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Neural dynamics encoding risky choices during deliberation reveal separate choice subspaces 在审议过程中编码风险选择的神经动力学揭示了单独的选择子空间。
IF 6.7 2区 医学 Q1 NEUROSCIENCES Pub Date : 2025-05-07 DOI: 10.1016/j.pneurobio.2025.102776
Logan M. Peters , Alec Roadarmel , Jacqueline A. Overton , Matthew P. Stickle , Zhaodon Kong , Ignacio Saez , Karen Anne Moxon
Human decision-making involves the coordinated activity of multiple brain areas, acting in concert, to enable humans to make choices. Most decisions are carried out under conditions of uncertainty, where the desired outcome may not be achieved if the wrong decision is made. In these cases, humans deliberate before making a choice. The neural dynamics underlying deliberation are unknown and intracranial recordings in clinical settings present a unique opportunity to record high temporal resolution electrophysiological data from many (hundreds) brain locations during behavior. Combined with dynamic systems modeling, these allow identification of latent brain states that describe the neural dynamics during decision-making, providing insight into these neural dynamics and computations. Results show that the neural dynamics underlying risky decisions, but not decisions without risk, converge to separate subspaces depending on the subject’s preferred choice and that the degree of overlap between these subspaces declines as choice approaches, suggesting a network level representation of evidence accumulation. These results bridge the gap between regression analyses and data driven models of latent states and suggest that during risky decisions, deliberation and evidence accumulation toward a final decision are represented by the same neural dynamics, providing novel insights into the neural computations underlying human choice.
人类的决策涉及多个大脑区域的协调活动,协同行动,使人类能够做出选择。大多数决策都是在不确定的情况下进行的,如果做出错误的决策,预期的结果可能无法实现。在这些情况下,人类在做出选择之前会深思熟虑。思考背后的神经动力学是未知的,在临床环境下的颅内记录提供了一个独特的机会,可以记录行为过程中来自许多(数百个)大脑位置的高时间分辨率电生理数据。与动态系统建模相结合,可以识别决策过程中描述神经动力学的潜在大脑状态,从而深入了解这些神经动力学和计算。结果表明,基于风险决策(而非无风险决策)的神经动力学根据受试者的偏好收敛到独立的子空间,并且这些子空间之间的重叠程度随着选择的接近而下降,表明证据积累的网络级表示。这些结果弥合了回归分析和潜在状态数据驱动模型之间的差距,并表明在风险决策过程中,深思熟虑和最终决策的证据积累由相同的神经动力学表示,为人类选择背后的神经计算提供了新的见解。
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引用次数: 0
Bidirectional control of generalized absence epilepsy networks via real-time direct depolarization of thalamocortical neurons 通过丘脑皮质神经元实时直接去极化双向控制广泛性缺失癫痫网络。
IF 6.1 2区 医学 Q1 NEUROSCIENCES Pub Date : 2025-05-06 DOI: 10.1016/j.pneurobio.2025.102774
Tatiana P. Morais , Hannah L. Taylor , Olivér Nagy , Ferenc Mátyás , Francois David , Vincenzo Crunelli , Magor L. Lőrincz
Absence seizures (ASs), characterized by bilateral spike-and-wave discharges (SWDs), are a hallmark of idiopathic generalized epilepsies. We investigated the role of thalamocortical (TC) neurons in the generation and termination of ASs using optogenetic techniques in freely behaving GAERS rats, a well-established AS model. We demonstrate that direct depolarization of ChR2-transfected TC neurons in the ventrobasal thalamic nuclei during quiet wakefulness (QW) reliably elicits ethosuximide-sensitive ASs that have similar duration and frequency to those of spontaneous ASs, while showing little and no effect during active wakefulness (AW) and slow wave sleep (SWS), respectively. Light-stimulation of TC neurons fails to elicit ASs during AW, QW and SWS in non-epileptic control (NEC) rats, whereas it could evoke short ASs in Wistar rats, prevalently during QW. Notably, brief light stimulation effectively halted ongoing spontaneous ASs in GAERS rats (i.e. both SWDs and immobility), immediately altering thalamic multi-unit activity from rhythmic to irregular firing, irrespective of the SWD phase at which it was delivered. These findings support the view that the excitability of cortico-thalamic-cortical network is highly behavioural state-dependent, with increased susceptibility to the induction of ASs during QW, thus questioning the necessity of low-threshold burst firing of TC neurons in the generation of these seizures. Moreover, they highlight the dual control of ASs by TC neurons, underscoring their potential as therapeutic targets for AS modulation.
