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The correct connectivity of the DG-CA3 circuits involved in declarative memory processes depends on Vangl2-dependent planar cell polarity signaling.
IF 6.7 2区 医学 Q1 NEUROSCIENCES Pub Date : 2025-02-15 DOI: 10.1016/j.pneurobio.2025.102728
Noémie Depret, Marie Gleizes, Maïté Marie Moreau, Sonia Poirault-Chassac, Anne Quiedeville, Steve Dos Santos Carvalho, Vasika Venugopal, Alice Shaam Al Abed, Jérôme Ezan, Gael Barthet, Christophe Mulle, Aline Desmedt, Aline Marighetto, Claudia Racca, Mireille Montcouquiol, Nathalie Sans

In the hippocampus, dentate gyrus granule cells connect to CA3 pyramidal cells via their axons, the mossy fibers (Mf). The synaptic terminals of Mfs (Mf boutons, MfBs) form large and complex synapses with thorny excrescences (TE) on the proximal dendrites of CA3 pyramidal cells (PCs). MfB/TE synapses have distinctive "detonator" properties due to low initial release probability and large presynaptic facilitation. The molecular mechanisms shaping the morpho-functional properties of MfB/TE synapses are still poorly understood, though alterations in their morphology are associated with Down syndrome, intellectual disabilities, and Alzheimer's disease. Here, we identify the core PCP gene Vangl2 as essential to the morphogenesis and function of MfB/TE synapses. Vangl2 colocalises with the presynaptic heparan sulfate proteoglycan glypican 4 (GPC4) to stabilise the postsynaptic orphan receptor GPR158. Embryonic loss of Vangl2 disrupts the morphology of MfBs and TEs, impairs ultrastructural and molecular organisation, resulting in defective synaptic transmission and plasticity. In adult, the early loss of Vangl2 results in a number of hippocampus-dependent memory deficits including characteristic flexibility of declarative memory, organisation and retention of working / everyday-like memory. These deficits also lead to abnormal generalisation of memories to salient cues and diminished ability to form detailed contextual memories. Together, these results establish Vangl2 as a key regulator of DG-CA3 connectivity and functions.

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引用次数: 0
Cyto-, gene, and multireceptor architecture of the early postnatal mouse hippocampal complex 出生后早期小鼠海马复合体的细胞、基因和多受体结构。
IF 6.7 2区 医学 Q1 NEUROSCIENCES Pub Date : 2025-02-01 DOI: 10.1016/j.pneurobio.2024.102704
Ling Zhao , Menno P. Witter , Nicola Palomero-Gallagher
Neurotransmitter receptors are key molecules in signal transmission in the adult brain, and their precise spatial and temporal balance expressions also play a critical role in normal brain development. However, the specific balance expression of multiple receptors during hippocampal development is not well characterized. In this study, we used quantitative in vivo receptor autoradiography to measure the distributions and densities of 18 neurotransmitter receptor types in the mouse hippocampal complex at postnatal day 7, and compared them with the expressions of their corresponding encoding genes. We provide a novel and comprehensive characterization of the cyto-, gene, and multireceptor architecture of the developing mouse hippocampal and subicular regions during the developmental period, which typically differs from that in the adult brain. High-density receptor expressions with distinct regional and laminar distributions were observed for AMPA, Kainate, mGluR2/3, GABAA, GABAA/BZ, α2, and A1 receptors during this specific period, whereas NMDA, GABAB, α1, M1, M2, M3, nicotinic α4β2, 5-HT1A, 5-HT2, D1 and D2/D3 receptors exhibited relatively low and homogeneous expressions. This specific balance of multiple receptors aligns with regional cytoarchitecture, neurotransmitter distributions, and gene expressions. Moreover, contrasting with previous findings, we detected a high α2 receptor density, with distinct regional and laminar distribution patterns. A non-covariation differentiation phenomenon between α2 receptor distributions and corresponding gene expressions is also demonstrated in this early developmental period. The multimodal data provides new insights into understanding the hippocampal development from the perspective of cell, gene, and multireceptor levels, and contributes important resources for further interdisciplinary analyses.
