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Auditory encoding of natural speech at subcortical and cortical levels is not indicative of cognitive decline. 在皮层下和皮层水平对自然语音进行听觉编码并不表明认知能力下降。
Pub Date : 2024-04-24 DOI: 10.1523/ENEURO.0545-23.2024
Elena Bolt, Nathalie Giroud
More and more patients worldwide are diagnosed with dementia, which emphasizes the urgent need for early detection markers. In this study, we built on the auditory hypersensitivity theory of a previous study-which postulated that responses to auditory input in the subcortex as well as cortex are enhanced in cognitive decline-, and examined auditory encoding of natural continuous speech at both neural levels for its indicative potential for cognitive decline. We recruited study participants aged 60 years and older, who were divided into two groups based on the Montreal Cognitive Assessment, one group with low scores (n = 19, participants with signs of cognitive decline), and a control group (n = 25). Participants completed an audiometric assessment and then we recorded their electroencephalography while they listened to an audiobook and click sounds. We derived Temporal Response Functions and evoked potentials from the data and examined response amplitudes for their potential to predict cognitive decline, controlling for age and hearing loss. Contrary to our expectations, no evidence of auditory hypersensitivity was observed in participants with signs of cognitive decline; response amplitudes were comparable in both cognitive groups. Moreover, the combination of response amplitudes showed no predictive value for cognitive decline. These results challenge the proposed hypothesis and emphasize the need for further research to identify reliable auditory markers for the early detection of cognitive decline.Significance statement Research on cognitive decline needs more studies uncovering markers for subtle neural changes in the pre-dementia stage. Neural markers for auditory processing have a potential that has not been widely explored in studies. Here, for the first time, we used natural, continuously spoken language to examine neural processing in two groups of older adults with and without cognitive decline. We quantified how well the brain tracks speech not only at the cortical but also at the subcortical level. In contrast to previous research suggesting that subcortical and cortical auditory responses are enhanced in cognitive decline, we found no group differences. We believe that this study represents an important contribution to the search for markers of cognitive health in old age.
全世界越来越多的患者被诊断出患有痴呆症,因此迫切需要早期检测标记物。在本研究中,我们以之前研究中的听觉超敏理论为基础--该理论推测认知能力下降时皮层下和皮层对听觉输入的反应都会增强--在两个神经水平上对自然连续语音的听觉编码进行了研究,以了解其对认知能力下降的指示潜力。我们招募了 60 岁及以上的参与者,根据蒙特利尔认知评估将他们分为两组,一组为低分组(n = 19,有认知衰退迹象的参与者),另一组为对照组(n = 25)。参试者完成听力评估后,我们记录了他们聆听有声读物和点击声时的脑电图。我们从这些数据中得出了时程反应函数和诱发电位,并检查了反应振幅,以确定其预测认知能力下降的潜力,同时对年龄和听力损失进行了控制。与我们的预期相反,在有认知能力下降迹象的参与者中没有观察到听觉过敏的证据;两个认知能力组的反应幅度相当。此外,反应振幅的组合对认知能力下降没有预测价值。这些结果对提出的假设提出了质疑,并强调了进一步研究的必要性,以确定早期检测认知能力下降的可靠听觉标记。听觉处理的神经标记具有潜力,但尚未在研究中得到广泛探索。在这里,我们首次使用自然、连续的口语来研究两组有认知功能衰退和没有认知功能衰退的老年人的神经处理过程。我们不仅量化了大脑皮层对语言的追踪能力,还量化了大脑皮层下对语言的追踪能力。以往的研究表明,认知能力下降时皮层下和皮层听觉反应都会增强,与此不同的是,我们没有发现任何群体差异。我们相信,这项研究是对寻找老年认知健康标志物的重要贡献。
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引用次数: 0
Loss of Midbrain Dopamine Neurons Does Not Alter GABAergic Inhibition Mediated by Parvalbumin-Expressing Interneurons in Mouse Primary Motor Cortex. 中脑多巴胺神经元的缺失不会改变小鼠初级运动皮层中由表达副斑蝥素的中间神经元介导的 GABA 能抑制作用
Pub Date : 2024-04-24 DOI: 10.1523/ENEURO.0010-24.2024
Suraj Cherian, Gabriel Simms, Liqiang Chen, Hong-Yuan Chu
The primary motor cortex (M1) integrates sensory and cognitive inputs to generate voluntary movement. Its functional impairments have been implicated in the pathophysiology of motor symptoms in Parkinson's disease (PD). Specifically, dopaminergic degeneration and basal ganglia dysfunction entrain M1 neurons into the abnormally synchronized bursting pattern of activity throughout the cortico-basal ganglia-thalamocortical network. However, how degeneration of the midbrain dopaminergic neurons affects the anatomy, microcircuit connectivity, and function of the M1 network remains poorly understood. The present study examined whether and how loss of dopamine (DA) affects the morphology, cellular excitability, and synaptic physiology of layer 5 parvalbumin-expressing (PV+) cells in the M1 of mice of both sexes. Here we reported that loss of midbrain dopaminergic neurons does not alter the number, morphology, and physiology of layer 5 PV+ cells in M1. Moreover, we demonstrated that the number of perisomatic PV+ puncta of M1 pyramidal neurons as well as their functional innervation of cortical pyramidal neurons were not altered following the loss of DA. Together, the present study documents an intact GABAergic inhibitory network formed by PV+ cells following the loss of midbrain dopaminergic neurons.Significance statement The pyramidal neurons in the motor cortex manifests highly synchronized bursting pattern of activity in parkinsonian state, but the underlying circuit mechanisms are poorly understood. One can easily consider PV interneurons-mediated inhibitory network as a potential microcircuitry mechanism. However, whether loss of DA affects cortical PV+ network remains unknown. The present work documented that loss of DA in parkinsonian state does not alter the number, morphology, cellular excitability, and synaptic physiology of PV+ cells in M1. An intact robust PV+ perisomatic inhibition of pyramidal neurons provides a microcircuit substrate for thalamic afferents to entrain cortical neurons to pathological oscillations throughout the cortico-basal ganglia-thalamocortical network in parkinsonian state.
