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Acid-sensing ion channels drive the generation of tactile impulses in Merkel cell-neurite complexes of the glabrous skin of rodent hindpaws. 酸感应离子通道驱动啮齿动物后爪无毛皮肤的梅克尔细胞-神经元复合体产生触觉冲动。
IF 4.4 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-10-08 DOI: 10.1523/JNEUROSCI.0885-24.2024
Akihiro Yamada, Mayank Gautam, Ayaka I Yamada, Jennifer Ling, Saurav Gupta, Hidemasa Furue, Wenqin Luo, Jianguo G Gu

Merkel cell-neurite complexes (MNCs) are enriched in touch-sensitive areas, including whisker hair follicles and the glabrous skin of the rodent's paws, where tactile stimulation elicits slowly adapting type 1 (SA1) tactile impulses to encode for the sense of touch. Recently, we have shown with rodent whisker hair follicles that SA1 impulses are generated through fast excitatory synaptic transmission at MNCs and driven by acid-sensing ion channels (ASICs). However, it is currently unknown whether, besides whisker hair follicles, ASICs also play an essential role in generating SA1 impulses from MNCs of other body parts in mammals. In the present study, we attempted to address this question by using the skin-nerve preparations made from the hindpaw glabrous skin and tibial nerves of both male and female rodents and applying the pressure-clamped single-fiber recordings. We showed that SA1 impulses elicited by tactile stimulation to the rat hindpaw glabrous skin were largely diminished in the presence of amiloride and diminazene, two ASIC channel blockers. Furthermore, using the hindpaw glabrous skin and tibial nerve preparations made from the mice genetically deleted of ASIC3 channels (ASIC3-/-), we showed that the frequency of SA1 impulses was significantly lower in ASIC3-/- mice than in littermate wildtype ASIC3+/+ mice, a result consistent with the pharmacological experiments with ASIC channel blockers. Our findings suggest that ASIC channels are essential for generating SA1 impulses to underlie the sense of touch in the glabrous skin of rodent hindpaws.Significance Statement Merkel cell-neurite complexes (MNCs) are enriched in touch-sensitive areas, including whisker hair follicles and the glabrous skin of the rodent's paws, where tactile stimulation elicits slowly adapting type 1 (SA1) tactile impulses to encode for the sense of touch. Here, using the skin-nerve preparations made from the hindpaw glabrous skin and tibial nerves of rodents and applying the pressure-clamped single-fiber recordings, we have demonstrated that ASIC channels are essential for generating SA1 impulses at MNCs in the glabrous skin of rodent hindpaws. Thus, ASIC channels at MNCs may play a key role in the sense of touch to the skin of mammals.

梅克尔细胞-神经元复合体(MNCs)富集于触觉敏感区域,包括啮齿动物的胡须毛囊和爪部无毛皮肤,触觉刺激会引起缓慢适应的 1 型(SA1)触觉冲动,从而编码触觉。最近,我们用啮齿动物的胡须毛囊证明,SA1 脉冲是通过 MNC 的快速兴奋性突触传递和酸感应离子通道(ASIC)驱动产生的。然而,除了须毛囊外,ASIC 是否也在哺乳动物其他身体部位的 MNC 产生 SA1 脉冲中发挥重要作用,目前尚不清楚。在本研究中,我们尝试利用雌雄啮齿动物的后爪无毛皮和胫神经制备的皮肤神经制剂,并应用压力钳单纤记录来解决这一问题。我们的研究表明,在阿米洛利和地米那嗪这两种ASIC通道阻断剂的作用下,大鼠后爪无毛皮受到触觉刺激时产生的SA1冲动会大大减少。此外,我们还利用从基因上删除了ASIC3通道(ASIC3-/-)的小鼠的后爪无毛皮肤和胫神经制备物,发现ASIC3-/-小鼠的SA1脉冲频率明显低于同窝野生型ASIC3+/+小鼠,这一结果与ASIC通道阻断剂的药理实验结果一致。我们的研究结果表明,ASIC 通道对产生 SA1 脉冲至关重要,是啮齿动物后爪无毛皮肤触觉的基础。 重要意义 声明 梅克尔细胞-神经元复合体(MNCs)富集在触觉敏感区域,包括胡须毛囊和啮齿动物爪子的无毛皮肤,触觉刺激会引起缓慢适应的 1 型(SA1)触觉脉冲,从而编码触觉。在这里,我们利用从啮齿动物后爪无毛皮和胫神经制备的皮肤神经制剂,并应用压力钳夹单纤维记录,证明了 ASIC 通道对于在啮齿动物后爪无毛皮的 MNC 上产生 SA1 脉冲是必不可少的。因此,MNCs 上的 ASIC 通道可能在哺乳动物皮肤的触觉中起着关键作用。
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引用次数: 0
A dynamic link between respiration and arousal. 呼吸与唤醒之间的动态联系
IF 4.4 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-10-08 DOI: 10.1523/JNEUROSCI.1173-24.2024
Daniel S Kluger, Joachim Gross, Christian Keitel