以双侧峰波放电(SWDs)为特征的失神性癫痫(ASs)是特发性全身性癫痫的一个标志。我们利用光遗传学技术在自由行为的GAERS大鼠(一种成熟的AS模型)中研究了丘脑皮质(TC)神经元在AS的产生和终止中的作用。我们证明,在安静清醒(QW)期间,腹基底丘脑核中chr2转染的TC神经元的直接去极化可靠地引发了与自发asa相似的持续时间和频率的乙氧亚胺敏感asa,而在活跃清醒(AW)和慢波睡眠(SWS)期间分别显示很少或没有影响。在非癫痫对照(NEC)大鼠中,光刺激TC神经元在AW、QW和SWS期间不能诱发ASs,而在Wistar大鼠中,光刺激可以诱发短ASs,主要在QW期间。值得注意的是,短暂的光刺激有效地阻止了GAERS大鼠(即SWD和静止)正在进行的自发性ASs,立即改变丘脑多单位活动,从有节奏的到不规则的放电,而不管它是在哪个SWD阶段传递的。这些发现支持了以下观点,即皮质-丘脑-皮质网络的兴奋性是高度依赖行为状态的,在QW期间对诱导ASs的易感性增加,因此质疑TC神经元在这些癫痫发作的产生中是否需要低阈值爆发放电。此外,他们强调了TC神经元对as的双重控制,强调了它们作为as调节的治疗靶点的潜力。
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引用次数: 0
Temporal impact of sepsis on Alzheimer's disease pathology and neuroinflammation 脓毒症对阿尔茨海默病病理和神经炎症的时间影响
IF 6.7 2区 医学 Q1 NEUROSCIENCES Pub Date : 2025-05-03 DOI: 10.1016/j.pneurobio.2025.102775
Quan Vo , Dina C. Nacionales , Karen N. McFarland , Carmelina Gorski , Evan L. Barrios , Gwoncheol Park , Lyle L. Moldawer , Gemma Casadesus , Ravinder Nagpal , Philip A. Efron , Paramita Chakrabarty
Epidemiological evidence has revealed an associative link between sepsis survivorship and increased risk of dementia, particularly Alzheimer's disease (AD). Paradoxically, population studies show females are less susceptible to sepsis but more vulnerable to post-sepsis dementia. Here, we examined the temporal impacts of sepsis in the context of AD by using an AD-amyloidosis model (TgCRND8) and their wild-type littermates and assessing outcomes at 7 days and 3 months post-sepsis in male and female mice. Following 7-days recovery, the microglia and astrocytes in AD-model mice were largely refractile to the systemic immune stimuli. Notably, the female AD-model mice accumulated higher hippocampal amyloid-beta (Aβ) burden and upregulated AD-type transcriptomic signature at this time. On the other hand, male AD-model mice showed no Aβ changes. At this time, the wild-type post-septic males, but not females, displayed robust astrocytosis, with nominal microgliosis. By 3 months post-sepsis, microgliosis was specifically elevated in wild-type females, indicating a prolonged central immune response. At this time, both male and female AD-model mice showed exacerbated Aβ and anxiety indices. Gene network analysis revealed a stronger immune response in females, while the male response was linked to estrogen receptor (ESR) signaling, with ERα protein upregulated in the brains of post-septic AD-model males. Together, our data highlights a sex-dimorphic temporal response in post-sepsis neuroinflammation, with ESR signaling playing a key role in males, while Aβ burden is affected similarly in both males and females.