初级运动皮层(M1)整合了感觉和认知输入,从而产生自主运动。其功能障碍与帕金森病(PD)运动症状的病理生理学有关。具体来说,多巴胺能退化和基底节功能障碍会将 M1 神经元纳入整个皮质-基底节-丘脑网络的异常同步突发性活动模式。然而,人们对中脑多巴胺能神经元的退化如何影响M1网络的解剖结构、微电路连接和功能仍知之甚少。本研究考察了多巴胺(DA)的缺失是否以及如何影响雌雄小鼠 M1 中第 5 层副发光素表达(PV+)细胞的形态、细胞兴奋性和突触生理学。在这里,我们报告了中脑多巴胺能神经元的缺失不会改变 M1 中第 5 层 PV+ 细胞的数量、形态和生理机能。此外,我们还证明,DA缺失后,M1锥体神经元周围PV+点的数量以及它们对皮层锥体神经元的功能支配也没有改变。综上所述,本研究记录了中脑多巴胺能神经元缺失后,PV+细胞形成的完整的GABA能抑制网络。我们很容易将 PV 中间神经元介导的抑制网络视为一种潜在的微电路机制。然而,DA的缺失是否会影响皮质PV+网络仍是未知数。本研究发现,帕金森病患者体内 DA 的缺失不会改变 M1 中 PV+ 细胞的数量、形态、细胞兴奋性和突触生理。在帕金森状态下,PV+细胞对锥体神经元完整而强大的周围抑制作用为丘脑传入提供了一个微电路基底,使皮质神经元与整个皮质-基底节-丘脑网络的病理振荡相联系。
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引用次数: 0
Increased retinal metabolism induced by flicker in the isolated mouse retina. 小鼠离体视网膜闪烁引起的视网膜新陈代谢增加
Pub Date : 2024-04-19 DOI: 10.1523/ENEURO.0509-23.2024
R. Linsenmeier, Andrey V Dmitriev
Both the retina and brain exhibit neurovascular coupling, increased blood flow during increased neural activity. In the retina increased blood flow can be evoked by flickering light, but the magnitude of the metabolic change that underlies this not known. Local changes in oxygen consumption (QO2) are difficult to measure in vivo when both supply and demand are changing. Here we isolated the C57BL/6J mouse retina and supplied it with oxygen from both sides of the tissue. Microelectrode recordings of PO2 were made in darkness and during 20 sec of high scotopic flickering light at 1 Hz. Flicker led to a PO2 increase in the outer retina and a decrease in the inner retina, indicating that outer retinal QO2 (QOR) decreased and inner retinal QO2 (QIR) increased. A four-layer oxygen diffusion model was fitted to PO2 values obtained in darkness and at the end of flicker to determine the values of QOR and QIR QOR in flicker was 76 ± 14% (mean and SD, n=10) of QOR in darkness. The increase in QIR was smaller, 6.4 ± 5.0%. These metabolic changes are likely smaller than the maximum changes, because with no regeneration of pigment in the isolated retina, we limited the illumination. Further modeling indicated that at high illumination, QIR could increase by up to 45%, which is comparable to the magnitude of flow changes. This suggests that the blood flow increase is at least roughly matched to the increased metabolic demands of activity in the retina.Significance Statement Neural activity increases blood flow in the inner half of the retina as in the brain, but the underlying change in metabolism has been difficult to measure. Here we have measured the increase in metabolism (oxygen consumption, QO2) in mouse retina during flicker. Flicker at high scotopic illumination increased inner retinal QO2 by less than 10% compared to darkness, considerably smaller in magnitude than the well-known light-evoked decrease in QO2 in the outer retina under the same conditions. In the brain, the blood flow increase is larger than is required by the increase in QO2, but in the retina the increase in metabolism and blood flow appear to be more closely matched.