神经递质受体是成人大脑信号传递的关键分子,其精确的时空平衡表达在大脑正常发育中也起着至关重要的作用。然而,多种受体在海马发育过程中的具体平衡表达尚未得到很好的表征。在本研究中,我们采用定量体内受体放射自成像技术测量了出生后第7天小鼠海马复合体中18种神经递质受体的分布和密度,并将其与相应编码基因的表达进行了比较。我们提供了一种新的和全面的细胞、基因和多受体结构的特征,在发育期间发育中的小鼠海马和潜区,这通常不同于成人大脑。在此期间,AMPA、Kainate、mGluR2/3、GABAA、GABAA/BZ、α2和A1受体的高密度受体表达具有明显的区域和层流分布,而NMDA、GABAB、α1、M1、M2、M3、烟碱α4β2、5-HT1A、5-HT2、D1和D2/D3受体的表达相对较低且均匀。这种特定的多受体平衡与区域细胞结构、神经递质分布和基因表达一致。此外,与以往的研究结果相比,我们检测到较高的α2受体密度,具有明显的区域和层流分布模式。在这一发育早期,α2受体分布与相应基因表达之间也存在非共变分化现象。多模态数据提供了从细胞、基因和多受体水平理解海马发育的新视角,并为进一步的跨学科分析提供了重要的资源。
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引用次数: 0
Social odors drive hippocampal CA2 place cell responses to social stimuli 社交气味驱动海马体CA2位置细胞对社交刺激的反应。
IF 6.7 2区 医学 Q1 NEUROSCIENCES Pub Date : 2025-02-01 DOI: 10.1016/j.pneurobio.2024.102708
Emma Robson , Margaret M. Donahue , Alexandra J. Mably , Peyton G. Demetrovich , Lauren T. Hewitt , Laura Lee Colgin
Hippocampal region CA2 is essential for social memory processing. Interaction with social stimuli induces changes in CA2 place cell firing during active exploration and sharp wave-ripples during rest following a social interaction. However, it is unknown whether these changes in firing patterns are caused by integration of multimodal social stimuli or by a specific sensory modality associated with a social interaction. Rodents rely heavily on chemosensory cues in the form of olfactory signals for social recognition processes. To determine the extent to which social olfactory signals contribute to CA2 place cell responses to social stimuli, we recorded CA2 place cells in rats freely exploring environments containing stimuli that included or lacked olfactory content. We found that CA2 place cell firing patterns significantly changed only when social odors were prominent. Also, place cells that increased their firing in the presence of social odors alone preferentially increased their firing during subsequent sharp wave-ripples. Our results suggest that social olfactory cues are essential for changing CA2 place cell firing patterns during and after social interactions. These results support prior work suggesting CA2 performs social functions and shed light on processes underlying CA2 responses to social stimuli.
海马区CA2对社会记忆加工至关重要。与社会刺激的相互作用诱导CA2位置细胞在积极探索期间放电的变化和在社会相互作用后休息时尖锐的波纹。然而,尚不清楚这些放电模式的变化是由多模态社会刺激的整合引起的,还是由与社会互动相关的特定感觉模态引起的。啮齿动物在社会识别过程中严重依赖嗅觉信号形式的化学感觉线索。为了确定社会嗅觉信号在多大程度上促进CA2定位细胞对社会刺激的反应,我们记录了大鼠自由探索含有或缺乏嗅觉内容的刺激环境中的CA2定位细胞。我们发现CA2位置细胞放电模式只有在社交气味突出时才会发生显著变化。同样,在社交气味存在时增加放电的位置细胞,在随后的剧烈波纹中优先增加放电。我们的研究结果表明,社交嗅觉线索对于在社交互动期间和之后改变CA2位置细胞放电模式至关重要。这些结果支持了先前的研究,表明CA2具有社会功能,并揭示了CA2对社会刺激的反应过程。
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引用次数: 0
Memory load influences our preparedness to act on visual representations in working memory without affecting their accessibility 记忆负荷影响我们对工作记忆中的视觉表征采取行动的准备,而不影响其可及性。
IF 6.7 2区 医学 Q1 NEUROSCIENCES Pub Date : 2025-02-01 DOI: 10.1016/j.pneurobio.2025.102717
Rose Nasrawi, Mika Mautner-Rohde, Freek van Ede
It is well established that when we hold more content in working memory, we are slower to act upon part of that content when it becomes relevant for behavior. Here, we asked whether this load-related slowing is due to slower access to the sensory representations held in working memory (as predicted by serial working-memory search), or by a reduced preparedness to act upon those sensory representations once accessed. To address this, we designed a visual-motor working-memory task in which participants memorized the orientation of two or four colored bars, of which one was cued for reproduction. We independently tracked EEG markers associated with the selection of visual (cued item location) and motor (relevant manual action) information from the EEG time-frequency signal, and compared their latencies as a function of memory load. We confirm slower memory-guided behavior with higher working-memory load and show that this is associated with delayed motor selection. In contrast, we find no evidence for a concomitant delay in the latency of visual selection. Moreover, we show that variability in decision times within each memory-load condition is associated with corresponding changes in the latency of motor, but not visual selection. These results reveal how memory load affects our preparedness to act on sensory representations in working memory, while leaving sensory access itself unaffected. This posits action readiness as a key factor that shapes the speed of memory-guided behavior and that underlies delayed responding with higher working-memory load.