流行病学证据显示败血症存活与痴呆风险增加之间存在关联,尤其是阿尔茨海默病(AD)。矛盾的是,人口研究表明,女性不太容易患败血症,但更容易患败血症后痴呆。在这里,我们通过使用AD-淀粉样变模型(TgCRND8)和它们的野生型窝代,研究了败血症在AD背景下的时间影响,并评估了雄性和雌性小鼠败血症后7天和3个月的结果。恢复7天后,ad模型小鼠的小胶质细胞和星形胶质细胞对全身免疫刺激有很大的折射性。值得注意的是,雌性ad模型小鼠此时积累了更高的海马淀粉样蛋白- β (Aβ)负担和上调的ad型转录组特征。另一方面,雄性ad模型小鼠未见Aβ变化。此时,野生型感染后的雄性,而不是雌性,表现出强大的星形细胞增生,并伴有名义上的小胶质细胞增生。脓毒症后3个月,野生型女性的小胶质瘤特异性升高,表明中枢免疫反应延长。此时,雄性和雌性ad模型小鼠的Aβ和焦虑指数均升高。基因网络分析显示,雌性的免疫反应更强,而雄性的反应与雌激素受体(ESR)信号有关,在败血性ad模型雄性的大脑中,ERα蛋白上调。总之,我们的数据强调了脓毒症后神经炎症中的性别二态时间反应,ESR信号在男性中起关键作用,而a β负荷在男性和女性中都受到相似的影响。
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引用次数: 0
EphB2 receptor tyrosine kinase-mediated excitatory synaptic functions are negatively modulated by MDGA2 MDGA2负向调节EphB2受体酪氨酸激酶介导的兴奋性突触功能
IF 6.7 2区 医学 Q1 NEUROSCIENCES Pub Date : 2025-05-01 DOI: 10.1016/j.pneurobio.2025.102772
Hyeonho Kim , Younghyeon Jeon , Seunghye Kim , Yuxuan Guo , Dongwook Kim , Gyubin Jang , Julia Brasch , Ji Won Um , Jaewon Ko
MDGA2 is an excitatory synapse-specific suppressor that uses distinct extracellular mechanisms to negatively regulate various postsynaptic properties. Here, we identify EphB2, an excitatory synapse-specific receptor tyrosine kinase, as a new binding partner for MDGA2. The first three immunoglobulin domains of MDGA2 undergo cis-binding to the ligand-binding domain of EphB2, enabling MDGA2 to compete with Ephrin-B1 for binding to EphB2. Moreover, EphB2 forms complexes with MDGA2 and GluN2B-containing NMDA receptors (NMDARs) in mouse brains. MDGA2 deletion promotes formation of the EphB2/Ephrin-B1 complex but does not alter the surface expression levels and Ephrin-stimulated activation of EphB2 receptors and downstream GluN2B-containing NMDARs in cultured neurons. AlphaFold-based molecular replacement experiments reveal that MDGA2 must bind EphB2 to suppress spontaneous synaptic transmission and NMDAR-mediated, but not AMPAR-mediated, postsynaptic responses at excitatory synapses in cultured neurons. These results collectively suggest that MDGA2 is a versatile factor that suppresses distinct excitatory postsynaptic properties via different transsynaptic pathways.
MDGA2是一种兴奋性突触特异性抑制因子,使用不同的细胞外机制负性调节各种突触后特性。在这里,我们发现EphB2,一种兴奋性突触特异性受体酪氨酸激酶,作为MDGA2的新结合伙伴。MDGA2的前三个免疫球蛋白域与EphB2的配体结合域进行顺式结合,使MDGA2与Ephrin-B1竞争EphB2的结合。此外,EphB2在小鼠脑内与含有MDGA2和glun2b的NMDA受体(NMDARs)形成复合物。MDGA2缺失促进EphB2/Ephrin-B1复合物的形成,但不改变培养神经元中EphB2受体的表面表达水平和ephrin刺激的EphB2受体和下游含glun2b的NMDARs的激活。基于alphafold的分子替代实验表明,MDGA2必须结合EphB2才能抑制神经元兴奋性突触的自发突触传递和nmdar介导的突触后反应,而不是ampar介导的突触后反应。这些结果共同表明MDGA2是一个多用途因子,通过不同的跨突触途径抑制不同的兴奋性突触后特性。
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引用次数: 0
Glycine-gated extrasynaptic NMDARs activated during glutamate spillover drive burst firing in nigral dopamine neurons 甘氨酸门控的突触外NMDARs在谷氨酸溢出驱动的突发放电中激活
IF 6.7 2区 医学 Q1 NEUROSCIENCES Pub Date : 2025-04-26 DOI: 10.1016/j.pneurobio.2025.102773
Sofian Ringlet , Zoraide Motta , Laura Vandries , Vincent Seutin , Kevin Jehasse , Laura Caldinelli , Loredano Pollegioni , Dominique Engel
Burst firing in substantia nigra pars compacta dopamine neurons is a critical biomarker temporally associated to movement initiation. This phasic change is generated by the tonic activation of NMDARs but the respective role of synaptic versus extrasynaptic NMDARs in the ignition of a burst and what is their level of activation remains unknown. Using ex vivo electrophysiological recordings from adolescent rats, we demonstrate that extrasynaptic NMDARs are the primary driver of burst firing. This pool of receptors is recruited during intense synaptic activity via spillover of glutamate and require the binding of NMDAR co-agonist glycine for full activation. Basal synaptic transmission activating only synaptic NMDARs with the support of D-serine is insufficient to generate a burst. Notably, both synaptic and extrasynaptic NMDARs share the same subunit composition but are regulated by distinct co-agonists. Location of NMDARs and regionalization of co-agonists but not NMDAR subunit composition underly burst generation and may serve as a guideline in understanding the physiological role of dopamine in signaling movement.