视网膜和大脑都表现出神经血管耦合,即神经活动增加时血流量增加。在视网膜中,闪烁的光线可诱发血流量增加,但导致这种情况的新陈代谢变化的程度尚不清楚。当供需双方都发生变化时,很难在体内测量局部耗氧量(QO2)的变化。在这里,我们分离了 C57BL/6J 小鼠视网膜,并从组织两侧向其供氧。在黑暗中和 20 秒钟的 1 Hz 高闪烁光照期间,对 PO2 进行了微电极记录。闪烁导致视网膜外层的 PO2 上升,视网膜内层的 PO2 下降,表明视网膜外层的 QO2 (QOR) 下降,视网膜内层的 QO2 (QIR) 上升。将四层氧扩散模型拟合到黑暗中和闪烁结束时获得的 PO2 值,以确定 QOR 和 QIR 的值。QIR 的增幅较小,为 6.4 ± 5.0%。这些代谢变化可能小于最大变化,因为在离体视网膜中没有色素再生,我们限制了光照。进一步的建模表明,在高照度下,QIR 最多可增加 45%,这与血流变化的幅度相当。这表明,血流量的增加至少与视网膜活动对新陈代谢需求的增加大致匹配。 意义声明 神经活动会增加视网膜内半部分的血流量,就像在大脑中一样,但新陈代谢的基本变化一直难以测量。在这里,我们测量了闪烁时小鼠视网膜新陈代谢(耗氧量,QO2)的增加。与黑暗相比,高光照度下的闪烁会使视网膜内层的 QO2 增加不到 10%,其幅度大大小于众所周知的在相同条件下光引起的视网膜外层 QO2 的减少。在大脑中,血流量的增加大于 QO2 的增加所需的血流量,但在视网膜中,新陈代谢的增加和血流量的增加似乎更加匹配。
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引用次数: 0
Modulation of neural spiking in motor cortex-cerebellar networks during sleep spindles. 睡眠纺锤期运动皮层-小脑网络的神经尖峰调节
Pub Date : 2024-04-19 DOI: 10.1523/ENEURO.0150-23.2024
Pierson Fleischer, Aamir Abbasi, T. Gulati
Sleep spindles appear to play an important role in learning new motor skills. Motor skill learning engages several regions in the brain with two important areas being the motor cortex (M1) and the cerebellum. However, the neurophysiological processes in these areas during sleep, especially how spindle oscillations affect local and cross-region spiking, are not fully understood. We recorded activity from the M1 and cerebellar cortex in 8 rats during spontaneous activity to investigate how sleep spindles in these regions are related to local spiking as well as cross-region spiking. We found that M1 firing was significantly changed during both M1 and cerebellum spindles and this spiking occurred at a preferred phase of the spindle. On average, M1 and cerebellum neurons showed most spiking at the M1 or cerebellum spindle peaks. These neurons also developed a preferential phase-locking to local or cross-area spindles with the greatest phase-locking value at spindle peaks; however, this preferential phase-locking wasn't significant for cerebellar neurons when compared to cerebellum spindles. Additionally, we found the percentage of task-modulated cells in the M1 and cerebellum that fired with non-uniform spike-phase distribution during M1/ cerebellum spindle peaks were greater in the rats that learned a reach-to-grasp motor task robustly. Finally, we found that spindle-band LFP coherence (for M1 and cerebellum LFPs) showed a positive correlation with success rate in the motor task. These findings support the idea that sleep spindles in both the M1 and cerebellum recruit neurons that participate in the awake task to support motor memory consolidation.Significance Statement Neural processing during sleep spindles is linked to memory consolidation. However, little is known about sleep activity in the cerebellum and whether cerebellum spindles can affect spiking activity in local or distant areas. We report the effect of sleep spindles on neuron activity in the M1 and cerebellum-specifically their firing rate and phase-locking to spindle oscillations. Our results indicate that awake practice neuronal activity is tempered during local M1 and cerebellum spindles, and during cross-region spindles, which may support motor skill learning. We describe spiking dynamics in motor networks spindle oscillations that may aid in the learning of skills. Our results support the sleep reactivation hypothesis and suggest that awake M1 activity may be reactivated during cerebellum spindles.
睡眠棘似乎在学习新的运动技能中扮演着重要角色。运动技能学习涉及大脑的多个区域,其中两个重要区域是运动皮层(M1)和小脑。然而,这些区域在睡眠时的神经生理过程,尤其是纺锤体振荡如何影响局部和跨区域的尖峰脉冲,尚未完全清楚。我们记录了 8 只大鼠自发活动时 M1 和小脑皮层的活动,以研究这些区域的睡眠纺锤与局部尖峰和跨区域尖峰的关系。我们发现,在 M1 和小脑纺锤运动期间,M1 的发射都发生了显著变化,而且这种尖峰现象发生在纺锤运动的首选阶段。平均而言,M1 和小脑神经元在 M1 或小脑纺锤峰出现最多尖峰脉冲。这些神经元还对局部或跨区纺锤体产生了偏好锁相,在纺锤体峰值处锁相值最大;然而,与小脑纺锤体相比,小脑神经元的这种偏好锁相并不显著。此外,我们还发现,在M1/小脑纺锤峰期间以不均匀尖峰相位分布发射的M1和小脑任务调制细胞的比例,在强力学习 "伸手抓握 "运动任务的大鼠中更高。最后,我们发现主轴带 LFP 相干性(M1 和小脑 LFP)与运动任务的成功率呈正相关。这些发现支持了这样一种观点,即M1和小脑的睡眠纺锤招募参与清醒任务的神经元,以支持运动记忆的巩固。然而,人们对小脑的睡眠活动以及小脑棘是否会影响局部或远处区域的尖峰活动知之甚少。我们报告了睡眠纺锤对 M1 和小脑神经元活动的影响,特别是它们的发射率和与纺锤振荡的锁相。我们的研究结果表明,在局部 M1 和小脑纺锤运动以及跨区域纺锤运动中,清醒练习神经元的活动会受到抑制,这可能有助于运动技能的学习。我们描述了可能有助于技能学习的运动网络纺锤体振荡中的尖峰动态。我们的研究结果支持睡眠再激活假说,并表明在小脑纺锤运动期间,清醒的 M1 活动可能会被重新激活。
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引用次数: 0
Inhibition of Neuron Restrictive Silencing Factor (REST/NRSF) Chromatin Binding Attenuates Epileptogenesis. 抑制神经元限制性沉默因子(REST/NRSF)染色质结合可减轻癫痫发生。
Pub Date : 2024-04-19 DOI: 10.1523/ENEURO.0006-24.2024
Alicia M Hall, Noriko Kamei, M. Shao, Hyun-Seung Mun, Kevin Chen, Yuncai Chen, T. Baram
The mechanisms by which brain insults lead to subsequent epilepsy remain unclear. Insults including trauma, stroke, infections and long seizures (status epilepticus; SE) increase the nuclear expression and chromatin binding of the neuronal restrictive silencing factor / RE-1 silencing transcription factor (NRSF/REST). REST/NRSF orchestrates major disruption of the expression of key neuronal genes, including ion channels and neurotransmitter receptors, potentially contributing to epileptogenesis. Accordingly, transient interference with REST/NRSF chromatin binding after an epilepsy-provoking SE suppressed spontaneous seizures for the 12- day duration of a prior study. However, whether the onset of epileptogenesis was suppressed or only delayed has remained unresolved. The current experiments determined if transient interference with REST/NRSF chromatin