Viewing brain function through the lense of other physiological processes has critically added to our understanding of human cognition. Further advances though may need a closer look at the interactions between these physiological processes themselves. Here we characterise the interplay of the highly periodic, and metabolically vital respiratory process and fluctuations in arousal neuromodulation, a process classically seen as non-periodic. In data of three experiments (N = 56 / 27 / 25 women and men) we tested for covariations in respiratory and pupil size (arousal) dynamics. After substantiating a robust coupling in the largest dataset, we further show that coupling strength decreases during task performance compared with rest, and that it mirrors a decreased respiratory rate when participants take deeper breaths. Taken together, these findings suggest a stronger link between respiratory and arousal processes than previously thought. Moreover, these links imply a stronger coupling during periods of rest, and the effect of respiratory rate on the coupling suggests a driving role. As a consequence, studying the role of neuromodulatory arousal on cortical function may also need to consider respiratory influences.Significance statement We characterise the interplay of the respiratory rhythm and pupil diameter dynamics as a well-known proxy for arousal. Although we consistently find respiratory modulation of pupillary changes, they were most pronounced during periods of rest (compared to during task performance) and dependent on respiratory rate (deep vs. normal breathing).

通过其他生理过程来观察大脑功能,极大地促进了我们对人类认知的理解。不过,要取得进一步的进展,可能需要更仔细地研究这些生理过程之间的相互作用。在这里,我们描述了具有高度周期性和新陈代谢活力的呼吸过程与唤醒神经调节波动之间的相互作用。在三项实验数据(N = 56 / 27 / 25 名女性和男性)中,我们测试了呼吸和瞳孔大小(唤醒)动态的共变。在最大的数据集中证实了稳健的耦合之后,我们进一步表明,与休息相比,任务执行期间的耦合强度会降低,而且当参与者进行深呼吸时,耦合强度会反映呼吸频率的降低。综上所述,这些研究结果表明,呼吸过程与唤醒过程之间的联系比以往认为的更为紧密。此外,这些联系意味着在休息期间会有更强的耦合作用,而呼吸频率对耦合作用的影响表明呼吸频率起着驱动作用。因此,在研究神经调节唤醒对大脑皮层功能的作用时,可能也需要考虑呼吸的影响。意义声明 我们描述了呼吸节律和瞳孔直径动态之间的相互作用,这是众所周知的唤醒替代物。尽管我们始终发现呼吸对瞳孔变化的调节作用,但这种调节作用在休息期间(与执行任务期间相比)最为明显,并且取决于呼吸频率(深呼吸与正常呼吸)。
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引用次数: 0
How distributed subcortical integration of reward and threat may inform subsequent approach-avoidance decisions. 皮层下对奖赏和威胁的分布式整合如何为随后的接近-回避决策提供信息。
IF 4.4 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-10-08 DOI: 10.1523/JNEUROSCI.0794-24.2024
Anneloes M Hulsman, Felix H Klaassen, Lycia D de Voogd, Karin Roelofs, Floris Klumpers

Healthy and successful living involves carefully navigating rewarding and threatening situations by balancing approach and avoidance behaviours. Excessive avoidance to evade potential threats often leads to forfeiting potential rewards. However, little is known about how reward and threat information is integrated neurally to inform approach or avoidance decisions. In this preregistered study, participants (Nbehaviour=31, 17F; NMRI=28, 15F) made approach-avoidance decisions under varying reward (monetary gains) and threat (electrical stimulations) prospects during functional MRI scanning. In contrast to theorized parallel subcortical processing of reward and threat information before cortical integration, Bayesian Multivariate Multilevel analyses revealed subcortical reward and threat integration prior to indicating approach-avoidance decisions. This integration occurred in the ventral striatum, thalamus, and bed nucleus of the stria terminalis (BNST). When reward was low, risk-diminishing avoidance decisions dominated, which was linked to more positive tracking of threat magnitude prior to indicating avoidance than approach decisions across these regions. In contrast, the amygdala exhibited dual sensitivity to reward and threat. While anticipating outcomes of risky approach decisions, we observed positive tracking of threat magnitude within the salience network (dorsal anterior cingulate cortex, thalamus, periaqueductal gray, BNST). Conversely, after risk-diminishing avoidance, characterized by reduced reward prospects, we observed more negative tracking of reward magnitude in the ventromedial prefrontal cortex and ventral striatum. These findings shed light on the temporal dynamics of approach-avoidance decision-making. Importantly, they demonstrate the role of subcortical integration of reward and threat information in balancing approach and avoidance, challenging theories positing predominantly separate subcortical processing prior to cortical integration.Significance statement When deciding whether to approach or avoid situations, our decision-making involves balancing potential rewards and threats. Widespread theories of decision-making in humans propose parallel processing of reward and threat information in subcortical regions, followed by cortical integration. Challenging these notions, we found evidence for dual and integrated processing of reward and threat in subcortical regions during decision-making. In contrast, after decision-making, we observed the expected parallel processing while anticipating decision outcomes. These findings advance our understanding of approach-avoidance decision-making processes, opposing traditional views that segregate brain regions as predominantly reward-sensitive or threat-sensitive, thereby paving the way for a more nuanced perspective that takes into account the stage of decision-making.

