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Shifting GnRH neuron ensembles underlie successive preovulatory luteinizing hormone surges. 排卵前黄体生成素连续激增的基础是不断变化的 GnRH 神经元组合。
IF 4.4 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-11-06 DOI: 10.1523/JNEUROSCI.1383-24.2024
Shel-Hwa Yeo, Su Young Han, Allan E Herbison

The gonadotropin-releasing hormone (GnRH) neurons operate as a neuronal ensemble exhibiting coordinated activity once every reproductive cycle to generate the preovulatory GnRH surge. Using GCaMP fibre photometry at the GnRH neuron distal dendrons to measure the output of this widely scattered population in female mice, we find that the onset, amplitude, and profile of GnRH neuron surge activity exhibits substantial variability from cycle to cycle both between and within individual mice. This was also evident when measuring successive proestrous luteinizing hormone surges. Studies combining short (c-Fos and c-Jun) and long (genetic Robust Activity Marking) term indices of immediate early gene activation revealed that, while ∼50% of GnRH neurons were activated at the time of each surge, only half of these neurons had been active during the previous proestrous surge. These observations reveal marked inter- and intra-individual variability in the GnRH surge mechanism. Remarkably, different sub-populations of overlapping GnRH neurons are recruited to the ensemble each estrous cycle to generate the GnRH surge. While engendering variability in the surge mechanism itself, this likely provides substantial robustness to a key event underlying mammalian reproduction.Significance Statement The mid-cycle luteinizing hormone (LH) surge driven by the gonadotropin-releasing hormone (GnRH) neurons represents the key event triggering ovulation in all mammals. Using GCaMP fibre photometry and genetic activation markers, we unexpectedly find that different sub-populations of GnRH neurons are responsible for driving consecutive LH surges every 4-5 days in cycling female mice. This remarkable oscillatory pattern of network plasticity within the ensemble occurs under normal physiological conditions and likely contributes to the variable timing of the onset of LH surge both within and between individuals. The ability of individual GnRH neurons to take turns within the ensemble in driving the LH surge likely provides a robust fail-safe mechanism for ovulation and contributes to the robustness of mammalian fertility.

促性腺激素释放激素(GnRH)神经元是一个神经元组合,每个生殖周期都会有一次协调活动,以产生排卵前的 GnRH 激增。我们在雌性小鼠的 GnRH 神经元远端树突处使用 GCaMP 纤维光度法测量这一广泛分散的神经元群的输出,发现 GnRH 神经元激增活动的起始、振幅和轮廓在不同周期之间和小鼠个体内部都表现出很大的差异性。在测量连续的发情黄体生成素激增时,这一点也很明显。结合即刻早期基因激活的短期(c-Fos 和 c-Jun)和长期(遗传稳健活动标记)指标进行的研究显示,虽然每次激增时有 50% 的 GnRH 神经元被激活,但其中只有一半的神经元在前一次雌激素激增时处于活跃状态。这些观察结果表明,GnRH激增机制在个体间和个体内存在明显差异。值得注意的是,重叠的 GnRH 神经元的不同亚群在每个发情周期被招募到集合体中,以产生 GnRH 激增。意义声明 由促性腺激素释放激素(GnRH)神经元驱动的周期中期黄体生成素(LH)激增是触发所有哺乳动物排卵的关键事件。利用 GCaMP 纤维光度法和基因激活标记,我们意外地发现,在周期性雌性小鼠体内,不同的 GnRH 神经元亚群负责驱动每 4-5 天一次的 LH 激增。在正常生理条件下,神经元网络可塑性的这种显著振荡模式会在神经元网络中出现,这很可能是导致个体内部和个体之间 LH 激增开始时间不同的原因。单个 GnRH 神经元在集合体中轮流驱动 LH 激增的能力可能为排卵提供了一种稳健的故障安全机制,并有助于提高哺乳动物生育能力的稳健性。
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引用次数: 0
Neural Representations of Concreteness and Concrete Concepts Are Specific to the Individual. 具体性和具体概念的神经表征是个人特有的。
IF 4.4 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-11-06 DOI: 10.1523/JNEUROSCI.0288-24.2024
Thomas L Botch, Emily S Finn

Different people listening to the same story may converge upon a largely shared interpretation while still developing idiosyncratic experiences atop that shared foundation. What linguistic properties support this individualized experience of natural language? Here, we investigate how the "concrete-abstract" axis-the extent to which a word is grounded in sensory experience-relates to within- and across-subject variability in the neural representations of language. Leveraging a dataset of human participants of both sexes who each listened to four auditory stories while undergoing functional magnetic resonance imaging, we demonstrate that neural representations of "concreteness" are both reliable across stories and relatively unique to individuals, while neural representations of "abstractness" are variable both within individuals and across the population. Using natural language processing tools, we show that concrete words exhibit similar neural representations despite spanning larger distances within a high-dimensional semantic space, which potentially reflects an underlying representational signature of sensory experience-namely, imageability-shared by concrete words but absent from abstract words. Our findings situate the concrete-abstract axis as a core dimension that supports both shared and individualized representations of natural language.