binding prevented epileptogenesis enduringly, or, alternatively, slowed epilepsy onset.Epileptogenesis was elicited in adult male rats via systemic kainic acid-induced SE (KA-SE). We then determined if decoy, NRSF-binding-motif oligodeoxynucleotides (NRSE-ODNs), given twice following KA-SE (a) prevented REST/NRSF binding to chromatin, using chromatin immunoprecipitation; (b) prevented the onset of spontaneous seizures, measured with chronic digital video-EEG.Blocking NRSF function transiently after KA-SE significantly lengthened the latent period to a first spontaneous seizure. Whereas this intervention did not influence the duration and severity of spontaneous seizures, total seizure number and seizure burden were lower in the NRSE- ODN compared with scrambled-ODN cohorts.Transient interference with REST/NRSF function after KA-SE delays and moderately attenuates insult-related hippocampal epilepsy, but does not abolish it. Thus, the anticonvulsant and antiepileptogenic actions of NRSF are but one of the multifactorial mechanisms generating epilepsy in the adult brain.Significance Statement The mechanisms by which brain insults can lead to subsequent epilepsy remain unclear. Insults may influence neuronal functions by enduringly changing their gene expression programs, often via changes in master regulators such as transcription factors (TFs). The TF REST/NRSF is activated by insults, alters gene expression selectively, and thus promotes aberrant neuronal function and connectivity. Previously, blocking REST/NRSF function transiently in developing brain prevented cognitive problems that accompany SE-induced epilepsy. Here, blocking REST/NRSF DNA binding transiently following SE in adult rats delayed and attenuated epileptogenesis, but did not abolish it.
脑损伤导致继发性癫痫的机制仍不清楚。包括创伤、中风、感染和长时间癫痫发作(癫痫状态;SE)在内的各种脑损伤会增加神经元限制性沉默因子/RE-1沉默转录因子(NRSF/REST)的核表达和染色质结合。REST/NRSF会对包括离子通道和神经递质受体在内的关键神经元基因的表达造成严重破坏,从而可能导致癫痫发生。因此,在先前的一项研究中,癫痫诱发 SE 后对 REST/NRSF 染色质结合的短暂干扰抑制了持续 12 天的自发性癫痫发作。然而,究竟是抑制了癫痫的发生,还是仅仅延迟了癫痫的发生,这个问题仍未解决。目前的实验确定了瞬时干扰 REST/NRSF 染色质结合是否能持久阻止癫痫发生,或者是否能延缓癫痫发生。然后,我们确定了在 KA-SE 后给予两次诱饵 NRSF 结合型寡脱氧核苷酸(NRSE-ODNs)是否会(a)阻止 REST/NRSF 与染色质结合(使用染色质免疫沉淀法);(b)阻止自发性癫痫发作(使用慢性数字视频脑电图测量)。虽然这种干预并不影响自发性癫痫发作的持续时间和严重程度,但与加扰-ODN组群相比,NRSE- ODN组群的总发作次数和发作负担较低。因此,NRSF 的抗惊厥和抗致痫作用只是成人大脑癫痫产生的多因素机制之一。损伤可能通过持久改变基因表达程序来影响神经元功能,通常是通过改变转录因子(TFs)等主调控因子来实现。转录因子 REST/NRSF 会被损伤激活,选择性地改变基因表达,从而促进异常的神经元功能和连接。此前,在发育中的大脑中短暂阻断 REST/NRSF 的功能可预防 SE 诱发的癫痫所伴随的认知问题。在这里,在成年大鼠发生 SE 后瞬时阻断 REST/NRSF DNA 结合可延缓和减轻癫痫的发生,但并不能消除癫痫。
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引用次数: 0
Modulatory effects on laminar neural activity induced by near-infrared light stimulation with a continuous waveform to the mouse inferior colliculus in vivo. 用连续波形的近红外光刺激小鼠下丘对体内层状神经活动的调节作用。
Pub Date : 2024-04-16 DOI: 10.1523/ENEURO.0521-23.2024
Hiromu Sato, Futoshi Sugimoto, Takahiro Yoshikawa, Takashi Tateno
Infrared neural stimulation (INS) is a promising area of interest for the clinical application of a neuromodulation method. This is in part because of its low invasiveness, whereby INS modulates the activity of neural tissue mainly through temperature changes. Additionally, INS may provide localized brain stimulation with less tissue damage. The inferior colliculus (IC) is a crucial auditory relay nuclei, and a potential target for clinical application of INS to treat auditory diseases and develop artificial hearing devices. Here, using continuous INS with low to high power density, we demonstrate laminar modulation of neural activity in the mouse IC in the presence and absence of sound. We investigated stimulation parameters of INS to effectively modulate neural activity in a facilitatory or inhibitory manner. A mathematical model of INS-driven brain tissue was first simulated, temperature distributions were numerically estimated, and stimulus parameters were selected from the simulation results. Subsequently, INS was administered to the IC of anesthetized mice, and the modulation effect on neural activity was measured using an electrophysiological approach. We found that the modulatory effect of INS on spontaneous neural activity was bidirectional between facilitatory and inhibitory effects. The modulatory effect on sound-evoked responses produced only an inhibitory effect to all examined stimulus intensities. Thus, this study provides important physiological evidence on the response properties of IC neurons to INS. Overall, INS can be used for the development of new therapies for neurological diseases and functional support devices for auditory central processing.Significance statement Using continuous infrared neural stimulation (INS) of low to high power density, we sought to examine laminar modulation of neural activity in the mouse inferior colliculus (IC) in the presence and absence of sound. We found that the modulatory effect of INS on spontaneous neural activity was bidirectional between facilitatory and inhibitory effects. Additionally, the modulatory effect on sound-evoked responses produced only an inhibitory effect at all examined stimulus intensities. Thus, this study provides important physiological evidence on the response properties of IC neurons to INS. Moreover, INS can be used for the development of new therapies for neurological diseases and functional support devices for auditory central processing.