黑质致密部多巴胺神经元的突发放电是与运动启动时间相关的关键生物标志物。这种相位变化是由NMDARs的强直性激活产生的,但突触NMDARs和突触外NMDARs在爆发的点燃中各自的作用以及它们的激活水平仍然未知。利用青春期大鼠的离体电生理记录,我们证明了突触外NMDARs是突发放电的主要驱动因素。这一受体库是在强烈的突触活动中通过谷氨酸溢出而募集的,需要与NMDAR共激动剂甘氨酸结合才能完全激活。仅在d -丝氨酸的支持下激活突触NMDARs不足以产生爆发。值得注意的是,突触和突触外的NMDARs具有相同的亚基组成,但受不同的共激动剂调节。NMDAR的位置和共激动剂的区域化而不是NMDAR亚基组成是爆发产生的基础,可能作为理解多巴胺在信号运动中的生理作用的指导。
{"title":"Glycine-gated extrasynaptic NMDARs activated during glutamate spillover drive burst firing in nigral dopamine neurons","authors":"Sofian Ringlet ,&nbsp;Zoraide Motta ,&nbsp;Laura Vandries ,&nbsp;Vincent Seutin ,&nbsp;Kevin Jehasse ,&nbsp;Laura Caldinelli ,&nbsp;Loredano Pollegioni ,&nbsp;Dominique Engel","doi":"10.1016/j.pneurobio.2025.102773","DOIUrl":"10.1016/j.pneurobio.2025.102773","url":null,"abstract":"<div><div>Burst firing in substantia nigra pars compacta dopamine neurons is a critical biomarker temporally associated to movement initiation. This phasic change is generated by the tonic activation of NMDARs but the respective role of synaptic versus extrasynaptic NMDARs in the ignition of a burst and what is their level of activation remains unknown. Using ex vivo electrophysiological recordings from adolescent rats, we demonstrate that extrasynaptic NMDARs are the primary driver of burst firing. This pool of receptors is recruited during intense synaptic activity via spillover of glutamate and require the binding of NMDAR co-agonist glycine for full activation. Basal synaptic transmission activating only synaptic NMDARs with the support of D-serine is insufficient to generate a burst. Notably, both synaptic and extrasynaptic NMDARs share the same subunit composition but are regulated by distinct co-agonists. Location of NMDARs and regionalization of co-agonists but not NMDAR subunit composition underly burst generation and may serve as a guideline in understanding the physiological role of dopamine in signaling movement.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"249 ","pages":"Article 102773"},"PeriodicalIF":6.7,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143881428","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Whole-brain effective connectivity of the sensorimotor system using 7 T fMRI with electrical microstimulation in non-human primates 使用7 T功能磁共振成像与电微刺激在非人类灵长类动物的感觉运动系统的全脑有效连接
IF 6.7 2区 医学 Q1 NEUROSCIENCES Pub Date : 2025-04-23 DOI: 10.1016/j.pneurobio.2025.102760
Min-Jun Han , Younghyun Oh , Yejin Ann , Sangyun Kang , Eunha Baeg , Seok Jun Hong , Hansem Sohn , Seong-Gi Kim
The sensorimotor system is a crucial interface between the brain and the environment, and it is endowed with multiple computational mechanisms that enable efficient behaviors. For example, predictive processing via an efference copy of a motor command has been proposed as one of the key computations used to compensate for the sensory consequence of movement. However, the neural pathways underlying this process remain unclear, particularly regarding whether the M1-to-S1 pathway plays a dominant role in predictive processing and how its influence compares to that of other pathways. In this study, we present a causally inferable input–output map of the sensorimotor effective connectivity that we made by combining ultrahigh-field functional MRI, electrical microstimulation of the S1/M1 cortex, and dynamic causal modeling for the whole sensorimotor network in anesthetized primates. We investigated how motor signals from M1 are transmitted to S1 at the circuit level, either via direct cortico-cortical projections or indirectly via subcortical structures such as the thalamus. Across different stimulation conditions, we observed a robust asymmetric connectivity