in Thy1-EGFP mice and evaluated by electrophysiology. We found that photothrombotic stroke induced sensorimotor deficits and upregulated the expression of CXCL10, whereas suppressing the expression of CXCL10 by adeno-associated virus (AAV) ameliorated sensorimotor deficits and increased the levels of synapse-related proteins, the density of dendritic spines, and synaptic strength. Furthermore, the cyclic GMP-AMP (cGAMP) synthase (cGAS)-stimulus of interferon genes (STING) pathway was activated by stroke and induced CXCL10 release, and cGAS or STING antagonists downregulated the levels of CXCL10 and improved synaptic plasticity after stroke. Collectively, our results indicate that cGAS-STING pathway activation promoted CXCL10 release and impaired synaptic plasticity during stroke recovery.NEW & NOTEWORTHY Chemokine-mediated inflammatory response plays a critical role in stroke. CXCL10 plays an important role in multiple brain disorders by mediating synaptic plasticity, yet its role in stroke recovery is still unclear. Herein, we identified a new mechanism that cyclic GMP-AMP (cGAMP) synthase (cGAS)-stimulus of interferon genes (STING) pathway activation promoted CXCL10 release and impaired synaptic plasticity during stroke recovery. Our findings highlight the potential therapeutic strategy of targeting the cGAS-STING pathway to treat stroke.
{"title":"CXCL10 impairs synaptic plasticity and was modulated by cGAS-STING pathway after stroke in mice.","authors":"Yi Wang, Juan Du, Youfang Hu, Sufen Zhang","doi":"10.1152/jn.00079.2024","DOIUrl":"10.1152/jn.00079.2024","url":null,"abstract":"<p><p>Sensorimotor deficits following stroke remain a major cause of disability, but little is known about the specific pathological mechanisms. Exploring the pathological mechanisms and identifying potential therapeutic targets to promote functional rehabilitation after stroke are essential. CXCL10, also known as interferon-γ-inducible protein 10 (IP-10), plays an important role in multiple brain disorders by mediating synaptic plasticity, yet its role in stroke is still unclear. In this study, mice were subjected to photothrombotic (PT) stroke, and sensorimotor deficits were determined by the ladder walking tests, tape removal tests, and rotarod tests. The density of dendritic spines and synaptic plasticity was determined in Thy1-EGFP mice and evaluated by electrophysiology. We found that photothrombotic stroke induced sensorimotor deficits and upregulated the expression of CXCL10, whereas suppressing the expression of CXCL10 by adeno-associated virus (AAV) ameliorated sensorimotor deficits and increased the levels of synapse-related proteins, the density of dendritic spines, and synaptic strength. Furthermore, the cyclic GMP-AMP (cGAMP) synthase (cGAS)-stimulus of interferon genes (STING) pathway was activated by stroke and induced CXCL10 release, and cGAS or STING antagonists downregulated the levels of CXCL10 and improved synaptic plasticity after stroke. Collectively, our results indicate that cGAS-STING pathway activation promoted CXCL10 release and impaired synaptic plasticity during stroke recovery.<b>NEW & NOTEWORTHY</b> Chemokine-mediated inflammatory response plays a critical role in stroke. CXCL10 plays an important role in multiple brain disorders by mediating synaptic plasticity, yet its role in stroke recovery is still unclear. Herein, we identified a new mechanism that cyclic GMP-AMP (cGAMP) synthase (cGAS)-stimulus of interferon genes (STING) pathway activation promoted CXCL10 release and impaired synaptic plasticity during stroke recovery. Our findings highlight the potential therapeutic strategy of targeting the cGAS-STING pathway to treat stroke.</p>","PeriodicalId":16563,"journal":{"name":"Journal of neurophysiology","volume":null,"pages":null},"PeriodicalIF":2.1,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141450729","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-01Epub Date: 2024-07-25DOI: 10.1152/jn.00164.2024
Zilong Wang, Jörn Diedrichsen, Karin Saltoun, Christopher Steele, Sheeba Rani Arnold-Anteraper, B T Thomas Yeo, Jeremy D Schmahmann, Danilo Bzdok
The human cerebellum is increasingly recognized to be involved in nonmotor and higher-order cognitive functions. Yet, its ties with the entire cerebral cortex have not been holistically studied in a whole brain exploration with a unified analytical framework. Here, we characterized dissociable cortical-cerebellar structural covariation patterns based on regional gray matter volume (GMV) across the brain in n = 38,527 UK Biobank participants. Our results invigorate previous observations in that important shares of cortical-cerebellar structural covariation are described as 1) a dissociation between the higher-level cognitive system and lower-level sensorimotor system and 2) an anticorrelation between the visual-attention system and advanced associative networks within the cerebellum. We also discovered a novel pattern of ipsilateral, rather than contralateral, cerebral-cerebellar associations. Furthermore, phenome-wide association assays revealed key phenotypes, including cognitive phenotypes, lifestyle, physical properties, and blood assays, associated with each decomposed covariation pattern, helping to understand their real-world implications. This systems neuroscience view paves the way for future studies to explore the implications of these structural covariations, potentially illuminating new pathways in our understanding of neurological and cognitive disorders.NEW & NOTEWORTHY Cerebellum's association with the entire cerebral cortex has not been holistically studied in a unified way. Here, we conjointly characterize the population-level cortical-cerebellar structural covariation patterns leveraging ∼40,000 UK Biobank participants whole brain structural scans and ∼1,000 phenotypes. We revitalize the previous hypothesis of an anticorrelation between the visual-attention system and advanced associative networks within the cerebellum. We also discovered a novel ipsilateral cerebral-cerebellar associations. Phenome-wide association (PheWAS) revealed real-world implications of the structural covariation patterns.