红外线神经刺激(INS)是神经调控方法临床应用的一个前景广阔的领域。这部分是因为它的低侵入性,INS 主要通过温度变化来调节神经组织的活动。此外,INS 还可以在对组织损伤较小的情况下对大脑进行局部刺激。下丘(IC)是重要的听觉中继核,也是 INS 临床应用于治疗听觉疾病和开发人工听力设备的潜在目标。在这里,我们使用低功率密度到高功率密度的连续 INS,证明了在有声和无声状态下小鼠 IC 神经活动的层状调制。我们研究了 INS 的刺激参数,以便以促进或抑制的方式有效调节神经活动。首先模拟 INS 驱动的脑组织数学模型,对温度分布进行数值估计,并从模拟结果中选择刺激参数。随后,在麻醉小鼠的集成电路中注射 INS,并使用电生理学方法测量其对神经活动的调节作用。我们发现 INS 对自发神经活动的调节作用是双向的,既有促进作用,也有抑制作用。对声音诱发反应的调节作用只对所有考察的刺激强度产生抑制作用。因此,这项研究为 IC 神经元对 INS 的反应特性提供了重要的生理证据。总之,INS 可用于开发神经系统疾病的新疗法和听觉中枢处理的功能支持设备。意义声明 我们使用低功率密度到高功率密度的连续红外神经刺激(INS),试图研究在有声音和无声的情况下小鼠下丘(IC)神经活动的层状调节。我们发现,INS 对自发神经活动的调节作用是双向的,既有促进作用,也有抑制作用。此外,对声音诱发反应的调节作用在所有考察的刺激强度下都只产生抑制作用。因此,这项研究为 IC 神经元对 INS 的反应特性提供了重要的生理证据。此外,INS 还可用于开发神经系统疾病的新疗法和听觉中枢处理的功能支持设备。
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引用次数: 0
Electrophysiological properties of proprioception-related neurons in the intermediate thoracolumbar spinal cord. 中间胸腰脊髓本体感觉相关神经元的电生理特性
Pub Date : 2024-04-16 DOI: 10.1523/ENEURO.0331-23.2024
Felipe Espinosa, Iliodora V. Pop, H. Lai
Proprioception, the sense of limb and body position, is required to produce accurate and precise movements. Proprioceptive sensory neurons transmit muscle length and tension information to the spinal cord. The function of excitatory neurons in the intermediate spinal cord, which receive this proprioceptive information, remains poorly understood. Using genetic labeling strategies and patch clamp techniques in acute spinal cord preparations in mice, we set out to uncover how two sets of spinal neurons, Clarke's column (CC) and Atoh1-lineage neurons, respond to electrical activity and how their inputs are organized. Both sets of neurons are located in close proximity in lamina V-VII of the thoracolumbar spinal cord and have been described to receive proprioceptive signals. We find that a majority of CC neurons have a tonic firing-type and express a distinctive hyperpolarization-activated current (Ih). Atoh1-lineage neurons, which cluster into two spatially distinct populations, are mostly a fading firing-type and display similar electrophysiological properties to each other, possibly due to their common developmental lineage. Finally, we find that CC neurons respond to stimulation of lumbar dorsal roots, consistent with prior knowledge that CC neurons receive hindlimb proprioceptive information. In contrast, using a combination of electrical stimulation, optogenetic stimulation, and transsynaptic rabies virus tracing, we found that Atoh1-lineage neurons receive heterogeneous, predominantly local thoracic inputs that include Parvalbumin-lineage sensory afferents and local interneuron presynaptic inputs. Altogether, we find that CC and Atoh1-lineage neurons have distinct membrane properties and sensory input organization, representing different subcircuit modes of proprioceptive information processing.Significance Statement How excitatory spinal cord neurons in the intermediate spinal cord integrate and relay proprioceptive sensory information is not well understood. Our investigation focuses on two sets of spinal neurons that receive proprioceptive information, but whose electrophysiological response properties have not been previously described. We characterize both their passive and active electrophysiological properties in addition to their input connectivity. We identify unique electrophysiological signatures of each population as well as features of their input organization. We find that a hyperpolarization-activated current distinguishes Clarke's column neurons and that Atoh1-lineage neurons receive predominantly local inputs. These experiments lay the foundation for future endeavors aimed at understanding the mechanisms by which proprioceptive information is integrated and relayed through these neurons.