健康和成功的生活需要通过平衡接近和回避行为,谨慎地驾驭有回报和有威胁的情况。为了躲避潜在威胁而过度回避,往往会导致失去潜在的奖励。然而,人们对奖励和威胁信息是如何通过神经整合来为接近或回避决策提供信息的却知之甚少。在这项预先登记的研究中,参与者(Nbehaviour=31,17F;NMRI=28,15F)在功能磁共振成像扫描过程中,根据不同的奖励(金钱收益)和威胁(电刺激)前景做出接近-回避决策。贝叶斯多变量多层次分析显示,在做出接近-回避决策之前,皮层下会对奖赏和威胁信息进行并行处理。这种整合发生在腹侧纹状体、丘脑和纹状体末端床核(BNST)。当奖赏较低时,降低风险的回避决策占主导地位,这与这些区域在做出回避决策之前对威胁程度的积极追踪有关。相反,杏仁核对奖赏和威胁表现出双重敏感性。在预测有风险的接近决策的结果时,我们观察到在显著性网络(背侧前扣带回皮层、丘脑、丘脑周围灰质、BNST)中对威胁程度的正向追踪。相反,在以奖励前景减少为特征的风险减少型回避之后,我们在腹内侧前额叶皮层和腹侧纹状体中观察到了更多的奖励幅度负追踪。这些发现揭示了接近-回避决策的时间动态。重要的是,它们证明了皮层下整合奖赏和威胁信息在平衡接近和回避中的作用,这对皮层下整合之前主要进行独立处理的理论提出了挑战。人类普遍的决策理论认为,奖励和威胁信息在皮层下区域并行处理,然后在皮层进行整合。我们发现了决策过程中皮层下区域对奖赏和威胁进行双重整合处理的证据,这对这些观点提出了挑战。相反,在决策后,我们观察到了预期的平行处理,同时预期决策结果。这些发现推进了我们对接近-回避决策过程的理解,反对了将大脑区域划分为主要对奖赏敏感或对威胁敏感的传统观点,从而为考虑决策阶段的更细微差别的观点铺平了道路。
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引用次数: 0
Glutamine Oxidation in Mouse Dorsal Root Ganglia Regulates Pain Resolution and Chronification. 小鼠背根神经节中的谷氨酰胺氧化调节疼痛的缓解和慢性化。
IF 4.4 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-10-08 DOI: 10.1523/JNEUROSCI.1442-24.2024
Md Mamunul Haque, Panjamurthy Kuppusamy, Ohannes K Melemedjian

Chronic pain remains a significant health challenge with limited effective treatments. This study investigates the metabolic changes underlying pain progression and resolution, uncovering a novel compensatory mechanism in sensory neurons. Using the hyperalgesic priming model in male mice, we demonstrate that nerve growth factor (NGF) initially disrupted mitochondrial pyruvate oxidation, leading to acute allodynia. Surprisingly, this metabolic disruption persisted even after the apparent resolution of allodynia. We discovered that during the resolution phase, sensory neurons exhibit increased glutamine oxidation and upregulation of the major glutamine transporter ASCT2 in dorsal root ganglia (DRGs). This compensatory response plays a crucial role in pain resolution, as demonstrated by our experiments. Knockdown of ASCT2 prevents the resolution of NGF-induced allodynia and precipitates the transition to a chronic state. Furthermore, we show that the glutamine catabolite α-ketoglutarate attenuated glycolytic flux and alleviated allodynia in both acute and chronic phases of the hyperalgesic priming model. The importance of ASCT2 is further confirmed in a translational model, where its knockdown prevented the resolution of allodynia following plantar incision. These findings highlight the pivotal role of metabolic changes in pain resolution and identify ASCT2-mediated glutamine metabolism as a potential therapeutic target for chronic pain. Understanding these endogenous mechanisms that promote pain resolution can guide the development of novel interventions to prevent the transition pain from acute to chronic.Significance Statement Chronic pain is a widespread health issue with limited effective treatments. This study unveils a critical metabolic mechanism in sensory neurons that determines whether acute pain resolves or becomes chronic. We discovered that pain resolution depends on a compensatory increase in glutamine metabolism, mediated by the transporter ASCT2, rather than normalization of initial metabolic disruptions. This finding significantly advances our understanding of pain chronification and identifies a novel therapeutic target. By elucidating how the body naturally resolves pain, we open new avenues for developing treatments that could prevent acute pain from transitioning to chronic pain or treat existing chronic pain. This research has the potential to transform pain management strategies and improve quality of life for millions of pain sufferers.