不同的人在聆听同一个故事时,可能会趋同于大致相同的解释,但同时仍会在这个共同的基础上发展出特异的体验。是什么语言特性支持了这种个性化的自然语言体验?在这里,我们研究了 "具体-抽象 "轴(即一个词在多大程度上以感官体验为基础)与语言神经表征的主体内和主体间变异的关系。我们利用一个由男女人类参与者组成的数据集,让他们在接受功能性核磁共振成像检查的同时聆听四个听觉故事,结果表明 "具体性 "的神经表征在不同的故事中都是可靠的,而且对个体来说也是相对独特的,而 "抽象性 "的神经表征在个体内部和人群中都是可变的。通过使用自然语言处理工具,我们发现尽管具体词语在高维语义空间中的距离更大,但它们却表现出相似的神经表征,这可能反映了感官体验的潜在表征特征--即形象性--具体词语具有这种特征,而抽象词语却不具备这种特征。我们的研究结果表明,具体-抽象轴是支持自然语言的共享表征和个性化表征的核心维度。因此,尽管面对相同的信息,人们可能会形成不同的解释。大脑利用了语言的哪些特性来形成这种不同的个性化体验?对功能性核磁共振成像(MRI)数据的分析表明,"具体性",即语言与感官体验的相关程度,唤起了可靠的神经模式,这些模式对每个受试者来说都是独一无二的,使我们能够仅根据神经数据来识别个体。机器学习方法的应用表明,具体概念集(而非抽象概念集)显示出稳定的神经模式,这可能是由于一种感官特征:形象性。总之,这项研究将具体性描述为支持真实世界语言个性化体验的核心属性。
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引用次数: 0
The Hippocampus Preorders Movements for Skilled Action Sequences. 海马体为熟练动作序列预设动作顺序
IF 4.4 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-11-06 DOI: 10.1523/JNEUROSCI.0832-24.2024
Rhys Yewbrey, Katja Kornysheva

Plasticity in the subcortical motor basal ganglia-thalamo-cerebellar network plays a key role in the acquisition and control of long-term memory for new procedural skills, from the formation of population trajectories controlling trained motor skills in the striatum to the adaptation of sensorimotor maps in the cerebellum. However, recent findings demonstrate the involvement of a wider cortical and subcortical brain network in the consolidation and control of well-trained actions, including a brain region traditionally associated with declarative memory-the hippocampus. Here, we probe which role these subcortical areas play in skilled motor sequence control, from sequence feature selection during planning to their integration during sequence execution. An fMRI dataset (N = 24; 14 females) collected after participants learnt to produce four finger press sequences entirely from memory with high movement and timing accuracy over several days was examined for both changes in BOLD activity and their informational content in subcortical regions of interest. Although there was a widespread activity increase in effector-related striatal, thalamic, and cerebellar regions, in particular during sequence execution, the associated activity did not contain information on the motor sequence identity. In contrast, hippocampal activity increased during planning and predicted the order of the upcoming sequence of movements. Our findings suggest that the hippocampus preorders movements for skilled action sequences, thus contributing to the higher-order control of skilled movements that require flexible retrieval. These findings challenge the traditional taxonomy of episodic and procedural memory and carry implications for the rehabilitation of individuals with neurodegenerative disorders.

皮层下运动基底节-丘脑-小脑网络的可塑性在获得和控制新程序性技能的长期记忆中起着关键作用,从纹状体中控制训练有素的运动技能的群体轨迹的形成到小脑中传感器运动图的适应。然而,最近的研究结果表明,在巩固和控制训练有素的动作过程中,有更广泛的皮层和皮层下大脑网络的参与,包括传统上与陈述性记忆相关的大脑区域--海马。在这里,我们探究了这些皮层下区域在熟练的运动序列控制中扮演的角色,包括从计划过程中的序列特征选择到序列执行过程中的整合。我们收集了参与者在数天内学会完全凭记忆制作四个手指按压序列后的 fMRI 数据集(24 人,14 名女性),这些数据集具有很高的运动和计时准确性,我们对这些数据集的 BOLD 活动变化及其在皮层下相关区域的信息含量进行了研究。虽然与效应相关的纹状体、丘脑和小脑区域的活动普遍增加,尤其是在序列执行过程中,但相关活动并不包含运动序列特征的信息。与此相反,海马区的活动在计划过程中有所增加,并能预测即将发生的运动序列的顺序。我们的研究结果表明,海马对熟练动作序列的运动进行了预先排序,从而有助于对需要灵活检索的熟练动作进行高阶控制。这些研究结果对传统的外显记忆和程序记忆分类法提出了挑战,并对神经退行性疾病患者的康复具有重要意义。这项 fMRI 研究表明,传统上与外显记忆和空间导航有关的海马体在执行训练有素的动作序列之前会预先排序。这些发现挑战了外显记忆和程序记忆系统之间的典型分离以及熟练运动行为的神经基础。
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引用次数: 0
Spatiotemporal Neural Network for Sublexical Information Processing: An Intracranial SEEG Study. 用于副词汇信息处理的时空神经网络:颅内 SEEG 研究。
IF 4.4 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-11-06 DOI: 10.1523/JNEUROSCI.0717-24.2024
Chunyu Zhao, Yi Liu, Jiahong Zeng, Xiangqi Luo, Weijin Sun, Guoming Luan, Yuxin Liu, Yumei Zhang, Gaofeng Shi, Yuguang Guan, Zaizhu Han