要做出准确无误的动作,就必须要有肢体和身体位置的感觉。本体感觉神经元向脊髓传递肌肉长度和张力信息。中间脊髓的兴奋神经元接收本体感觉信息,但其功能仍不甚明了。利用基因标记策略和小鼠急性脊髓制备中的膜片钳技术,我们试图揭示两组脊髓神经元(克拉克氏柱(CC)神经元和 Atoh1 系神经元)如何对电活动做出反应,以及它们的输入是如何组织的。这两组神经元紧邻胸腰椎脊髓的 V-VII 层,据描述它们都能接收本体感觉信号。我们发现,大多数 CC 神经元具有强直性发射型,并表达一种独特的超极化激活电流(Ih)。Atoh1系神经元聚集成两个空间上不同的群体,它们大多属于消退发射型,并显示出彼此相似的电生理特性,这可能是由于它们具有共同的发育谱系。最后,我们发现 CC 神经元对腰背根的刺激有反应,这与之前 CC 神经元接收后肢本体感觉信息的知识一致。与此相反,利用电刺激、光遗传刺激和经突触狂犬病毒追踪相结合的方法,我们发现 Atoh1 系神经元接收异质的、主要是局部胸廓输入的信息,其中包括 Parvalbumin 系感觉传入和局部中间神经元突触前输入。总之,我们发现 CC 和 Atoh1 系神经元具有不同的膜特性和感觉输入组织,代表了本体感觉信息处理的不同子回路模式。我们的研究重点是两组脊髓神经元,它们接收本体感觉信息,但其电生理反应特性以前从未描述过。除了输入连接外,我们还描述了它们的被动和主动电生理特性。我们确定了每个群体的独特电生理特征及其输入组织特征。我们发现,超极化激活电流可将克拉克柱神经元区分开来,而 Atoh1 系神经元主要接受局部输入。这些实验为今后了解本体感觉信息通过这些神经元进行整合和传递的机制奠定了基础。
{"title":"Electrophysiological properties of proprioception-related neurons in the intermediate thoracolumbar spinal cord.","authors":"Felipe Espinosa, Iliodora V. Pop, H. Lai","doi":"10.1523/ENEURO.0331-23.2024","DOIUrl":"https://doi.org/10.1523/ENEURO.0331-23.2024","url":null,"abstract":"Proprioception, the sense of limb and body position, is required to produce accurate and precise movements. Proprioceptive sensory neurons transmit muscle length and tension information to the spinal cord. The function of excitatory neurons in the intermediate spinal cord, which receive this proprioceptive information, remains poorly understood. Using genetic labeling strategies and patch clamp techniques in acute spinal cord preparations in mice, we set out to uncover how two sets of spinal neurons, Clarke's column (CC) and Atoh1-lineage neurons, respond to electrical activity and how their inputs are organized. Both sets of neurons are located in close proximity in lamina V-VII of the thoracolumbar spinal cord and have been described to receive proprioceptive signals. We find that a majority of CC neurons have a tonic firing-type and express a distinctive hyperpolarization-activated current (Ih). Atoh1-lineage neurons, which cluster into two spatially distinct populations, are mostly a fading firing-type and display similar electrophysiological properties to each other, possibly due to their common developmental lineage. Finally, we find that CC neurons respond to stimulation of lumbar dorsal roots, consistent with prior knowledge that CC neurons receive hindlimb proprioceptive information. In contrast, using a combination of electrical stimulation, optogenetic stimulation, and transsynaptic rabies virus tracing, we found that Atoh1-lineage neurons receive heterogeneous, predominantly local thoracic inputs that include Parvalbumin-lineage sensory afferents and local interneuron presynaptic inputs. Altogether, we find that CC and Atoh1-lineage neurons have distinct membrane properties and sensory input organization, representing different subcircuit modes of proprioceptive information processing.Significance Statement How excitatory spinal cord neurons in the intermediate spinal cord integrate and relay proprioceptive sensory information is not well understood. Our investigation focuses on two sets of spinal neurons that receive proprioceptive information, but whose electrophysiological response properties have not been previously described. We characterize both their passive and active electrophysiological properties in addition to their input connectivity. We identify unique electrophysiological signatures of each population as well as features of their input organization. We find that a hyperpolarization-activated current distinguishes Clarke's column neurons and that Atoh1-lineage neurons receive predominantly local inputs. These experiments lay the foundation for future endeavors aimed at understanding the mechanisms by which proprioceptive information is integrated and relayed through these neurons.","PeriodicalId":506486,"journal":{"name":"eneuro","volume":"36 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140695814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Topography and ensemble activity in auditory cortex of a mouse model of Fragile-X-Syndrome. 脆性-X-综合征小鼠模型听觉皮层的拓扑和集合活动。
Pub Date : 2024-04-16 DOI: 10.1523/ENEURO.0396-23.2024
Simon L. Wadle, Tamara C Ritter, Tatjana T X Wadle, J. J. Hirtz
Autism spectrum disorder (ASD) is often associated with social communication impairments and specific sound processing deficits, for example problems in following speech in noisy environments. To investigate underlying neuronal processing defects located in the auditory neocortex (AC), we performed two-photon Ca2+ imaging in FMR1 (Fragile X Messenger Ribonucleoprotein 1) knockout (KO) mice, a model for Fragile-X-Syndrome (FXS), the most common cause of hereditary ASD in humans. For primary AC (A1) and the anterior auditory field (AAF), topographic frequency representation was less ordered compared to control animals. We additionally analyzed ensemble AC activity in response to various sounds and found subfield-specific differences. In A1, ensemble correlations were lower in general, while in secondary AC (A2), correlations were higher in response to complex sounds, yet not to pure tones (PT). Furthermore, sound specificity of ensemble activity was decreased in AAF. Repeating these experiments one week later revealed no major differences regarding representational drift. Nevertheless, we found subfield- and genotype-specific changes in ensemble correlation values between the two times points, hinting at alterations in network stability in FMR1 KO mice. These detailed insights into AC networks activity and topography in FMR1 KO mice add to the understanding of auditory processing defects in FXS.Significance statement Communicative challenges often observed in people with autism spectrum disorder might be due to defects in cortical brain circuits responsible for sound analysis. To investigate these in detail, we used a mouse model of Fragile-X-Syndrome, which often is associated with autism spectrum disorder in humans. We found several alterations compared to control animals, including a less well-ordered topography of frequency analysis in auditory cortex. Furthermore, neuronal population activity patterns in response to various sounds were altered. This was also highly dependent on whether pure tones or complex sounds were presented. These data help to understand the causes of sound processing defects in Fragile-X-Syndrome.