from M1 to S1 that was also the most prominent output from M1. In the thalamus, we identified distinct activations: M1 stimulation showed connections to the anterior part of ventral thalamic nuclei, whereas S1 was linked to the more posterior regions of the ventral thalamic nuclei. These findings suggest that the cortico-cortical projection from M1 to S1, rather than the cortico-thalamic loop, plays a dominant role in transmitting movement-related information. Together, our detailed dissection of the sensorimotor circuitry underscores the importance of M1-to-S1 connectivity in sensorimotor coordination.
感觉运动系统是大脑和环境之间的关键接口,它被赋予了多种计算机制,使有效的行为。例如,通过对运动指令的复制进行预测处理被认为是用来补偿运动的感觉后果的关键计算之一。然而,这一过程背后的神经通路尚不清楚,特别是M1-to-S1通路是否在预测加工中起主导作用,以及它与其他通路的影响如何。在这项研究中,我们提出了一个因果推理的感觉运动有效连接的输入-输出图,我们结合了超强场功能MRI, S1/M1皮层的电微刺激,以及对麻醉灵长类动物整个感觉运动网络的动态因果建模。我们研究了M1的运动信号是如何在回路水平上通过皮质-皮层直接投射或间接通过皮层下结构(如丘脑)传递到S1的。在不同的增产条件下,我们观察到M1到S1之间存在强大的不对称连通性,这也是M1最突出的输出。在丘脑中,我们发现了不同的激活:M1刺激显示与丘脑腹侧核的前部相连,而S1与丘脑腹侧核的后部相连。这些发现表明,从M1到S1的皮质-皮质投射,而不是皮质-丘脑回路,在传递运动相关信息中起主导作用。总之,我们对感觉运动电路的详细剖析强调了m1到s1连接在感觉运动协调中的重要性。
{"title":"Whole-brain effective connectivity of the sensorimotor system using 7 T fMRI with electrical microstimulation in non-human primates","authors":"Min-Jun Han ,&nbsp;Younghyun Oh ,&nbsp;Yejin Ann ,&nbsp;Sangyun Kang ,&nbsp;Eunha Baeg ,&nbsp;Seok Jun Hong ,&nbsp;Hansem Sohn ,&nbsp;Seong-Gi Kim","doi":"10.1016/j.pneurobio.2025.102760","DOIUrl":"10.1016/j.pneurobio.2025.102760","url":null,"abstract":"<div><div>The sensorimotor system is a crucial interface between the brain and the environment, and it is endowed with multiple computational mechanisms that enable efficient behaviors. For example, predictive processing via an efference copy of a motor command has been proposed as one of the key computations used to compensate for the sensory consequence of movement. However, the neural pathways underlying this process remain unclear, particularly regarding whether the M1-to-S1 pathway plays a dominant role in predictive processing and how its influence compares to that of other pathways. In this study, we present a causally inferable input–output map of the sensorimotor effective connectivity that we made by combining ultrahigh-field functional MRI, electrical microstimulation of the S1/M1 cortex, and dynamic causal modeling for the whole sensorimotor network in anesthetized primates. We investigated how motor signals from M1 are transmitted to S1 at the circuit level, either via direct cortico-cortical projections or indirectly via subcortical structures such as the thalamus. Across different stimulation conditions, we observed a robust asymmetric connectivity from M1 to S1 that was also the most prominent output from M1. In the thalamus, we identified distinct activations: M1 stimulation showed connections to the anterior part of ventral thalamic nuclei, whereas S1 was linked to the more posterior regions of the ventral thalamic nuclei. These findings suggest that the cortico-cortical projection from M1 to S1, rather than the cortico-thalamic loop, plays a dominant role in transmitting movement-related information. Together, our detailed dissection of the sensorimotor circuitry underscores the importance of M1-to-S1 connectivity in sensorimotor coordination.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"250 ","pages":"Article 102760"},"PeriodicalIF":6.7,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143906878","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Slumber under pressure: REM sleep and stress response 压力下的睡眠:快速眼动睡眠和应激反应
IF 6.7 2区 医学 Q1 NEUROSCIENCES Pub Date : 2025-04-22 DOI: 10.1016/j.pneurobio.2025.102771