Words offer a unique opportunity to separate the processing mechanisms of object subcomponents from those of the whole object, because the phonological or semantic information provided by the word subcomponents (i.e., sublexical information) can conflict with that provided by the whole word (i.e., lexical information). Previous studies have revealed some of the specific brain regions and temporal information involved in sublexical information processing. However, a comprehensive spatiotemporal neural network for sublexical processing remains to be fully elucidated due to the low temporal or spatial resolutions of previous neuroimaging studies. In this study, we recorded stereoelectroencephalography signals with high spatial and temporal resolutions from a large sample of 39 epilepsy patients (both sexes) during a Chinese character oral reading task. We explored the activated brain regions and their connectivity related to three sublexical effects: phonological regularity (whether the whole character's pronunciation aligns with its phonetic radical), phonological consistency (whether characters with the same phonetic radical share the same pronunciation), and semantic transparency (whether the whole character's meaning aligns with its semantic radical). The results revealed that sublexical effects existed in the inferior frontal gyrus, precentral and postcentral gyri, temporal lobe, and middle occipital gyrus. Additionally, connectivity from the middle occipital gyrus to the postcentral gyrus and from postcentral gyrus to the fusiform gyrus was associated with the sublexical effects. These findings provide valuable insights into the spatiotemporal dynamics of sublexical processing and object recognition in the brain.

单词提供了一个独特的机会,可以将对象子成分的加工机制与整个对象的加工机制分开,因为单词子成分提供的语音或语义信息(即亚词汇信息)可能与整个单词提供的信息(即词汇信息)相冲突。以往的研究已经揭示了次词汇信息处理所涉及的一些特定脑区和时间信息。然而,由于之前的神经影像学研究的时间或空间分辨率较低,用于次词汇处理的全面时空神经网络仍有待全面阐明。在本研究中,我们记录了 39 名癫痫患者(男女均有)在汉字口语阅读任务中的高时空分辨率立体脑电图(SEEG)信号。我们探究了与三种亚词汇效应相关的激活脑区及其连通性:语音规则性(整个汉字的发音是否与其语音部首一致)、语音一致性(具有相同语音部首的汉字是否具有相同的发音)和语义透明度(整个汉字的意义是否与其语义部首一致)。结果显示,在额下回、中央前回和中央后回、颞叶和枕中回存在亚词汇效应。此外,从枕中回到中央后回以及从中央后回到纺锤形回的连接也与亚词汇效应有关。这些发现为了解大脑中次词汇加工和物体识别的时空动态提供了宝贵的见解。 意义声明 阐明次词汇加工背后错综复杂的神经机制对于了解人脑中语言理解和物体识别的复杂性至关重要。本研究采用颅内立体脑电图(SEEG)记录来研究汉字阅读任务中次词汇处理的时空动态。我们构建了亚词汇处理的神经网络,并描绘了其在不同脑区的时序。此外,我们还确定了该网络中的信息流,并观察了其在阅读包含不同次词汇信息的汉字时的变化。这些研究结果不仅加深了我们对控制次词汇处理的大脑机制的理解,还为更广泛的物体识别过程框架提供了启示。
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引用次数: 0
Alpha Traveling Waves during Working Memory: Disentangling Bottom-up Gating and Top-down Gain Control. 工作记忆中的α游走波:区分自下而上的门控和自上而下的增益控制
IF 4.4 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-11-06 DOI: 10.1523/JNEUROSCI.0532-24.2024
Yifan Zeng, Paul Sauseng, Andrea Alamia