慢性疼痛仍然是一项重大的健康挑战,但有效的治疗方法却很有限。本研究调查了疼痛进展和缓解背后的代谢变化,发现了感觉神经元中的一种新型补偿机制。我们利用雄性小鼠的超痛引物模型证明,神经生长因子(NGF)最初会破坏线粒体丙酮酸氧化,从而导致急性痛觉过敏。令人惊讶的是,即使在痛觉明显缓解后,这种代谢紊乱仍然存在。我们发现,在缓解阶段,感觉神经元表现出谷氨酰胺氧化增加以及背根神经节(DRGs)中主要谷氨酰胺转运体 ASCT2 的上调。正如我们的实验所证明的那样,这种代偿反应在疼痛缓解过程中起着至关重要的作用。敲除 ASCT2 会阻止 NGF 诱导的痛觉失调的缓解,并促使痛觉失调向慢性状态过渡。此外,我们还发现,谷氨酰胺代谢产物α-酮戊二酸可减轻糖酵解通量,并减轻超痛引物模型急性和慢性阶段的异动症。ASCT2 的重要性在转化模型中得到了进一步证实,在该模型中,ASCT2 的敲除阻止了足底切口后异痛症的缓解。这些发现强调了新陈代谢变化在疼痛缓解中的关键作用,并将 ASCT2 介导的谷氨酰胺新陈代谢确定为慢性疼痛的潜在治疗靶点。了解这些促进疼痛缓解的内源性机制可以指导新型干预措施的开发,防止疼痛从急性向慢性过渡。本研究揭示了感觉神经元中决定急性疼痛是缓解还是转为慢性的关键代谢机制。我们发现,疼痛的缓解取决于谷氨酰胺代谢的代偿性增加(由转运体 ASCT2 介导),而不是最初代谢紊乱的正常化。这一发现大大推进了我们对疼痛慢性化的理解,并确定了一个新的治疗靶点。通过阐明人体如何自然地解决疼痛问题,我们为开发可防止急性疼痛转变为慢性疼痛或治疗现有慢性疼痛的疗法开辟了新途径。这项研究有可能改变疼痛管理策略,改善数百万疼痛患者的生活质量。
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引用次数: 0
Different subregions of monkey lateral prefrontal cortex respond to abstract sequences and their components. 猴子外侧前额叶皮层不同亚区对抽象序列及其成分的反应
IF 4.4 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-10-08 DOI: 10.1523/JNEUROSCI.1353-24.2024
Nadira Yusif Rodriguez, Aarit Ahuja, Debaleena Basu, Theresa H McKim, Theresa M Desrochers

Sequential information permeates daily activities, such as when watching for the correct series of buildings to determine when to get off the bus or train. These sequences include periodicity (the spacing of the buildings), the identity of the stimuli (the kind of house), and higher-order more abstract rules that may not depend on the exact stimulus (e.g. house, house, house, business). Previously, we found that the posterior fundus of area 46 in the monkey lateral prefrontal cortex (LPFC) responds to rule changes in such abstract visual sequences. However, it is unknown if this region responds to other components of the sequence, i.e., image periodicity and identity, in isolation. Further, it is unknown if this region dissociates from other, more ventral LPFC subregions that have been associated with sequences and their components. To address these questions, we used awake functional magnetic resonance imaging in three male macaque monkeys during two no-report visual tasks. One task contained abstract visual sequences, and the other contained no visual sequences but maintained the same image periodicity and identities. We found the fundus of area 46 responded only to abstract sequence rule violations. In contrast, the ventral bank of area 46 responded to changes in image periodicity and identity, but not changes in the abstract sequence. These results suggest a functional specialization within anatomical substructures of LPFC to signal different kinds of stimulus regularities. This specialization may provide key scaffolding to identify abstract patterns and construct complex models of the world for daily living.Significance Statement Daily tasks, such as a bus commute, require tracking or monitoring your place (same, same, same, different building) until your stop. Sequence components such as rule, periodicity (timing), and item identity are involved in this process. While prior work located responses to sequence rule changes to area 46 of monkey lateral prefrontal cortex (LPFC) using awake monkey fMRI, less was known about other components. We found that LPFC subregions differentiated between sequence components. Area 46 posterior fundus responded to abstract visual sequence rule changes, but not to changes in image periodicity or identity. The converse was true for the more ventral, adjacent shoulder region. These results suggest that interactions between adjacent LPFC subregions provide key scaffolding for complex daily behaviors.