众所周知,当我们在工作记忆中拥有更多的内容时,当这些内容与行为相关时,我们对其中一部分的行动就会变慢。在这里,我们询问这种与负荷相关的减速是由于对工作记忆中保存的感觉表征的访问速度较慢(正如串行工作记忆搜索所预测的那样),还是由于一旦访问了这些感觉表征,对这些感觉表征采取行动的准备程度降低。为了解决这个问题,我们设计了一个视觉运动工作记忆任务,在这个任务中,参与者记住两个或四个彩色条的方向,其中一个是提示复制的。我们独立追踪了与脑电时频信号中视觉(提示物品位置)和运动(相关手动动作)信息选择相关的脑电标记,并比较了它们的潜伏期与记忆负荷的关系。我们确认较慢的记忆引导行为具有较高的工作记忆负荷,并表明这与延迟的运动选择有关。相反,我们发现没有证据表明视觉选择的延迟会伴随延迟。此外,我们表明,在每个记忆负荷条件下,决策时间的变化与运动延迟的相应变化有关,而与视觉选择无关。这些结果揭示了记忆负荷如何影响我们在工作记忆中对感觉表征采取行动的准备,而感觉访问本身不受影响。这表明行动准备是决定记忆引导行为速度的关键因素,也是高工作记忆负荷下延迟反应的基础。
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引用次数: 0
Face pareidolia minimally engages macaque face selective neurons 猕猴面部选择神经元对面部视错觉的影响最小。
IF 6.7 2区 医学 Q1 NEUROSCIENCES Pub Date : 2025-02-01 DOI: 10.1016/j.pneurobio.2024.102709
Kenji W. Koyano , Jessica Taubert , William Robison , Elena N. Waidmann , David A. Leopold
The macaque cerebral cortex contains concentrations of neurons that prefer faces over inanimate objects. Although these so-called face patches are thought to be specialized for the analysis of facial signals, their exact tuning properties remain unclear. For example, what happens when an object by chance resembles a face? Everyday objects can sometimes, through the accidental positioning of their internal components, appear as faces. This phenomenon is known as face pareidolia. Behavioral experiments have suggested that macaques, like humans, perceive illusory faces in such objects. However, it is an open question whether such stimuli would naturally stimulate neurons residing in cortical face patches. To address this question, we recorded single unit activity from four fMRI-defined face-selective regions: the anterior medial (AM), anterior fundus (AF), prefrontal orbital (PO), and perirhinal cortex (PRh) face patches. We compared neural responses elicited by images of real macaque faces, pareidolia-evoking objects, and matched control objects. Contrary to expectations, we found no evidence of a general preference for pareidolia-evoking objects over control objects. Although a subset of neurons exhibited stronger responses to pareidolia-evoking objects, the population responses to both categories of objects were similar, and collectively much less than to real macaque faces. These results suggest that neural responses in the four regions we tested are principally concerned with the analysis of realistic facial characteristics, whereas the special attention afforded to face-like pareidolia stimuli is supported by activity elsewhere in the brain.