While previous works established the inhibitory role of alpha oscillations during working memory maintenance, it remains an open question whether such an inhibitory control is a top-down process. Here, we attempted to disentangle this issue by considering the spatio-temporal component of waves in the alpha band, i.e., alpha traveling waves. We reanalyzed two pre-existing and open-access EEG datasets (N = 180, 90 males, 80 females, 10 unknown) where participants performed lateralized, visual delayed match-to-sample working memory tasks. In the first dataset, the distractor load was manipulated (2, 4, or 6), whereas in the second dataset, the memory span varied between 1, 3, and 6 items. We focused on the propagation of alpha waves on the anterior-posterior axis during the retention period. Our results reveal an increase in alpha-band forward waves as the distractor load increased, but also an increase in forward waves and a decrease in backward waves as the memory set size increased. Our results also showed a lateralization effect: alpha forward waves exhibited a more pronounced increase in the hemisphere contralateral to the distractors, whereas the reduction in backward waves was stronger in the hemisphere contralateral to the targets. In short, the forward waves were regulated by distractors, whereas targets inversely modulated backward waves. Such a dissociation of goal-related and goal-irrelevant physiological signals suggests the co-existence of bottom-up and top-down inhibitory processes: alpha forward waves might convey a gating effect driven by distractor load, while backward waves may represent direct top-down gain control of downstream visual areas.Significance Statement When exploring the functional role of alpha band neural oscillations during working memory, mostly amplitude modulations have been considered so far, with relatively limited exploration of spatial-temporal dynamics of this rather global brain oscillatory signature. The present study seeks to address this gap by examining the directionality of alpha wave propagation during working memory retention. Our findings offer novel insights into the well-established inhibitory role of alpha waves, demonstrating that this function is manifested differently according to their propagation directions: forward waves seem to facilitate bottom-up gating, while backward waves might mediate top-down gain control.

虽然之前的研究证实了阿尔法振荡在工作记忆维持过程中的抑制作用,但这种抑制控制是否是一个自上而下的过程仍是一个未决问题。在这里,我们试图通过考虑α波段波的时空成分,即α行波,来厘清这一问题。我们重新分析了两个已有的、开放存取的脑电图数据集(N = 180,90 名男性,80 名女性,10 名未知者),在这两个数据集中,参与者进行了侧向、视觉延迟匹配到样本的工作记忆任务。在第一个数据集中,分散注意力的负荷是可调的(2、4 或 6),而在第二个数据集中,记忆跨度在 1、3 和 6 个项目之间变化。我们重点研究了保留期间α波在前后轴上的传播。我们的结果表明,随着分心负荷的增加,α波段的前向波也会增加,但随着记忆集大小的增加,前向波也会增加,而后向波则会减少。我们的结果还显示了侧化效应:α前向波在分心者对侧半球的增加更为明显,而后向波在目标对侧半球的减少更为强烈。简而言之,前向波受到干扰物的调节,而目标则反向调节后向波。这种目标相关和目标无关生理信号的分离表明,自下而上和自上而下的抑制过程是并存的:α前向波可能传达了由分心物负荷驱动的门控效应,而后向波可能代表了对下游视觉区域直接的自上而下的增益控制。 意义声明 在探索工作记忆过程中α波段神经振荡的功能作用时,迄今为止考虑的主要是振幅调制,而对这一相当全面的大脑振荡特征的时空动态的探索相对有限。本研究试图通过研究工作记忆保持过程中阿尔法波传播的方向性来填补这一空白。我们的研究结果为α波行之有效的抑制作用提供了新的见解,证明这一功能根据其传播方向的不同而有不同的表现:前向波似乎有助于自下而上的门控,而后向波可能介导自上而下的增益控制。
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引用次数: 0
Persistent threat avoidance following negative reinforcement is not associated with elevated state anxiety. 负强化后的持续威胁回避与状态焦虑升高无关。
IF 4.4 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-11-06 DOI: 10.1523/JNEUROSCI.0815-24.2024
E A Crummy, B L Chamberlain, J P Gamboa, J L Pierson, S E Ahmari