自闭症谱系障碍(ASD)通常与社会交流障碍和特定的声音处理缺陷有关,例如在嘈杂环境中的跟读问题。为了研究位于听觉新皮层(AC)的潜在神经元处理缺陷,我们对脆性X信使核糖核蛋白1(FMR1)基因敲除(KO)小鼠进行了双光子Ca2+成像。与对照组动物相比,初级听觉交流(A1)和前听觉区域(AAF)的地形频率表征较无序。此外,我们还分析了对各种声音做出反应的集合 AC 活动,并发现了特定子场的差异。在 A1 中,合奏相关性一般较低,而在次级 AC(A2)中,对复杂声音的相关性较高,但对纯音(PT)的相关性则不高。此外,在 AAF 中,合奏活动的声音特异性降低了。一周后重复这些实验,发现在表象漂移方面没有重大差异。然而,我们发现在两个时间点之间,集合相关值发生了亚场和基因型特异性变化,这表明 FMR1 KO 小鼠的网络稳定性发生了改变。这些对 FMR1 KO 小鼠交流网络活动和拓扑结构的详细了解,加深了人们对 FXS 听觉处理缺陷的理解。为了详细研究这些问题,我们使用了一种脆性 X-Syndrome (脆性 X-Syndrome 常与人类自闭症谱系障碍相关)小鼠模型。与对照组动物相比,我们发现了一些变化,包括听觉皮层中频率分析拓扑结构的有序性降低。此外,对各种声音做出反应的神经元群活动模式也发生了改变。这也在很大程度上取决于呈现的是纯音还是复杂的声音。这些数据有助于了解脆性X综合征声音处理缺陷的原因。
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引用次数: 0
Distinct hippocampal oscillation dynamics in trace eye-blink conditioning task for retrieval and consolidation of associations. 跟踪眨眼条件反射任务中海马振荡动态的不同之处在于联想的检索和巩固。
Pub Date : 2024-04-16 DOI: 10.1523/ENEURO.0030-23.2024
Kayeon Kim, M. Nokia, Satu Palva
Trace eyeblink conditioning (TEBC) has been widely used to study associative learning in both animals and humans. In this paradigm, conditioned responses (CRs) to conditioned stimuli (CS) serve as a measure for retrieving learned associations between the CS and the unconditioned stimuli (US) within a trial. Memory consolidation i.e. learning over time, can be quantified as an increase in the proportion of CRs across training sessions. However, how hippocampal oscillations differentiate between successful memory retrieval within a session and consolidation across TEBC training sessions remains unknown. To address this question, we recorded local-field potentials (LFPs) from the rat dorsal hippocampus during TEBC and investigated hippocampal oscillation dynamics associated with these two functions. We show that transient broadband responses to the CS were correlated with memory consolidation, as indexed by an increase in CRs across TEBC sessions. In contrast, induced alpha (8-10 Hz) and beta (16-20 Hz) band responses were correlated with the successful retrieval of the CS-US association within a session, as indexed by the difference in trials with and without CR.Significance statement Trace eyeblink conditioning is widely used to study the neural basis of learning. How brain oscillatory signatures for instantaneous retrieval of associations differ from those reflecting long-term memory consolidation is not well understood. We recorded local-field potentials from the rat hippocampus during conditioning to dissociate oscillation dynamics associated with these functions. We show that a transient, early, broadband response is correlated with memory consolidation (increase in conditioned responses across training sessions) whereas long-latency sustained alpha and gamma oscillations are associated with the performance within a given trial in a session.