Bernhard Schaefke , Jingfei Li , Binghao Zhao , Liping Wang , Yu-Ting Tseng
Sleep, a state of reduced responsiveness and distinct brain activity, is crucial across the animal kingdom. This review explores the potential adaptive functions of REM sleep in adapting to stress, emphasizing its role in memory consolidation, emotional regulation, and threat processing. We further explore the underlying neural mechanisms linking stress responses to REM sleep. By synthesizing current findings, we propose that REM sleep allows animals to "rehearse" or simulate responses to danger in a secure, offline state, while also maintaining emotional balance. Environmental factors, such as predation risk and social dynamics, further influence REM sleep. This modulation may enhance survival by optimizing stress responses while fulfilling physiological needs in animals. Insights into REM sleep's role in animals may shed light on human sleep in the context of modern stressors and sleep disruptions. This review also explores the complex interplay between stress, immunity, sleep disruptions—particularly involving REM sleep—and their evolutionary underpinnings.
睡眠是一种反应能力降低、大脑活动明显的状态,在动物王国中至关重要。本文探讨了快速眼动睡眠在适应压力方面的潜在适应功能,强调了其在记忆巩固、情绪调节和威胁处理方面的作用。我们进一步探讨了应激反应与快速眼动睡眠之间的潜在神经机制。通过综合目前的研究结果,我们提出快速眼动睡眠允许动物在安全的离线状态下“排练”或模拟对危险的反应,同时也保持情绪平衡。环境因素,如捕食风险和社会动态,进一步影响快速眼动睡眠。这种调节可以通过优化应激反应来提高动物的存活率,同时满足动物的生理需求。对动物快速眼动睡眠作用的深入了解,可能会在现代压力源和睡眠中断的背景下,为人类睡眠提供启示。这篇综述还探讨了压力、免疫力、睡眠中断(特别是涉及快速眼动睡眠)及其进化基础之间复杂的相互作用。
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引用次数: 0
Modulation of premotor cortex excitability mitigates the behavioral and electrophysiological abnormalities in a Parkinson's disease mouse model 运动前皮层兴奋性的调节减轻了帕金森病小鼠模型的行为和电生理异常
IF 6.7 2区 医学 Q1 NEUROSCIENCES Pub Date : 2025-04-19 DOI: 10.1016/j.pneurobio.2025.102761
In Sun Choi , Jinmo Kim , Joon Ho Choi , Eun-Mee Kim , Ji-Woong Choi , Jong-Cheol Rah
The subthalamic nucleus (STN) plays a crucial role in suppressing prepotent response tendency. The prefrontal regions innervating the STN exhibit increased activity during the stop-signal responses, and the optogenetic activation of these neurons suppresses ongoing behavior. High-frequency electrical stimulation of the STN effectively treats the motor symptoms of Parkinson's disease (PD), yet its underlying circuit mechanisms remain unclear. Here, we investigated the involvement of STN-projecting premotor (M2) neurons in PD mouse models and the impact of deep brain stimulation targeting the STN (DBS-STN). We found that the M2 neurons exhibited enhanced burst firing and synchronous oscillations in the PD mouse model. Remarkably, high-frequency stimulation of STN-projecting M2 neurons, simulating antidromic activation during DBS-STN relieved motor symptoms and hyperexcitability. These changes were attributed to reduced firing frequency vs. current relationship through normalized hyperpolarization-activated inward current (Ih). The M2 neurons in the PD model mouse displayed increased Ih, which was reversed by high-frequency stimulation. Additionally, the infusion of ZD7288, an HCN channel blocker, into the M2 replicated the effects of high-frequency stimulation. In conclusion, our study reveals excessive excitability and suppressive motor control through M2-STN synapses in a PD mouse model. Antidromic excitation of M2 neurons during DBS-STN alleviates this suppression, thereby improving motor impairment. These findings provide insights into the circuit-level dynamics underlying deep brain stimulation's therapeutic effects in PD, suggesting that M2-STN synapses could serve as potential targets for future therapeutic strategies.