Obsessive-Compulsive Disorder (OCD) is a debilitating illness consisting of obsessions and compulsions. OCD severity and treatment response are correlated with avoidant behaviors thought be performed to alleviate obsession-related anxiety. However, little is known about either the role of avoidance in the development of OCD or the interplay between anxiety states and avoidance behaviors. We have developed an instrumental negative reinforcement (i.e. active avoidance) paradigm in which mice must lever-press to avoid upcoming foot shocks. We show that mice (both sexes) can learn this task with high acquisition rates (75%) and that this behavior is largely stable when introducing uncertainty and modifying task structure. Furthermore, mice continue to perform avoidance responses on trials where lever pressing is not reinforced and increase response rates as they are maintained on this paradigm. With this paradigm, we did not find a relationship between negative reinforcement history and anxiety-related behaviors in well-established anxiety assays. Finally, we performed exploratory analyses to identify candidate regions involved in well-trained negative reinforcement using expression of the immediate early gene c-Fos. We detected correlated c-Fos expression in 1) cortico-striatal regions which regulate active avoidance in other paradigms and 2) amygdala circuits known to regulate conditioned defensive behaviors.Significance Statement Studies in patients with OCD suggest that compulsions are performed to avoid perceived threats and modulate anxiety tied to obsessions and/or compulsions. The negative reinforcement of avoidance and alleviated anxiety could therefore be a key driver of compulsive behaviors. However, there are still outstanding questions concerning the relationship between these two behaviors and the neural circuits involved in mediating negative reinforcement. We have developed an operant negative reinforcement paradigm in mice with discrete avoid and escape behaviors that can be learned without prior reward training with high throughput (75% acquisition) with responding that persists during nonreinforced trials. However, no differences were observed between negative reinforcement vs. unshocked and inescapably shocked controls, suggesting that continued negative reinforcement did not impact anxiety.

强迫症(OCD)是一种由强迫观念和强迫行为组成的使人衰弱的疾病。强迫症的严重程度和治疗反应与回避行为有关,回避行为被认为是为了减轻与强迫症相关的焦虑。然而,人们对回避在强迫症发展过程中的作用或焦虑状态与回避行为之间的相互作用知之甚少。我们开发了一种工具性负强化(即主动回避)范例,在该范例中,小鼠必须通过按压杠杆来避免即将到来的脚震。我们的研究表明,小鼠(雌雄均可)能以较高的习得率(75%)学会这项任务,而且当引入不确定性和改变任务结构时,这种行为在很大程度上是稳定的。此外,小鼠在不强化按压杠杆的试验中会继续做出回避反应,并且在该范式中的反应率会不断提高。通过这种范式,我们在成熟的焦虑试验中没有发现负强化历史与焦虑相关行为之间的关系。最后,我们利用即时早期基因 c-Fos 的表达进行了探索性分析,以确定参与训练有素的负强化的候选区域。我们在以下两个区域检测到了相关的 c-Fos 表达:1)在其他范式中调节主动回避的皮质纹状体区域;2)已知调节条件性防御行为的杏仁核回路。因此,回避和减轻焦虑的负强化可能是强迫行为的主要驱动力。然而,关于这两种行为之间的关系以及介导负强化的神经回路,仍然存在悬而未决的问题。我们在小鼠中开发了一种操作性负强化范式,该范式具有离散的回避和逃避行为,无需事先进行奖赏训练即可学习,且学习效率高(75% 的习得率),反应在非强化试验期间持续存在。然而,在负强化与未电击和不可避免电击的对照组之间没有观察到差异,这表明持续的负强化不会影响焦虑。
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引用次数: 0
The scope and limits of fine-grained image and category information in the ventral visual pathway. 腹侧视觉通路中细粒度图像和类别信息的范围和局限。
IF 4.4 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-11-06 DOI: 10.1523/JNEUROSCI.0936-24.2024
Markus W Badwal, Johanna Bergmann, Johannes Roth, Christian F Doeller, Martin N Hebart

Humans can easily abstract incoming visual information into discrete semantic categories. Previous research employing functional MRI (fMRI) in humans has identified cortical organizing principles that allow not only for coarse-scale distinctions such as animate versus inanimate objects but also more fine-grained distinctions at the level of individual objects. This suggests that fMRI carries rather fine-grained information about individual objects. However, most previous work investigating fine-grained category representations either additionally included coarse-scale category comparisons of objects, which confounds fine-grained and coarse-scale distinctions, or only used a single exemplar of each object, which confounds visual and semantic information. To address these challenges, here we used multisession human fMRI (female and male) paired with a broad yet homogenous stimulus class of 48 terrestrial mammals, with 2 exemplars per mammal. Multivariate decoding and representational similarity analysis (RSA) revealed high image-specific reliability in low- and high-level visual regions, indicating stable representational patterns at the image level. In contrast, analyses across exemplars of the same animal yielded only small effects in the lateral occipital complex (LOC), indicating rather subtle category effects in this region. Variance partitioning with a deep neural network and shape model showed that across exemplar effects in EVC were largely explained by low-level visual appearance, while representations in LOC appeared to also contain higher category-specific information. These results suggest that representations typically measured with fMRI are dominated by image-specific visual or coarse-grained category information but indicate that commonly employed fMRI protocols may reveal subtle yet reliable distinctions between individual objects.Significance Statement While it has been suggested that functional MRI (fMRI) responses in ventral visual cortex carry fine-grained information about individual objects, much previous research has confounded fine-grained with coarse-scale category information or only used individual visual exemplars, which potentially confounds semantic and visual object information. Here we address these challenges in a multisession fMRI study where participants viewed a highly homogenous stimulus set of 48 land mammals with 2 exemplars per animal. Our results reveal a strong dominance of image-specific effects and additionally indicate subtle yet reliable category-specific effects in lateral occipital complex, underscoring the capacity of commonly employed fMRI protocols to uncover fine-grained visual information.