猕猴的大脑皮层含有大量的神经元,这些神经元更喜欢人脸而不是无生命的物体。尽管这些所谓的面部补丁被认为是专门用于分析面部信号的,但它们的确切调谐特性尚不清楚。例如,当一个物体碰巧像一张脸时会发生什么?日常物品有时可以通过其内部组件的偶然定位,以面孔的形式出现。这种现象被称为面部空想性视错觉。行为实验表明,猕猴和人类一样,能从这些物体中感知到虚幻的面孔。然而,这种刺激是否会自然地刺激皮层面部斑块中的神经元,这是一个悬而未决的问题。为了解决这个问题,我们记录了四个fmri定义的面部选择区域的单个活动:内侧前部(AM)、眼底前部(AF)、前额眶部(PO)和鼻周皮质(PRh)面部斑块。我们比较了真实猕猴面部图像、唤起空想的物体和匹配的对照物体所引起的神经反应。与预期相反的是,我们没有发现任何证据表明,相对于控制对象,人们更喜欢唤起空想的对象。尽管神经元的一个子集对唤起空想的物体表现出更强的反应,但对这两类物体的总体反应是相似的,而且总体上比对真实猕猴面孔的反应要少得多。这些结果表明,我们测试的四个区域的神经反应主要与真实面部特征的分析有关,而对类似面部的空想性视刺激的特别关注是由大脑其他区域的活动支持的。
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引用次数: 0
Background white noise increases neuronal activity by reducing membrane fluctuations and slow-wave oscillations in auditory cortex
IF 6.7 2区 医学 Q1 NEUROSCIENCES Pub Date : 2025-01-24 DOI: 10.1016/j.pneurobio.2025.102720
Rasmus Kordt Christensen , Florian Studer, Tania Rinaldi Barkat
The brain faces the challenging task of preserving a consistent portrayal of the external world in the face of disruptive sensory inputs. What alterations occur in sensory representation amidst noise, and how does brain activity adapt to it? Although it has previously been shown that background white noise (WN) decreases responses to salient sounds, a mechanistic understanding of the brain processes responsible for such changes is lacking. We investigated the effect of background WN on neuronal spiking activity, membrane potential, and network oscillations in the mouse central auditory system. We found that, in addition to increasing background spiking activity in the auditory cortex and thalamus, background WN decreases neural activity fluctuations, as reflected in the membrane potential of single neurons and the local field potential. Blocking acetylcholine signaling in the auditory cortex eliminated the WN-dependent increase in background activity as well as the shift in slow-wave oscillations. Together, our observations show that background WN is not filtered away along the auditory pathway, but rather drives sustained changes in cortical activity that can be reverted by blocking cholinergic inputs.
{"title":"Background white noise increases neuronal activity by reducing membrane fluctuations and slow-wave oscillations in auditory cortex","authors":"Rasmus Kordt Christensen ,&nbsp;Florian Studer,&nbsp;Tania Rinaldi Barkat","doi":"10.1016/j.pneurobio.2025.102720","DOIUrl":"10.1016/j.pneurobio.2025.102720","url":null,"abstract":"<div><div>The brain faces the challenging task of preserving a consistent portrayal of the external world in the face of disruptive sensory inputs. What alterations occur in sensory representation amidst noise, and how does brain activity adapt to it? Although it has previously been shown that background white noise (WN) decreases responses to salient sounds, a mechanistic understanding of the brain processes responsible for such changes is lacking. We investigated the effect of background WN on neuronal spiking activity, membrane potential, and network oscillations in the mouse central auditory system. We found that, in addition to increasing background spiking activity in the auditory cortex and thalamus, background WN decreases neural activity fluctuations, as reflected in the membrane potential of single neurons and the local field potential. Blocking acetylcholine signaling in the auditory cortex eliminated the WN-dependent increase in background activity as well as the shift in slow-wave oscillations. Together, our observations show that background WN is not filtered away along the auditory pathway, but rather drives sustained changes in cortical activity that can be reverted by blocking cholinergic inputs.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"246 ","pages":"Article 102720"},"PeriodicalIF":6.7,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143041482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Ketamine administration during adolescence impairs synaptic integration and inhibitory synaptic transmission in the adult dentate gyrus
IF 6.7 2区 医学 Q1 NEUROSCIENCES Pub Date : 2025-01-22 DOI: 10.1016/j.pneurobio.2025.102718
Odra Santander , Sebastián B. Arredondo , Francisca García-Rojas , Sebastián F. Estay , Juan E. Belforte , Andrés E. Chávez , Lorena Varela-Nallar , Marco Fuenzalida
Ketamine administration during adolescence affects cognitive performance; however, its long-term impact on synaptic function and neuronal integration in the hippocampus a brain region critical for cognition remains unclear. Using functional and molecular analyses, we found that chronic ketamine administration during adolescence exerts long-term effects on synaptic integration, expanding the temporal window in an input-specific manner affecting the inner molecular layer but not the medial perforant path inputs in the adult mouse dorsal hippocampal dentate gyrus. Ketamine also alters the excitatory/inhibitory balance by reducing the efficacy of inhibitory inputs likely due to a reduction in parvalbumin-positive interneurons number and function. These findings indicate that during adolescence, ketamine exerts a strong effect on inhibitory synaptic function mediated by parvalbumin-positive neurons that ultimately impact synaptic integration in the dorsal adult dentate gyrus, which could help to understand the neurobiological and functional bases that confer greater vulnerability to the adolescent brain.