丘脑下核(STN)在抑制性早熟反应倾向中起重要作用。在停止信号反应期间,支配STN的前额叶区域表现出增加的活性,并且这些神经元的光遗传激活抑制了正在进行的行为。高频电刺激STN有效治疗帕金森病(PD)的运动症状,但其潜在的电路机制尚不清楚。在此,我们研究了PD小鼠模型中STN投射前运动(M2)神经元的参与以及针对STN的脑深部刺激(DBS-STN)的影响。我们发现,在PD小鼠模型中,M2神经元表现出增强的突发放电和同步振荡。值得注意的是,模拟DBS-STN过程中反向激活的stn投射M2神经元的高频刺激可缓解运动症状和高兴奋性。这些变化归因于通过标准化超极化激活的内向电流(Ih)降低了放电频率与电流的关系。PD模型小鼠M2神经元Ih升高,高频刺激可逆转Ih升高。此外,将HCN通道阻滞剂ZD7288注入M2可复制高频刺激的效果。总之,我们的研究揭示了PD小鼠模型通过M2-STN突触过度兴奋性和抑制性运动控制。DBS-STN时M2神经元的反向兴奋可缓解这种抑制,从而改善运动损伤。这些发现为深部脑刺激对PD治疗作用的回路水平动力学提供了见解,表明M2-STN突触可以作为未来治疗策略的潜在靶点。
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引用次数: 0
Lethal Interactions of neuronal networks in epilepsy mediated by both synaptic and volume transmission indicate approaches to prevention 由突触和体积传递介导的癫痫中神经元网络的致命相互作用表明了预防的方法
IF 6.7 2区 医学 Q1 NEUROSCIENCES Pub Date : 2025-04-19 DOI: 10.1016/j.pneurobio.2025.102770
Carl L. Faingold
Neuronal network interactions are important in normal brain physiology and also in brain disorders. Many mesoscopic networks, including the auditory and respiratory network, mediate a single brain function. Macroscopic networks, including the locomotor network, central autonomic network (CAN), and many seizure networks involve interactions among multiple mesoscopic networks. Network interactions are mediated by neuroactive substances, acting via synaptic transmission, which mediate rapid interactions between networks. Slower, but vitally important network interactions, are mediated by volume transmission. Changes in the interactions between networks, mediated by neuroactive substances, can significantly alter network function and interactions. The acoustic startle response involves interactions between auditory and locomotor networks, and also includes brainstem reticular formation (BRF) nuclei, which participate in many different networks. In the fear-potentiated startle paradigm this network interacts positively with the amygdala, induced by conditioning. Seizure networks can interact negatively with the respiratory network, which becomes lethal in sudden unexpected death in epilepsy (SUDEP), a tragic emergent property of the seizure network. SUDEP models that exhibit audiogenic seizures (AGSz) involve interactions between the auditory and locomotor networks with BRF nuclei. In the DBA/1 mouse SUDEP model the AGSz network interacts negatively with the respiratory network, resulting in postictal apnea. The apnea is lethal unless the CAN is able to initiate autoresuscitation. These network interactions involve synaptic transmission, mediated by GABA and glutamate and volume transmission mediated by adenosine, CO2 and serotonin. Altering these interaction mechanisms may prevent SUDEP. These epilepsy network interactions illustrate the complex mechanisms that can occur among neuronal networks.