人类可以轻松地将接收到的视觉信息抽象为离散的语义类别。此前对人类进行的功能性核磁共振成像(fMRI)研究发现,大脑皮层的组织原则不仅允许粗略区分有生命和无生命的物体,还允许在单个物体的层次上进行更精细的区分。这表明,fMRI 可携带有关单个物体的精细信息。然而,之前大多数研究细粒度类别表征的工作要么额外包含了物体的粗尺度类别比较,从而混淆了细粒度和粗尺度的区分;要么只使用了每个物体的单个示例,从而混淆了视觉和语义信息。为了应对这些挑战,我们在这里使用了多期人类 fMRI(女性和男性)与广泛但同质的刺激类别(48 种陆生哺乳动物)配对,每种哺乳动物使用 2 个示例。多变量解码和表征相似性分析(RSA)显示,在低级和高级视觉区域中,特定图像的可靠性很高,这表明图像水平上的表征模式是稳定的。与此相反,对同一动物的不同示例进行的分析仅在侧枕复合体(LOC)中产生了微小的影响,这表明该区域存在相当微妙的类别效应。利用深度神经网络和形状模型进行的方差划分表明,EVC 中的跨范例效应主要是由低级视觉外观解释的,而 LOC 中的表征似乎也包含较高的特定类别信息。这些结果表明,通常用fMRI测量的表征是由图像特异性视觉或粗粒度类别信息主导的,但也表明,常用的fMRI方案可能会揭示单个物体之间微妙而可靠的区别。意义声明 虽然有人认为,腹侧视觉皮层的功能磁共振成像(fMRI)反应携带着关于单个物体的细粒度信息,但之前的许多研究都将细粒度和粗粒度类别信息混为一谈,或者只使用单个视觉范例,这可能会混淆语义和视觉物体信息。在这里,我们通过一项多期 fMRI 研究来解决这些难题。在这项研究中,参与者观看了由 48 种陆地哺乳动物组成的高度同质化的刺激集,每种动物有 2 个范例。我们的研究结果表明,图像特异性效应占主导地位,此外,外侧枕叶复合体还显示出微妙但可靠的类别特异性效应,这突出表明常用的 fMRI 方案有能力揭示细粒度的视觉信息。
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引用次数: 0
Selective Vulnerability of GABAergic Inhibitory Interneurons to Bilirubin Neurotoxicity in the Neonatal Brain. 新生儿大脑中 GABA 能抑制性中间神经元对胆红素神经毒性的选择脆弱性
IF 4.4 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-11-06 DOI: 10.1523/JNEUROSCI.0442-24.2024
Li-Na Gong, Han-Wei Liu, Ke Lai, Zhen Zhang, Lin-Fei Mao, Zhen-Qi Liu, Ming-Xian Li, Xin-Lu Yin, Min Liang, Hai-Bo Shi, Lu-Yang Wang, Shan-Kai Yin

Hyperbilirubinemia (HB) is a key risk factor for hearing loss in neonates, particularly premature infants. Here, we report that bilirubin (BIL)-dependent cell death in the auditory brainstem of neonatal mice of both sexes is significantly attenuated by ZD7288, a blocker for hyperpolarization-activated cyclic nucleotide-gated (HCN) channel-mediated current (I h), or by genetic deletion of HCN1. GABAergic inhibitory interneurons predominantly express HCN1, on which BIL selectively acts to increase their intrinsic excitability and mortality by enhancing HCN1 activity and Ca2+-dependent membrane targeting. Chronic BIL elevation in neonatal mice in vivo increases the fraction of spontaneously active interneurons and their firing frequency, I h, and death, compromising audition at the young adult stage in HCN1+/+, but not in HCN1-/- genotype. We conclude that HB preferentially targets HCN1 to injure inhibitory interneurons, fueling a feedforward loop in which lessening inhibition cascades hyperexcitability, Ca2+ overload, neuronal death, and auditory impairments. These findings rationalize HCN1 as a potential target for managing HB encephalopathy.