{"title":"Structural covariation between cerebellum and neocortex intrinsic structural covariation links cerebellum subregions to the cerebral cortex.","authors":"Zilong Wang, Jörn Diedrichsen, Karin Saltoun, Christopher Steele, Sheeba Rani Arnold-Anteraper, B T Thomas Yeo, Jeremy D Schmahmann, Danilo Bzdok","doi":"10.1152/jn.00164.2024","DOIUrl":"10.1152/jn.00164.2024","url":null,"abstract":"<p><p>The human cerebellum is increasingly recognized to be involved in nonmotor and higher-order cognitive functions. Yet, its ties with the entire cerebral cortex have not been holistically studied in a whole brain exploration with a unified analytical framework. Here, we characterized dissociable cortical-cerebellar structural covariation patterns based on regional gray matter volume (GMV) across the brain in <i>n</i> = 38,527 UK Biobank participants. Our results invigorate previous observations in that important shares of cortical-cerebellar structural covariation are described as <i>1</i>) a dissociation between the higher-level cognitive system and lower-level sensorimotor system and <i>2</i>) an anticorrelation between the visual-attention system and advanced associative networks within the cerebellum. We also discovered a novel pattern of ipsilateral, rather than contralateral, cerebral-cerebellar associations. Furthermore, phenome-wide association assays revealed key phenotypes, including cognitive phenotypes, lifestyle, physical properties, and blood assays, associated with each decomposed covariation pattern, helping to understand their real-world implications. This systems neuroscience view paves the way for future studies to explore the implications of these structural covariations, potentially illuminating new pathways in our understanding of neurological and cognitive disorders.<b>NEW & NOTEWORTHY</b> Cerebellum's association with the entire cerebral cortex has not been holistically studied in a unified way. Here, we conjointly characterize the population-level cortical-cerebellar structural covariation patterns leveraging ∼40,000 UK Biobank participants whole brain structural scans and ∼1,000 phenotypes. We revitalize the previous hypothesis of an anticorrelation between the visual-attention system and advanced associative networks within the cerebellum. We also discovered a novel ipsilateral cerebral-cerebellar associations. Phenome-wide association (PheWAS) revealed real-world implications of the structural covariation patterns.</p>","PeriodicalId":16563,"journal":{"name":"Journal of neurophysiology","volume":null,"pages":null},"PeriodicalIF":2.1,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11427046/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141759205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-01Epub Date: 2024-08-14DOI: 10.1152/jn.00277.2024
Natasha G Boyes, Stephen A Klassen, Sarah E Baker, Wayne T Nicholson, Michael J Joyner, J Kevin Shoemaker, Jacqueline K Limberg
Efferent muscle sympathetic nerve activity (MSNA) is under tonic baroreflex control. The arterial baroreflex exerts the strongest influence over medium-sized sympathetic action potential (AP) subpopulations in efferent MSNA recordings. Prior work from multiunit MSNA recordings has shown baroreflex loading selectively abolishes the sympathetic response to hypoxia. The purpose of the study was to examine baroreflex control over different-sized AP clusters and characterize the neural recruitment strategies of sympathetic AP subpopulations with baroreflex and combined baroreflex/chemoreflex (i.e., hypoxia) activation. We loaded the arterial baroreceptors [intravenous phenylephrine (PE)] alone and in combination with systemic hypoxia ([Formula: see text] 80%) in nine healthy young men. We extracted sympathetic APs using the wavelet-based methodology and quantified baroreflex gain for individual AP clusters. AP baroreflex threshold gain was measured as the slope of the linear relationship between AP probability versus diastolic blood pressure for 10 normalized clusters. Baroreflex loading with phenylephrine decreased MSNA and AP firing compared with baseline (all P < 0.05). However, the phenylephrine-mediated decrease in AP firing was lost with concurrent hypoxia (P = 0.384). Compared with baseline, baroreflex loading reduced medium-sized AP cluster baroreflex threshold slope (condition P = 0.005) and discharge probability (condition P < 0.0001); these reductions from baseline were maintained during simultaneous hypoxia (both P < 0.05). Present findings indicate a key modulatory role of the baroreceptors on medium-sized APs in blood pressure regulation that withstands competing signals from peripheral chemoreflex activation.NEW & NOTEWORTHY This study provides a novel understanding on baroreflex control of efferent sympathetic nervous system activity during competing stressors: baroreflex loading and peripheral chemoreflex activation. We show chemoreflex activation buffers baroreflex-mediated reductions in sympathetic nervous system activity. More importantly, baroreflex loading reduced baroreflex threshold gain of sympathetic action potential clusters and this reduction withstood chemoreflex activation. These data suggest the arterial baroreflex holds a primary regulatory role over medium-sized sympathetic neurons despite competing chemoreflex signals.