{"title":"Ketamine administration during adolescence impairs synaptic integration and inhibitory synaptic transmission in the adult dentate gyrus","authors":"Odra Santander ,&nbsp;Sebastián B. Arredondo ,&nbsp;Francisca García-Rojas ,&nbsp;Sebastián F. Estay ,&nbsp;Juan E. Belforte ,&nbsp;Andrés E. Chávez ,&nbsp;Lorena Varela-Nallar ,&nbsp;Marco Fuenzalida","doi":"10.1016/j.pneurobio.2025.102718","DOIUrl":"10.1016/j.pneurobio.2025.102718","url":null,"abstract":"<div><div>Ketamine administration during adolescence affects cognitive performance; however, its long-term impact on synaptic function and neuronal integration in the hippocampus a brain region critical for cognition remains unclear. Using functional and molecular analyses, we found that chronic ketamine administration during adolescence exerts long-term effects on synaptic integration, expanding the temporal window in an input-specific manner affecting the inner molecular layer but not the medial perforant path inputs in the adult mouse dorsal hippocampal dentate gyrus. Ketamine also alters the excitatory/inhibitory balance by reducing the efficacy of inhibitory inputs likely due to a reduction in parvalbumin-positive interneurons number and function. These findings indicate that during adolescence, ketamine exerts a strong effect on inhibitory synaptic function mediated by parvalbumin-positive neurons that ultimately impact synaptic integration in the dorsal adult dentate gyrus, which could help to understand the neurobiological and functional bases that confer greater vulnerability to the adolescent brain.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"246 ","pages":"Article 102718"},"PeriodicalIF":6.7,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143041485","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
Spatiotemporal network dynamics and structural correlates in the human cerebral cortex in vitro
IF 6.7 2区 医学 Q1 NEUROSCIENCES Pub Date : 2025-01-21 DOI: 10.1016/j.pneurobio.2025.102719
Joana Covelo , Alessandra Camassa , Jose Manuel Sanchez-Sanchez , Arnau Manasanch , Leonardo Dalla Porta , Nathalia Cancino-Fuentes , Almudena Barbero-Castillo , Rita M. Robles , Miquel Bosch , Silvia Tapia-Gonzalez , Paula Merino-Serrais , Mar Carreño , Estefania Conde-Blanco , Jordi Rumià Arboix , Pedro Roldán , Javier DeFelipe , Maria V. Sanchez-Vives
Elucidating human cerebral cortex function is essential for understanding the physiological basis of both healthy and pathological brain states. We obtained extracellular local field potential recordings from slices of neocortical tissue from refractory epilepsy patients. Multi-electrode recordings were combined with histological information, providing a two-dimensional spatiotemporal characterization of human cortical dynamics in control conditions and following modulation of the excitation/inhibition balance. Slices expressed spontaneous rhythmic activity consistent with slow wave activity, comprising alternating active (Up) and silent (Down) states (Up-duration: 0.08 ± 0.03 s, Down-duration: 2.62 ± 2.12 s, frequency: 0.75 ± 0.39 Hz). Up states propagated from deep to superficial layers, with faster propagation speeds than in other species (vertical: 64.6 mm/s; horizontal: 65.9 mm/s). GABAA blockade progressively transformed the emergent activity into epileptiform discharges, marked by higher firing rates, faster network recruitment and propagation, and infraslow rhythmicity (0.01 Hz). This dynamical characterization broadens our understanding of the mechanistic organization of the human cortical network at the micro- and mesoscale.