高胆红素血症(HB)是新生儿,尤其是早产儿听力损失的一个关键风险因素。在此,我们报告了胆红素(BIL)依赖性细胞死亡在新生小鼠听性脑干(雌雄均有)中的表现,ZD7288(一种超极化激活环核苷酸门控(HCN)通道介导电流(Ih)的阻断剂)或遗传性HCN1缺失可显著减轻这种细胞死亡。GABA 能抑制性中间神经元主要表达 HCN1,BIL 通过增强 HCN1 活性和 Ca2+ 依赖性膜靶向作用,选择性地增加其内在兴奋性和死亡率。在体内对新生小鼠进行慢性 BIL 升高会增加自发活跃中间神经元的比例及其发射频率、Ih 和死亡,从而损害 HCN1+/+ 基因型小鼠在幼年期的听觉,但不会损害 HCN1-/- 基因型小鼠的听觉。我们的结论是,HB 优先靶向 HCN1,伤害抑制性中间神经元,形成一个前馈循环,在这个循环中,抑制作用的减弱会导致过度兴奋、Ca2+ 过载、神经元死亡和听觉障碍。该研究表明,胆红素优先靶向 GABA 能中间神经元,它不仅促进 HCN1 通道的门控,还以钙依赖方式将细胞内 HCN1 靶向质膜,导致神经元过度兴奋、损伤和感觉功能障碍。这些发现表明,HCN1 通道不仅是新生儿胆红素脑病患者听觉异常的潜在驱动因素,也是临床治疗与严重黄疸相关的神经损伤的潜在干预目标。中间神经元对神经毒性的选择性脆弱性可能对理解其他形式的脑损伤具有普遍意义。
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引用次数: 0
Targeting Endogenous Tau in Seeded Tauopathy Models Inhibits Tau Spread. 在种子型 Tauopathy 模型中靶向内源性 Tau 可抑制 Tau 的扩散。
IF 4.4 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-11-05 DOI: 10.1523/JNEUROSCI.0877-24.2024
Elliot Jang, Kevt'her Hoxha, Damian Mozier, Abigail Insana, Ethan Farber, Lakshmi Changolkar, Bin Zhang, Tak-Ian Chio, Alex Crowe, Richard Chen, Marc Mercken, Edward B Lee, Kelvin C Luk, Kurt R Brunden, Virginia M-Y Lee, Hong Xu

The transmission of tau pathology has been proposed as one of the major mechanisms for the spatiotemporal spreading of tau pathology in neurodegenerative diseases. Over the last decade, studies have demonstrated that targeting total or pathological tau using tau antibodies can mitigate the development of tau pathology in tauopathy or Alzheimer's disease (AD) mouse models, and multiple tau immunotherapy agents have progressed to clinical trials. Tau antibodies are believed to inhibit the internalization of pathologic seeds and/or block seed elongation after seed internalization. To further address the mechanism of tau antibody inhibition of pathological spread, we conducted immunotherapy studies in mouse primary neurons and wild-type mice (females) seeded with AD patient-derived tau to induce the formation and spreading of tau pathology. Notably, we evaluated the effect of a mouse tau-specific antibody (mTau8) which does not interact with AD-tau seeds in these models. Our results show that mTau8 crosses the blood-brain barrier at levels similar to other antibodies and effectively decreases AD-tau-seeded tau pathology in vitro and in vivo. Importantly, our data suggest that mTau8 binds to endogenous intraneuronal mouse tau, thereby inhibiting the elongation of internalized tau seeds. These findings provide valuable insights into the possible mechanism underlying antibody-based therapies for treating tauopathies.Significance Statement The transmission of tau pathology plays key role in the pathoclinical progression of tauopathy. Studies have shown that tau antibody treatment can mitigate tau pathology in transgenic and spreading models of tauopathy. To explore the mechanisms involved in this procedure, we conducted immunotherapy studies on human tau seeds induced tau spreading models using a mouse tau-specific antibody (mTau8), which does not interact with human-tau seeds. Our findings in the study enhance our understanding of antibody-based therapies for tauopathies.

tau病理学的传递被认为是神经退行性疾病中tau病理学时空扩散的主要机制之一。在过去的十年中,研究表明,使用tau抗体靶向总tau或病理tau可以缓解tau病或阿尔茨海默病(AD)小鼠模型中tau病理学的发展,多种tau免疫疗法药物已进入临床试验阶段。Tau抗体被认为能抑制病理种子的内化和/或阻止种子内化后的伸长。为了进一步研究 tau 抗体抑制病理扩散的机制,我们在小鼠原始神经元和野生型小鼠(雌性)的免疫疗法研究中播下了 AD 患者来源的 tau 种子,以诱导 tau 病理的形成和扩散。值得注意的是,我们评估了小鼠tau特异性抗体(mTau8)在这些模型中的效果,该抗体与AD-tau种子没有相互作用。我们的结果表明,mTau8能穿过血脑屏障,其水平与其他抗体相似,并能在体外和体内有效减少AD-tau种子的tau病理变化。重要的是,我们的数据表明,mTau8能与小鼠内源性神经元内tau结合,从而抑制内化tau种子的伸长。这些发现为基于抗体的治疗方法治疗tau病的可能机制提供了有价值的见解。 意义声明 tau病理学的传播在tau病的病理进展中起着关键作用。研究表明,在tau病的转基因模型和扩散模型中,tau抗体治疗可减轻tau病理变化。为了探索这一过程的相关机制,我们使用小鼠tau特异性抗体(mTau8)对人tau种子诱导的tau扩散模型进行了免疫治疗研究,该抗体与人tau种子没有相互作用。我们的研究结果加深了我们对基于抗体的tau病疗法的理解。
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引用次数: 0
Input / Output Relationships for the Primary Hippocampal Circuit. 初级海马回路的输入/输出关系
IF 4.4 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-11-05 DOI: 10.1523/JNEUROSCI.0130-24.2024
B G Gunn, B S Pruess, C M Gall, G Lynch