序列信息渗透到日常活动中,例如,当观察一系列正确的建筑物以确定何时下公共汽车或火车时。这些序列包括周期性(建筑物的间距)、刺激物的特征(房子的种类)以及可能不依赖于确切刺激物的高阶抽象规则(如房子、房子、房子、生意)。在此之前,我们发现猴子外侧前额叶皮层(LPFC)的 46 区后部基底会对此类抽象视觉序列中的规则变化做出反应。然而,该区域是否会单独对序列中的其他成分(即图像周期性和特征)做出反应,目前还不得而知。此外,该区域是否与其他与序列及其成分相关的更腹侧 LPFC 亚区域分离也是未知数。为了解决这些问题,我们对三只雄性猕猴在两项无报告视觉任务中进行了清醒功能磁共振成像。一项任务包含抽象的视觉序列,另一项任务不包含视觉序列,但保持相同的图像周期和特征。我们发现 46 区的基底只对违反抽象序列规则的行为做出反应。相比之下,46 区腹侧库对图像周期性和特征的变化有反应,但对抽象序列的变化没有反应。这些结果表明,LPFC 的解剖亚结构内部存在功能特化,可发出不同类型刺激规律性的信号。这种特化可能为识别抽象模式和构建日常生活中复杂的世界模型提供了关键的支架。 重要意义 声明 日常任务,如乘坐公共汽车上下班,需要跟踪或监测您的位置(相同、相同、相同、不同的建筑物),直到您到站为止。在这一过程中涉及到规则、周期性(定时)和项目标识等序列成分。之前的研究利用清醒猴子的 fMRI 将对序列规则变化的反应定位在猴子外侧前额叶皮层(LPFC)的 46 区,但对其他成分却知之甚少。我们发现,LPFC 亚区可区分序列成分。46区后部基底对抽象的视觉序列规则变化有反应,但对图像周期性或特征的变化没有反应。而更腹侧的相邻肩区则相反。这些结果表明,相邻 LPFC 亚区之间的相互作用为复杂的日常行为提供了关键的支架。
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引用次数: 0
The relationship between white matter architecture and language lateralisation in the healthy brain. 健康大脑白质结构与语言侧化之间的关系。
IF 4.4 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-10-07 DOI: 10.1523/JNEUROSCI.0166-24.2024
Ieva Andrulyte, Christophe De Bezenac, Francesca Branzi, Stephanie J Forkel, Peter N Taylor, Simon S Keller

Interhemispheric anatomical differences have long been thought to be related to language lateralisation. Previous studies have explored whether asymmetries in the diffusion characteristics of white matter language tracts are consistent with language lateralisation. These studies, typically with smaller cohorts, yielded mixed results. This study investigated whether connectomic analysis of quantitative anisotropy (QA) and shape features of white matter tracts across the whole brain are associated with language lateralisation. We analysed 1040 healthy individuals (562 females) from the Human Connectome Project database. Hemispheric language dominance for each participant was quantified using a laterality quotient (LQ) derived from fMRI activation in regions of interest (ROIs) associated with a language comprehension task compared against a math task. A linear regression model was used to examine the relationship between structural asymmetry and functional lateralisation. Connectometry revealed a significant negative correlation between LQs and QA of corpus callosum tracts, indicating that higher QA in these regions is associated with bilateral and right-hemisphere language representation in frontal and temporal regions, respectively. Left language laterality in temporal lobe was significantly associated with longer right inferior fronto-occipital fasciculus (IFOF) and forceps minor tracts. These results suggest that diffusion measures of microstructural architecture as well as geometrical features of reconstructed white matter tracts play a role in language lateralisation. People with increased dependence on right or both frontal hemispheres for language processing may have more developed commissural fibres, which may support more efficient interhemispheric communication.Significance statement The left cerebral hemisphere is dominant for language functions in most people. In some healthy people, language functions are lateralised to the right hemisphere or distributed across both hemispheres. The anatomy underlying patterns of hemispheric language dominance are not well established. Emerging evidence suggests that white matter connectivity and architecture is an important feature of cortical functional organisation. In this work, we report that people who have language functions distributed across both hemispheres have greater inter-hemispheric connectivity compared to lateralised people. Our findings provide further insights into the anatomical basis of language function and may have wider clinical implications.

长期以来,人们一直认为大脑半球间的解剖学差异与语言侧化有关。之前的研究探讨了白质语言束扩散特征的不对称性是否与语言侧化一致。这些研究通常以较小的群体为对象,结果不一。本研究调查了全脑白质束的定量各向异性(QA)和形状特征的连接分析是否与语言侧化有关。我们分析了人类连接组计划数据库中的 1040 名健康人(562 名女性)。根据与语言理解任务和数学任务相关的感兴趣区(ROI)的 fMRI 激活情况得出的侧向商(LQ),对每位参与者的半球语言优势进行了量化。线性回归模型用于研究结构不对称与功能侧化之间的关系。连接测量显示,LQs 与胼胝体束的 QA 之间存在明显的负相关,表明这些区域较高的 QA 分别与额叶和颞叶区域的双侧和右半球语言表征相关。颞叶的左侧语言与较长的右侧下额枕束(IFOF)和镊子小束显著相关。这些结果表明,微结构架构的弥散测量以及重建白质束的几何特征在语言侧化中发挥了作用。语言处理更多地依赖右侧或双侧额叶半球的人可能有更发达的共神经纤维,这可能支持更有效的半球间交流。在某些健康人中,语言功能偏向右半球或分布于两个半球。大脑半球语言优势模式的解剖学基础尚未完全确定。新的证据表明,白质连接和结构是大脑皮层功能组织的一个重要特征。在这项研究中,我们发现,语言功能分布在两个半球的人与偏侧的人相比,具有更强的半球间连通性。我们的发现进一步揭示了语言功能的解剖学基础,并可能具有更广泛的临床意义。
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引用次数: 0
Growth hormone receptor in lateral hypothalamic neurons is required for increased food-seeking behavior during food restriction in male mice. 雄性小鼠在食物限制期间增加寻食行为需要下丘脑外侧神经元中的生长激素受体。
IF 4.4 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-10-02 DOI: 10.1523/JNEUROSCI.1761-23.2024
Mariana R Tavares, Willian O Dos Santos, Isadora C Furigo, Edward O List, John J Kopchick, Jose Donato