痕迹眼动条件反射(TEBC)被广泛用于研究动物和人类的联想学习。在这一范例中,对条件刺激(CS)的条件反应(CRs)是在一次试验中检索 CS 与非条件刺激(US)之间已学关联的一种测量方法。记忆的巩固,即随着时间推移的学习,可以量化为各次训练中条件反射比例的增加。然而,海马振荡如何区分一次训练中成功的记忆检索和跨 TEBC 训练的记忆巩固仍是一个未知数。为了解决这个问题,我们记录了大鼠背侧海马在 TEBC 期间的局域场电位(LFPs),并研究了与这两种功能相关的海马振荡动态。我们的研究表明,对 CS 的瞬时宽带反应与记忆巩固相关,这体现在 CRs 在 TEBC 过程中的增加。与此相反,诱导的阿尔法(8-10赫兹)和贝塔(16-20赫兹)波段反应与在一个疗程内成功检索CS-US关联相关,以有CR和无CR试验的差异为指标。瞬时检索联想的大脑振荡特征与反映长期记忆巩固的大脑振荡特征有何不同,目前尚不十分清楚。我们记录了大鼠海马在条件反射过程中的局部场电位,以区分与这些功能相关的振荡动态。我们的研究表明,瞬时、早期、宽带反应与记忆巩固相关(条件反应在不同训练过程中的增加),而长周期持续的阿尔法和伽马振荡则与训练过程中特定试验的表现相关。
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引用次数: 0
Resting state networks of awake adolescent and adult squirrel monkeys using ultra-high field (9.4T) functional magnetic resonance imaging. 利用超高场(9.4T)功能磁共振成像技术研究清醒的青少年和成年松鼠猴的静息状态网络。
Pub Date : 2024-04-16 DOI: 10.1523/ENEURO.0173-23.2024
Walid Yassine, Fernando B de Moura, Sarah L. Withey, Lei Cao, Brian D. Kangas, Jack Bergman, S. Kohut
Resting state networks (RSNs) are increasingly forwarded as candidate biomarkers for neuropsychiatric disorders. Such biomarkers may provide objective measures for evaluating novel therapeutic interventions in nonhuman primates often used in translational neuroimaging research. This study aimed to characterize the RSNs of awake squirrel monkeys and compare the characteristics of those networks in adolescent and adult subjects. Twenty-seven squirrel monkeys (n=12 adolescents [6 male/6 female] ∼2.5 years and n=15 adults [7 male/8 female] ∼9.5 years) were gradually acclimated to awake scanning procedures; whole-brain fMRI images were acquired with a 9.4 Tesla scanner. Group level independent component (ICA) analysis (30 ICs) with dual regression was used to detect and compare RSNs. Twenty ICs corresponding to physiologically meaningful networks representing a range of neural functions, including motor, sensory, reward, and cognitive processes were identified in both adolescent and adult monkeys. The reproducibility of these RSNs was evaluated across several ICA model orders. Adults showed a trend for greater connectivity compared to adolescent subjects in two of the networks of interest: (1) in the right occipital region with the OFC network and (2) in the left temporal cortex, bilateral occipital cortex, and cerebellum with the posterior cingulate network. However, when age was entered into the above model, this trend for significance was lost. These results demonstrate that squirrel monkey RSNs are stable and consistent with RSNs previously identified in humans, rodents, and other nonhuman primate species. These data also identify several networks in adolescence that are conserved and others that may change into adulthood.Significance Statement Functional magnetic resonance imaging procedures have revealed important information about how the brain is modified by experimental manipulations, disease states, and aging throughout the lifespan. Preclinical neuroimaging, especially in nonhuman primates, has become a frequently used means to answer targeted questions related to brain resting-state functional connectivity. The present study characterized resting state networks (RSNs) in adult and adolescent squirrel monkeys; twenty RSNs corresponding to networks representing a range of neural functions were identified. The RSNs identified here can be utilized in future studies examining the effects of experimental manipulations on brain connectivity in squirrel monkeys. These data also may be useful for comparative analysis with other primate species to provide an evolutionary perspective for understanding brain function and organization.
静息状态网络(RSN)越来越多地被认为是神经精神疾病的候选生物标志物。这种生物标志物可以为评估非人灵长类动物的新型治疗干预措施提供客观的测量指标,通常用于神经影像转化研究。本研究旨在描述清醒松鼠猴 RSN 的特征,并比较这些网络在青少年和成年受试者中的特征。27只松鼠猴(n=12名青少年[6男/6女]∼2.5岁,n=15名成人[7男/8女]∼9.5岁)逐渐适应了清醒扫描程序;全脑fMRI图像由9.4特斯拉扫描仪采集。采用组级独立成分(ICA)分析(30 个 IC)和双重回归来检测和比较 RSN。在青少年猴和成年猴中发现了 20 个 IC,这些 IC 与代表一系列神经功能(包括运动、感觉、奖赏和认知过程)的有生理意义的网络相对应。在多个 ICA 模型阶次中对这些 RSN 的再现性进行了评估。与青少年受试者相比,成年猴在两个感兴趣的网络中表现出更大的连通性趋势:(1) 在右枕区与 OFC 网络;(2) 在左颞皮层、双侧枕皮层和小脑与后扣带回网络。然而,当年龄被纳入上述模型时,这种显著性趋势就消失了。这些结果表明,松鼠猴的RSN是稳定的,与之前在人类、啮齿类动物和其他非人灵长类物种中发现的RSN是一致的。意义声明 功能磁共振成像程序揭示了大脑在整个生命周期中如何被实验操作、疾病状态和衰老所改变的重要信息。临床前神经成像,尤其是非人灵长类动物的临床前神经成像,已成为回答与大脑静息状态功能连接相关的目标问题的常用手段。本研究描述了成年松鼠猴和青少年松鼠猴的静息态网络(RSNs)特征,确定了代表一系列神经功能的 20 个 RSNs 网络。在今后研究实验操作对松鼠猴大脑连通性的影响时,可以利用本研究确定的 RSNs。这些数据还可用于与其他灵长类物种的比较分析,为了解大脑功能和组织提供一个进化的视角。
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