{"title":"Spatiotemporal network dynamics and structural correlates in the human cerebral cortex in vitro","authors":"Joana Covelo ,&nbsp;Alessandra Camassa ,&nbsp;Jose Manuel Sanchez-Sanchez ,&nbsp;Arnau Manasanch ,&nbsp;Leonardo Dalla Porta ,&nbsp;Nathalia Cancino-Fuentes ,&nbsp;Almudena Barbero-Castillo ,&nbsp;Rita M. Robles ,&nbsp;Miquel Bosch ,&nbsp;Silvia Tapia-Gonzalez ,&nbsp;Paula Merino-Serrais ,&nbsp;Mar Carreño ,&nbsp;Estefania Conde-Blanco ,&nbsp;Jordi Rumià Arboix ,&nbsp;Pedro Roldán ,&nbsp;Javier DeFelipe ,&nbsp;Maria V. Sanchez-Vives","doi":"10.1016/j.pneurobio.2025.102719","DOIUrl":"10.1016/j.pneurobio.2025.102719","url":null,"abstract":"<div><div>Elucidating human cerebral cortex function is essential for understanding the physiological basis of both healthy and pathological brain states. We obtained extracellular local field potential recordings from slices of neocortical tissue from refractory epilepsy patients. Multi-electrode recordings were combined with histological information, providing a two-dimensional spatiotemporal characterization of human cortical dynamics in control conditions and following modulation of the excitation/inhibition balance<em>.</em> Slices expressed spontaneous rhythmic activity consistent with slow wave activity, comprising alternating active (Up) and silent (Down) states (Up-duration: 0.08 ± 0.03 s, Down-duration: 2.62 ± 2.12 s, frequency: 0.75 ± 0.39 Hz). Up states propagated from deep to superficial layers, with faster propagation speeds than in other species (vertical: 64.6 mm/s; horizontal: 65.9 mm/s). GABA<sub>A</sub> blockade progressively transformed the emergent activity into epileptiform discharges, marked by higher firing rates, faster network recruitment and propagation, and infraslow rhythmicity (0.01 Hz). This dynamical characterization broadens our understanding of the mechanistic organization of the human cortical network at the micro- and mesoscale.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"246 ","pages":"Article 102719"},"PeriodicalIF":6.7,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143029408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The unanticipated contribution of Zap70 in retinal degeneration: Implications for microglial inflammatory activation Zap70在视网膜变性中的意外贡献:对小胶质细胞炎症激活的影响。
IF 6.7 2区 医学 Q1 NEUROSCIENCES Pub Date : 2025-01-01 DOI: 10.1016/j.pneurobio.2024.102706
Kausik Bishayee , Seung-Hee Lee , Yeon-Jin Heo , Mi-La Cho , Yong Soo Park
Inflammation is a major mechanism of photoreceptor cell death in the retina during macular degeneration leading to the blindness. In this study, we investigated the role of the kinase molecule Zap70, which is an inflammatory regulator of the systemic immune system, to elucidate the control mechanism of inflammation in the retina. We observed activated microglial cells migrated and populated the retinal layer following blue LED-induced photoreceptor degeneration and activated microglial cells in the LED-injured retina expressed Zap70, unlike the inactive microglial cells in the normal retina. Visual function was considerably decreased in blue-LED light-exposed mice, and animals with Zap70 mutations were adversely affected. Furthermore, extensive photoreceptor cell death was observed in the SKG mice, bearing a Zap70 mutation that induces autoimmune disease. In the blue-LED light-exposed groups, SKG retinas had significantly higher levels of inflammatory cytokines than those in wild-type mice. Furthermore, regulating Zap70 activity has a significant influence on microglial inflammatory state. We discovered that active microglial cells expressing Zap70 could modify vascular endothelial growth factor A (Vegfa) signaling in primary retinal pigment epithelial (RPE) cells. Our novel study revealed that the production of Zap70 by retinal microglial cells is responsible for inflammatory signals that promote apoptosis in photoreceptor cells. Furthermore, Zap70-positive microglial cells were capable of regulating Vegfa signaling in RPE cells, which matches the hallmark of macular degeneration. Overall, we discovered Zap70's inflammatory activity in the retina, which is necessary for upregulating multiple inflammatory cytokines and cell death. Zap70 represents a novel therapeutic target for treating retinal degeneration.