Growth hormone (GH) action in the brain regulates neuroendocrine axes, energy and glucose homeostasis, and several neurological functions. The lateral hypothalamic area (LHA) contains numerous neurons that respond to a systemic GH injection by expressing the phosphorylated STAT5, a GH receptor (GHR) signaling marker. However, the potential role of GHR signaling in the LHA is unknown. In this study, we demonstrated that approximately 70% of orexin- and leptin receptor (LepR)-expressing neurons in the LHA are responsive to GH. Male mice carrying inactivation of the Ghr gene in the LHA were generated via bilateral injections of an adeno-associated virus. In ad libitum-fed mice, GHR ablation in LHA neurons did not significantly change energy and glucose homeostasis. Subsequently, mice were subjected to 5 days of 40% food restriction. Food restriction decreased body weight, energy expenditure, and carbohydrate oxidation. These effects were similarly observed in control and LHAΔGHR mice. While food-deprived control mice progressively increased ambulatory/exploratory activity and food-seeking behavior, LHAΔGHR mice did not show hyperactivity induced by food restriction. GHR ablation in the LHA reduced the percentage of orexin neurons expressing c-Fos during food restriction. Additionally, an acute GH injection increased the expression of c-Fos in LHAORX neurons. Inactivation of Ghr in LepR-expressing cells did not prevent hyperactivity in food-deprived mice, whereas whole-brain Ghr knockout mice showed reduced ambulatory activity during food restriction. Our findings indicate that GHR signaling in the LHA regulates the activity of orexin neurons and is necessary to increase food-seeking behavior in food-deprived male mice.Significance Statement Growth hormone (GH)-deficient patients frequently present problems in appetite, memory, mood, well-being, metabolism, and sleep. The mechanisms behind these alterations are unknown, but neurons in the lateral hypothalamic area (LHA) are involved in the regulation of all these functions. Here, we showed in male mice that orexin neurons in the LHA express GH receptors, and GH increases the activity of these cells. Unlike control animals, mice carrying inactivation of GH receptors in LHA neurons are unable to increase their ambulatory/exploratory activity when subjected to food restriction, which increases food-seeking behavior. Thus, our study revealed a new neuronal population affected by GH action that can regulate several neurological aspects, including feeding, arousal, reward, and motivated behaviors.

生长激素(GH)在大脑中的作用调节着神经内分泌轴、能量和葡萄糖平衡以及多种神经功能。下丘脑外侧区(LHA)含有大量神经元,这些神经元通过表达磷酸化的 STAT5(一种 GH 受体(GHR)信号标记)对全身性 GH 注射做出反应。然而,GHR 信号在 LHA 中的潜在作用尚不清楚。在这项研究中,我们证实 LHA 中约 70% 的奥曲肽和瘦素受体(LepR)表达神经元对 GH 有反应。通过双侧注射腺相关病毒产生了携带LHA中Ghr基因失活的雄性小鼠。在自由进食的小鼠中,LHA神经元中的GHR消减并没有显著改变能量和葡萄糖稳态。随后,对小鼠进行为期5天的40%食物限制。食物限制降低了体重、能量消耗和碳水化合物氧化。在对照组和 LHAΔGHR 小鼠身上也观察到了类似的效应。食物匮乏的对照组小鼠的活动/探索活动和寻食行为逐渐增加,而LHAΔGHR小鼠则没有表现出食物限制引起的多动症。LHA 中的 GHR 消融降低了食物限制期间表达 c-Fos 的奥曲肽神经元的百分比。此外,急性注射 GH 会增加 LHAORX 神经元中 c-Fos 的表达。LepR 表达细胞中的 Ghr 失活并不能阻止食物匮乏小鼠的过度活动,而全脑 Ghr 基因敲除小鼠在食物限制期间的活动减少。我们的研究结果表明,LHA中的GHR信号调节奥曲肽神经元的活性,是增加食物匮乏雄性小鼠寻食行为的必要条件。 意义声明 生长激素(GH)缺乏症患者经常出现食欲、记忆、情绪、幸福感、新陈代谢和睡眠等方面的问题。这些变化背后的机制尚不清楚,但下丘脑外侧区(LHA)的神经元参与了所有这些功能的调节。在这里,我们在雄性小鼠身上发现,LHA 中的奥曲肽神经元表达 GH 受体,而 GH 会增加这些细胞的活性。与对照组动物不同的是,LHA神经元中的GH受体失活的小鼠在受到食物限制时无法增加它们的活动/探索活动,从而增加了寻食行为。因此,我们的研究揭示了一个受 GH 作用影响的新神经元群,它可以调节多个神经系统方面,包括摄食、唤醒、奖赏和动机行为。
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引用次数: 0
Haploinsufficiency of Syngap1 in striatal indirect pathway neurons alters motor and goal-directed behaviors in mice. 纹状体间接通路神经元中 Syngap1 的单倍体缺陷会改变小鼠的运动和目标定向行为。
IF 4.4 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-10-02 DOI: 10.1523/JNEUROSCI.1264-23.2024
Laura M Haetzel, Jillian Iafrati, Katherine R Cording, Mahmoud Farhan, Sasan D Noveir, Gavin Rumbaugh, Helen S Bateup