神经网络的相互作用在正常的大脑生理和大脑疾病中都很重要。许多中观神经网络,包括听觉和呼吸神经网络,介导单一的大脑功能。包括运动网络、中枢自主神经网络(CAN)和许多癫痫网络在内的宏观网络涉及多个中观网络之间的相互作用。网络相互作用是由神经活性物质介导的,通过突触传递作用,突触传递介导网络之间的快速相互作用。较慢但至关重要的网络相互作用是由体积传输介导的。神经活性物质介导的神经网络间相互作用的改变可以显著改变神经网络的功能和相互作用。声惊反应涉及听觉和运动网络之间的相互作用,也包括参与许多不同网络的脑干网状形成(BRF)核。在恐惧增强的惊吓范式中,这个网络与杏仁核积极互动,由条件反射引起。癫痫发作网络可以与呼吸网络负向相互作用,这在癫痫猝死(SUDEP)中是致命的,这是癫痫发作网络的一个悲剧性突发特性。表现出听源性癫痫(AGSz)的SUDEP模型涉及听觉和运动网络与BRF核之间的相互作用。在DBA/1小鼠SUDEP模型中,AGSz网络与呼吸网络负相互作用,导致正性呼吸暂停。呼吸暂停是致命的,除非CAN能够启动自我复苏。这些网络相互作用包括由GABA和谷氨酸介导的突触传递和由腺苷、二氧化碳和血清素介导的体积传递。改变这些相互作用机制可以预防猝死。这些癫痫网络相互作用说明了神经元网络之间可能发生的复杂机制。
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引用次数: 0
Neural connections and molecular mechanisms underlying motor skill deficits in genetic models of autism spectrum disorders 自闭症谱系障碍遗传模型中运动技能缺陷的神经连接和分子机制
IF 6.7 2区 医学 Q1 NEUROSCIENCES Pub Date : 2025-04-18 DOI: 10.1016/j.pneurobio.2025.102759
Jingwen Duan , Deyang Zeng , Tong Wu , Zhenzhao Luo , Geng Jingwen , Wei Tan , Yan Zeng
Autism spectrum disorders (ASDs) comprise a broad category of neurodevelopmental disorders that include repetitive behaviors and difficulties in social interactions. Notably, individuals with ASDs exhibit significant impairments in motor skills even prior to the manifestation of other core symptoms. These skills are crucial for daily activities, such as communication, imitation, and exploration, and hold significant importance for individuals with ASDs. This review seeks to offer new insights into the understanding of motor skill impairments by delineating the pathological mechanisms underlying motor skill learning impairments associated with gene mutations in Fmr1, Chd8, Shank3, BTBR, 16p11.2, and Mecp2, predominantly drawing from well-characterized genetic mouse model studies and proposing potential targets for future therapeutic interventions. We further discuss the underlying pathogenic abnormalities associated with the development of specific brain regions within the cerebellum and cerebrum, as well as disruptions in the structure and function of critical neuronal connectivity pathways. Additional research utilizing epidemiological data, clinical observations, and animal research methodologies is warranted to enhance our understanding of the effect of motor skill learning on the growth, development, and social integration of children. Ultimately, our review suggests potential targets for future therapeutic interventions.
自闭症谱系障碍(ASDs)包括一大类神经发育障碍,包括重复性行为和社会互动困难。值得注意的是,asd患者甚至在其他核心症状出现之前就表现出了运动技能的显著损伤。这些技能对于日常活动至关重要,比如沟通、模仿和探索,对自闭症患者来说非常重要。本综述旨在通过描述与Fmr1、Chd8、Shank3、BTBR、16p11.2和Mecp2基因突变相关的运动技能学习障碍的病理机制,为理解运动技能障碍提供新的见解,主要来自于具有良好特征的遗传小鼠模型研究,并提出未来治疗干预的潜在目标。我们进一步讨论了与小脑和大脑内特定大脑区域发育相关的潜在致病性异常,以及关键神经元连接通路结构和功能的破坏。利用流行病学数据、临床观察和动物研究方法的进一步研究是有必要的,以增强我们对运动技能学习对儿童生长、发育和社会融合的影响的理解。最后,我们的综述提出了未来治疗干预的潜在目标。
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Progress in Neurobiology
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