炎症是黄斑变性导致失明的视网膜感光细胞死亡的主要机制。在这项研究中,我们研究了激酶分子Zap70的作用,这是一种全身免疫系统的炎症调节剂,以阐明视网膜炎症的控制机制。我们观察到激活的小胶质细胞在蓝光led诱导的光感受器变性后迁移并填充视网膜层,并且在led损伤的视网膜中激活的小胶质细胞表达Zap70,与正常视网膜中失活的小胶质细胞不同。暴露在蓝色led光下的小鼠的视觉功能明显下降,Zap70突变的动物受到不利影响。此外,在SKG小鼠中观察到广泛的光感受器细胞死亡,携带诱导自身免疫性疾病的Zap70突变。在蓝光照射组中,SKG视网膜的炎症细胞因子水平明显高于野生型小鼠。此外,调节Zap70活性对小胶质细胞炎症状态有显著影响。我们发现表达Zap70的活性小胶质细胞可以改变原代视网膜色素上皮(RPE)细胞中的血管内皮生长因子A (Vegfa)信号。我们的新研究表明,视网膜小胶质细胞产生的Zap70负责炎症信号,促进光感受器细胞凋亡。此外,zap70阳性的小胶质细胞能够调节RPE细胞中的Vegfa信号,这与黄斑变性的标志相匹配。总之,我们在视网膜中发现了Zap70的炎症活性,这是上调多种炎症细胞因子和细胞死亡所必需的。Zap70是治疗视网膜变性的新靶点。
{"title":"The unanticipated contribution of Zap70 in retinal degeneration: Implications for microglial inflammatory activation","authors":"Kausik Bishayee ,&nbsp;Seung-Hee Lee ,&nbsp;Yeon-Jin Heo ,&nbsp;Mi-La Cho ,&nbsp;Yong Soo Park","doi":"10.1016/j.pneurobio.2024.102706","DOIUrl":"10.1016/j.pneurobio.2024.102706","url":null,"abstract":"<div><div>Inflammation is a major mechanism of photoreceptor cell death in the retina during macular degeneration leading to the blindness. In this study, we investigated the role of the kinase molecule Zap70, which is an inflammatory regulator of the systemic immune system, to elucidate the control mechanism of inflammation in the retina. We observed activated microglial cells migrated and populated the retinal layer following blue LED-induced photoreceptor degeneration and activated microglial cells in the LED-injured retina expressed Zap70, unlike the inactive microglial cells in the normal retina. Visual function was considerably decreased in blue-LED light-exposed mice, and animals with Zap70 mutations were adversely affected. Furthermore, extensive photoreceptor cell death was observed in the SKG mice, bearing a Zap70 mutation that induces autoimmune disease. In the blue-LED light-exposed groups, SKG retinas had significantly higher levels of inflammatory cytokines than those in wild-type mice. Furthermore, regulating Zap70 activity has a significant influence on microglial inflammatory state. We discovered that active microglial cells expressing Zap70 could modify vascular endothelial growth factor A (Vegfa) signaling in primary retinal pigment epithelial (RPE) cells. Our novel study revealed that the production of Zap70 by retinal microglial cells is responsible for inflammatory signals that promote apoptosis in photoreceptor cells. Furthermore, Zap70-positive microglial cells were capable of regulating Vegfa signaling in RPE cells, which matches the hallmark of macular degeneration. Overall, we discovered Zap70's inflammatory activity in the retina, which is necessary for upregulating multiple inflammatory cytokines and cell death. Zap70 represents a novel therapeutic target for treating retinal degeneration.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"244 ","pages":"Article 102706"},"PeriodicalIF":6.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142877838","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
Glutamatergic neurons of basolateral amygdala mediate increased exploratory behaviors produced by mildly chronic restraint stress in adolescent mice 青春期小鼠基底外侧杏仁核谷氨酸能神经元介导轻度慢性约束应激产生的探索行为增加。
IF 6.7 2区 医学 Q1 NEUROSCIENCES Pub Date : 2025-01-01 DOI: 10.1016/j.pneurobio.2024.102705
Beining Wang , Huan Liu , Yunxia Shang , Yujie Xiong , Jiayi Yang , Zihao Zhan , Zhi Zhang , Kai Wang , Tingting Sun