SYNGAP1 is a high-confidence autism spectrum disorder (ASD) risk gene and mutations in SYNGAP1 lead to a neurodevelopmental disorder (NDD) that presents with epilepsy, ASD, motor developmental delay, and intellectual disability. SYNGAP1 codes for Ras/Rap GTP-ase activating protein SynGAP (SynGAP). In mice, SynGAP is located in the postsynaptic density of glutamatergic synapses and regulates glutamate receptor trafficking in an activity-dependent manner. In addition to forebrain glutamatergic neurons, Syngap1 is highly expressed in the striatum, although the functions of SynGAP in the striatum have not been extensively studied. Here we show that Syngap1 is expressed in both direct and indirect pathway striatal projection neurons (dSPNs and iSPNs) in mice of both sexes. In a mouse model of Syngap1 haploinsufficiency, dendritic spine density, morphology, and intrinsic excitability are altered primarily in iSPNs, but not dSPNs. At the behavioral level, SynGAP reduction alters striatal-dependent motor learning and goal-directed behavior. Several behavioral phenotypes are reproduced by iSPN-specific Syngap1 reduction and, in turn, prevented by iSPN-specific Syngap1 rescue. These results establish the importance of SynGAP to striatal neuron function and pinpoint the indirect pathway as a key circuit in the neurobiology of SYNGAP1-related NDD.Significance statement SYNGAP1 mutations cause a neurodevelopmental disorder presenting with intellectual disability, motor problems, epilepsy, autism spectrum disorder, and a constellation of other behavioral and psychiatric conditions. SynGAP protein is highly expressed in the striatum but its functions in this brain region have not yet been explored. This study shows that loss of one copy of the Syngap1 gene from striatal indirect, but not direct, pathway neurons alters synaptic properties, cellular excitability, motor behaviors, and goal-directed responding in mice. This work provides a new perspective on the functions of SynGAP and suggests that altered activity in striatal circuits may be an important driver of the motor and learning alterations in people with SYNGAP1 disorder.

SYNGAP1 是自闭症谱系障碍 (ASD) 的高危基因,SYNGAP1 基因突变会导致神经发育障碍 (NDD),表现为癫痫、ASD、运动发育迟缓和智力障碍。SYNGAP1 编码 Ras/Rap GTP 酶激活蛋白 SynGAP(SynGAP)。在小鼠中,SynGAP 位于谷氨酸能突触的突触后密度中,以活动依赖的方式调节谷氨酸受体的迁移。除了前脑谷氨酸能神经元外,Syngap1 在纹状体中也高度表达,但 SynGAP 在纹状体中的功能尚未得到广泛研究。在这里,我们发现 Syngap1 在雌雄小鼠的直接和间接通路纹状体投射神经元(dSPNs 和 iSPNs)中都有表达。在 Syngap1 单倍体缺失的小鼠模型中,树突棘密度、形态和内在兴奋性主要在 iSPNs 中发生改变,而在 dSPNs 中则没有改变。在行为水平上,SynGAP 的减少会改变纹状体依赖的运动学习和目标定向行为。iSPN 特异性的 Syngap1 减少可重现多种行为表型,反过来,iSPN 特异性的 Syngap1 挽救可防止这些行为表型。这些结果确定了 SynGAP 对纹状体神经元功能的重要性,并指出间接通路是 SYNGAP1 相关 NDD 神经生物学中的一个关键回路。SynGAP 蛋白在纹状体中高度表达,但其在这一脑区的功能尚未被探索。这项研究表明,小鼠纹状体间接通路神经元(而非直接通路神经元)的一个 Syngap1 基因拷贝缺失会改变小鼠的突触特性、细胞兴奋性、运动行为和目标定向反应。这项研究为了解 SynGAP 的功能提供了一个新的视角,并表明纹状体回路活动的改变可能是 SYNGAP1 障碍患者运动和学习能力改变的一个重要驱动因素。
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引用次数: 0
Glial Control of Cortical Neuronal Circuit Maturation and Plasticity. 皮层神经元回路成熟和可塑性的神经胶质控制
IF 4.4 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-10-02 DOI: 10.1523/JNEUROSCI.1208-24.2024
Travis E Faust, Benjamin A Devlin, Isabella Farhy-Tselnicker, Austin Ferro, Maggie Postolache, Wendy Xin