传出肌交感神经活动(MSNA)受强直性气压反射控制。在 MSNA 传出记录中,动脉气压反射对中等大小的交感神经动作电位亚群影响最大。之前的多单元 MSNA 记录显示,气压反射负荷会选择性地取消交感神经对缺氧的反应。本研究的目的是检查气压反射对不同大小 AP 簇的控制,并描述交感 AP 亚群在气压反射和联合气压反射/血流反射(即缺氧)激活下的神经招募策略。我们对 9 名健康的年轻男性单独或结合全身缺氧(SpO2 80%)加载动脉气压感受器(静脉注射苯肾上腺素)。我们使用基于小波的方法提取了交感神经 AP,并量化了单个 AP 簇的巴反射增益。AP 气压反射阈值增益是根据 10 个归一化簇的 AP 概率与舒张压之间线性关系的斜率来测量的。与基线相比,用苯肾上腺素加载巴反射会降低 MSNA 和 AP 发射(所有 P <0.05)。然而,在同时缺氧的情况下,苯肾上腺素介导的自律神经元发射降低的作用消失了(P = 0.384)。与基线相比,气压反射负荷降低了中型 AP 簇的气压反射阈值斜率(条件 P = 0.005)和放电概率(条件 P < 0.0001);这些与基线相比的降低在同时缺氧时保持不变(均 P < 0.05)。目前的研究结果表明,气压感受器对中型AP在血压调节中起着关键的调节作用,它能抵御来自外周化学反射激活的竞争信号。
{"title":"Interaction of simultaneous hypoxia and baroreflex loading on control of sympathetic action potential subpopulations.","authors":"Natasha G Boyes, Stephen A Klassen, Sarah E Baker, Wayne T Nicholson, Michael J Joyner, J Kevin Shoemaker, Jacqueline K Limberg","doi":"10.1152/jn.00277.2024","DOIUrl":"10.1152/jn.00277.2024","url":null,"abstract":"<p><p>Efferent muscle sympathetic nerve activity (MSNA) is under tonic baroreflex control. The arterial baroreflex exerts the strongest influence over medium-sized sympathetic action potential (AP) subpopulations in efferent MSNA recordings. Prior work from multiunit MSNA recordings has shown baroreflex loading selectively abolishes the sympathetic response to hypoxia. The purpose of the study was to examine baroreflex control over different-sized AP clusters and characterize the neural recruitment strategies of sympathetic AP subpopulations with baroreflex and combined baroreflex/chemoreflex (i.e., hypoxia) activation. We loaded the arterial baroreceptors [intravenous phenylephrine (PE)] alone and in combination with systemic hypoxia ([Formula: see text] 80%) in nine healthy young men. We extracted sympathetic APs using the wavelet-based methodology and quantified baroreflex gain for individual AP clusters. AP baroreflex threshold gain was measured as the slope of the linear relationship between AP probability versus diastolic blood pressure for 10 normalized clusters. Baroreflex loading with phenylephrine decreased MSNA and AP firing compared with baseline (all <i>P</i> < 0.05). However, the phenylephrine-mediated decrease in AP firing was lost with concurrent hypoxia (<i>P</i> = 0.384). Compared with baseline, baroreflex loading reduced medium-sized AP cluster baroreflex threshold slope (condition <i>P</i> = 0.005) and discharge probability (condition <i>P</i> < 0.0001); these reductions from baseline were maintained during simultaneous hypoxia (both <i>P</i> < 0.05). Present findings indicate a key modulatory role of the baroreceptors on medium-sized APs in blood pressure regulation that withstands competing signals from peripheral chemoreflex activation.<b>NEW & NOTEWORTHY</b> This study provides a novel understanding on baroreflex control of efferent sympathetic nervous system activity during competing stressors: baroreflex loading and peripheral chemoreflex activation. We show chemoreflex activation buffers baroreflex-mediated reductions in sympathetic nervous system activity. More importantly, baroreflex loading reduced baroreflex threshold gain of sympathetic action potential clusters and this reduction withstood chemoreflex activation. These data suggest the arterial baroreflex holds a primary regulatory role over medium-sized sympathetic neurons despite competing chemoreflex signals.</p>","PeriodicalId":16563,"journal":{"name":"Journal of neurophysiology","volume":null,"pages":null},"PeriodicalIF":2.1,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11427050/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141975910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}