The hippocampus is the most studied brain region but little is known about signal throughput -- the simplest, yet most essential of circuit operations -- across its multiple stages from perforant path input to CA1 output. Using hippocampal slices derived from male mice, we have found that single-pulse lateral perforant path (LPP) stimulation produces a two-part CA1 response generated by LPP projections to CA3 ('direct path') and the dentate gyrus ('indirect path'). The latter, indirect path was far more potent in driving CA1 but did so only after a lengthy delay. Rather than operating as expected from the much discussed trisynaptic circuit argument, the indirect path used the massive CA3 recurrent collateral system to trigger a high frequency sequence of fEPSPs and spikes. The latter events promoted reliable signal transfer to CA1 but the mobilization time for the stereotyped, CA3 response resulted in surprisingly slow throughput. The circuit transmitted theta (5Hz) but not gamma (50Hz) frequency input, thus acting as a low-pass filter. It reliably transmitted short bursts of gamma input separated by the period of theta wave - CA1 spiking output under these conditions closely resembled the input signal. In all, the primary hippocampal circuit does not behave as a linear, three-part system but instead uses novel filtering and amplification steps to shape throughput and restrict effective input to select patterns. We suggest that the operations described here constitute a default mode for processing cortical inputs with other types of functions being enabled by projections from outside the extended hippocampus.Significance statement Despite intense interest in hippocampal contributions to behavior, surprisingly little is known about how signals are processed across the network linking cortical input to CA1 output. Here, we describe the first input/output relationship for the system with results challenging the traditional tri-synaptic circuit concept. Signal throughput requires mobilization of recurrent activity within CA3 to amplify sparse input from the dentate gyrus into an unexpectedly stereotyped composite response. Potent low-pass filters determine effective input patterns. These results open the way to new analyses of how variables such as aging affect hippocampus and its contributions to behavior while providing material needed for biologically realistic models of the structure.

海马是研究最多的脑区,但人们对海马从穿孔路径输入到CA1输出的多个阶段的信号吞吐量却知之甚少。利用雄性小鼠的海马切片,我们发现单脉冲外侧穿孔路径(LPP)刺激会产生两部分 CA1 反应,分别由 LPP 投射到 CA3("直接路径")和齿状回("间接路径")产生。后一种间接路径对 CA1 的驱动力要强得多,但要经过长时间的延迟才能实现。间接路径并不像人们讨论较多的三突触回路论点所预期的那样,而是利用大规模的 CA3 循环旁路系统来触发高频率的 fEPSPs 和尖峰序列。后一事件促进了向 CA1 的可靠信号转移,但 CA3 定型反应的动员时间导致吞吐量出奇地缓慢。该电路能传输θ(5Hz)频率输入信号,但不能传输γ(50Hz)频率输入信号,因此起到了低通滤波器的作用。它能可靠地传输由θ波周期分隔的伽马输入短脉冲--在这些条件下,CA1尖峰输出与输入信号非常相似。总之,初级海马回路并不是一个线性的三部分系统,而是利用新颖的过滤和放大步骤来塑造吞吐量,并将有效输入限制在选择的模式上。我们认为,这里描述的操作构成了处理大脑皮层输入的默认模式,而其他类型的功能则由来自扩展海马外部的投射启用。意义声明 尽管人们对海马对行为的贡献有着浓厚的兴趣,但令人惊讶的是,人们对连接大脑皮层输入和CA1输出的整个网络是如何处理信号的知之甚少。在这里,我们首次描述了该系统的输入/输出关系,其结果对传统的三突触回路概念提出了挑战。信号吞吐需要调动 CA3 中的递归活动,将来自齿状回的稀疏输入放大为出乎意料的刻板复合反应。有效的低通滤波器决定了有效的输入模式。这些结果为分析衰老等变量如何影响海马及其对行为的贡献开辟了新的途径,同时也为该结构的生物现实模型提供了所需的材料。
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引用次数: 0
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