In response to stressors, individuals manifest varied behavioral responses directed toward satisfying physiological survival needs. Although the enduring effects of adolescent stress on both humans and animals are well-documented, the underlying mechanisms remain insufficiently elucidated. Utilizing immunofluorescence, viral injections, and brain slice electrophysiological recordings, we have delineated that heightened excitability among glutamatergic neurons in the basolateral amygdala (BLA) is responsible for inducing heightened exploratory behaviors in adolescent mice subjected to mild, chronic restraint stress. Activation of BLA glutamatergic neurons through chemogenetics increases exploratory behaviors in emotional assessments, whereas inhibition of these neurons diminishes exploratory behaviors in measures such as the open field and elevated plus maze test. Furthermore, an upregulation of glutamate receptor expression and a concomitant downregulation of GABA receptor expression in BLA glutamatergic neurons have been associated with enhanced exploratory behaviors, validated through in vivo receptor antagonists. These findings unveil the protective role of mild stress exposure during adolescence against adversity, providing novel insights for addressing stressful events.
个体在应激反应中表现出不同的行为反应,以满足生理生存需求。尽管青少年压力对人类和动物的持久影响已被充分证明,但其潜在机制仍未得到充分阐明。利用免疫荧光、病毒注射和脑切片电生理记录,我们已经描述了基底外侧杏仁核(BLA)谷氨酸能神经元之间的兴奋性增强是导致青春期小鼠在轻度、慢性约束压力下增强探索行为的原因。通过化学遗传学激活BLA谷氨酸能神经元会增加情绪评估中的探索性行为,而抑制这些神经元会减少开放性和高程迷宫测试中的探索性行为。此外,在BLA谷氨酸能神经元中,谷氨酸受体表达的上调和GABA受体表达的下调与探索性行为的增强有关,这一点已通过体内受体拮抗剂得到验证。这些发现揭示了青春期轻度压力暴露对逆境的保护作用,为解决压力事件提供了新的见解。
{"title":"Glutamatergic neurons of basolateral amygdala mediate increased exploratory behaviors produced by mildly chronic restraint stress in adolescent mice","authors":"Beining Wang ,&nbsp;Huan Liu ,&nbsp;Yunxia Shang ,&nbsp;Yujie Xiong ,&nbsp;Jiayi Yang ,&nbsp;Zihao Zhan ,&nbsp;Zhi Zhang ,&nbsp;Kai Wang ,&nbsp;Tingting Sun","doi":"10.1016/j.pneurobio.2024.102705","DOIUrl":"10.1016/j.pneurobio.2024.102705","url":null,"abstract":"<div><div>In response to stressors, individuals manifest varied behavioral responses directed toward satisfying physiological survival needs. Although the enduring effects of adolescent stress on both humans and animals are well-documented, the underlying mechanisms remain insufficiently elucidated. Utilizing immunofluorescence, viral injections, and brain slice electrophysiological recordings, we have delineated that heightened excitability among glutamatergic neurons in the basolateral amygdala (BLA) is responsible for inducing heightened exploratory behaviors in adolescent mice subjected to mild, chronic restraint stress. Activation of BLA glutamatergic neurons through chemogenetics increases exploratory behaviors in emotional assessments, whereas inhibition of these neurons diminishes exploratory behaviors in measures such as the open field and elevated plus maze test. Furthermore, an upregulation of glutamate receptor expression and a concomitant downregulation of GABA receptor expression in BLA glutamatergic neurons have been associated with enhanced exploratory behaviors, validated through in vivo receptor antagonists. These findings unveil the protective role of mild stress exposure during adolescence against adversity, providing novel insights for addressing stressful events.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"244 ","pages":"Article 102705"},"PeriodicalIF":6.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142897070","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
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Progress in Neurobiology
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