The brain is a highly adaptable organ that is molded by experience throughout life. Although the field of neuroscience has historically focused on intrinsic neuronal mechanisms of plasticity, there is growing evidence that multiple glial populations regulate the timing and extent of neuronal plasticity, particularly over the course of development. This review highlights recent discoveries on the role of glial cells in the establishment of cortical circuits and the regulation of experience-dependent neuronal plasticity during critical periods of neurodevelopment. These studies provide strong evidence that neuronal circuit maturation and plasticity are non-cell autonomous processes that require both glial-neuronal and glial-glial cross talk to proceed. We conclude by discussing open questions that will continue to guide research in this nascent field.

大脑是一个适应性很强的器官,一生都在被经验塑造。尽管神经科学领域历来关注可塑性的内在神经元机制,但越来越多的证据表明,多种胶质细胞群调节神经元可塑性的时间和程度,尤其是在发育过程中。这篇综述重点介绍了最近发现的神经胶质细胞在建立大脑皮层回路中的作用,以及在神经发育的关键时期对依赖经验的神经元可塑性的调控。这些研究提供了强有力的证据,证明神经元回路的成熟和可塑性是非细胞自主的过程,需要神经胶质细胞-神经元和神经胶质细胞-神经胶质细胞的交叉对话才能进行。最后,我们讨论了一些开放性问题,这些问题将继续指导这一新生领域的研究。
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引用次数: 0
Neural Encoding of Bodies for Primate Social Perception. 灵长类动物社会感知的身体神经编码
IF 4.4 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-10-02 DOI: 10.1523/JNEUROSCI.1221-24.2024
Etienne Abassi, Anna Bognár, Bea de Gelder, Martin Giese, Leyla Isik, Alexander Lappe, Albert Mukovskiy, Marta Poyo Solanas, Jessica Taubert, Rufin Vogels

Primates, as social beings, have evolved complex brain mechanisms to navigate intricate social environments. This review explores the neural bases of body perception in both human and nonhuman primates, emphasizing the processing of social signals conveyed by body postures, movements, and interactions. Early studies identified selective neural responses to body stimuli in macaques, particularly within and ventral to the superior temporal sulcus (STS). These regions, known as body patches, represent visual features that are present in bodies but do not appear to be semantic body detectors. They provide information about posture and viewpoint of the body. Recent research using dynamic stimuli has expanded the understanding of the body-selective network, highlighting its complexity and the interplay between static and dynamic processing. In humans, body-selective areas such as the extrastriate body area (EBA) and fusiform body area (FBA) have been implicated in the perception of bodies and their interactions. Moreover, studies on social interactions reveal that regions in the human STS are also tuned to the perception of dyadic interactions, suggesting a specialized social lateral pathway. Computational work developed models of body recognition and social interaction, providing insights into the underlying neural mechanisms. Despite advances, significant gaps remain in understanding the neural mechanisms of body perception and social interaction. Overall, this review underscores the importance of integrating findings across species to comprehensively understand the neural foundations of body perception and the interaction between computational modeling and neural recording.

灵长类动物作为社会性生物,进化出了复杂的大脑机制来驾驭错综复杂的社会环境。这篇综述探讨了人类和非人灵长类动物身体感知的神经基础,强调了对身体姿势、动作和互动所传达的社会信号的处理。早期研究发现了猕猴对身体刺激的选择性神经反应,尤其是在颞上沟(STS)内部和腹侧。这些区域被称为 "身体斑块",代表了身体中存在的视觉特征,但似乎并不是语义上的身体检测器。它们提供了有关身体姿势和视角的信息。最近利用动态刺激进行的研究拓展了人们对身体选择网络的认识,凸显了其复杂性以及静态和动态处理之间的相互作用。在人类中,体外体区(EBA)和纺锤体区(FBA)等身体选择区被认为与对身体及其相互作用的感知有关。此外,对社会互动的研究显示,人类的 STS 区域也能感知二人互动,这表明存在一条专门的社会横向通路。计算工作开发了身体识别和社会互动模型,为深入了解潜在的神经机制提供了线索。尽管取得了进展,但在理解身体感知和社会互动的神经机制方面仍存在很大差距。总之,本综述强调了整合不同物种的研究结果以全面了解身体感知的神经基础以及计算建模与神经记录之间相互作用的重要性。
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引用次数: 0
期刊
Journal of Neuroscience
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