Journal of Neuroscience最新文献

{"title":"The Icelandic Mutation (APP-A673T) Is Protective against Amyloid Pathology In Vivo.","authors":"Sho Shimohama, Ryo Fujioka, Naomi Mihira, Misaki Sekiguchi, Luca Sartori, Daisuke Joho, Takashi Saito, Takaomi C Saido, Jin Nakahara, Tomohito Hino, Atsushi Hoshino, Hiroki Sasaguri","doi":"10.1523/JNEUROSCI.0223-24.2024","DOIUrl":"10.1523/JNEUROSCI.0223-24.2024","url":null,"abstract":"<p><p>A previous epidemiological study in Northern Europe showed that the A673T mutation (Icelandic mutation) in the amyloid precursor protein gene (<i>APP</i>) can protect against Alzheimer's disease (AD). While the effect of the A673T mutation on APP processing has been investigated primarily in vitro, its in vivo impact has not been evaluated. This is mainly because most existing AD mouse models carry the Swedish mutation. The Swedish and Icelandic mutations are both located near the β-cleavage site, and each mutation is presumed to have the opposite effect on β-cleavage. Therefore, in the AD mouse models with the Swedish mutation, its effects could compete with the effects of the Icelandic mutation. Here, we introduced the A673T mutation into <i>App</i> knock-in mice devoid of the Swedish mutation (<i>App^G-F</i> mice) to avoid potential deleterious effects of the Swedish mutation and generated <i>App^G-F-A673T</i> mice. APP-A673T significantly downregulated β-cleavage and attenuated the production of Aβ and amyloid pathology in the brains of these animals. The Icelandic mutation also reduced neuroinflammation and neuritic alterations. Both sexes were studied. This is the first successful demonstration of the protective effect of the Icelandic mutation on amyloid pathology in vivo. Our findings indicate that specific inhibition of the APP-BACE1 interaction could be a promising therapeutic approach. Alternatively, the introduction of the disease-protective mutation such as APP-A673T using in vivo genome editing technology could be a novel treatment for individuals at high risk for AD, such as familial AD gene mutation carriers and <i>APOE</i> ε4 carriers.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11580785/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142576665","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}

{"title":"Decoding the Temporal Structures and Interactions of Multiple Face Dimensions Using Optically Pumped Magnetometer Magnetoencephalography (OPM-MEG).","authors":"Wei Xu, Bingjiang Lyu, Xingyu Ru, Dongxu Li, Wenyu Gu, Xiao Ma, Fufu Zheng, Tingyue Li, Pan Liao, Hao Cheng, Rui Yang, Jingqi Song, Zeyu Jin, Congcong Li, Kaiyan He, Jia-Hong Gao","doi":"10.1523/JNEUROSCI.2237-23.2024","DOIUrl":"10.1523/JNEUROSCI.2237-23.2024","url":null,"abstract":"<p><p>Humans possess a remarkable ability to rapidly access diverse information from others' faces with just a brief glance, which is crucial for intricate social interactions. While previous studies using event-related potentials/fields have explored various face dimensions during this process, the interplay between these dimensions remains unclear. Here, by applying multivariate decoding analysis to neural signals recorded with optically pumped magnetometer magnetoencephalography, we systematically investigated the temporal interactions between invariant and variable aspects of face stimuli, including race, gender, age, and expression. First, our analysis revealed unique temporal structures for each face dimension with high test-retest reliability. Notably, expression and race exhibited a dominant and stably maintained temporal structure according to temporal generalization analysis. Further exploration into the mutual interactions among face dimensions uncovered age effects on gender and race, as well as expression effects on race, during the early stage (∼200-300 ms postface presentation). Additionally, we observed a relatively late effect of race on gender representation, peaking ∼350 ms after the stimulus onset. Taken together, our findings provide novel insights into the neural dynamics underlying the multidimensional aspects of face perception and illuminate the promising future of utilizing OPM-MEG for exploring higher-level human cognition.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11580774/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142367201","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}

{"title":"The Nociceptor Primary Cilium Contributes to Mechanical Nociceptive Threshold and Inflammatory and Neuropathic Pain.","authors":"Lindsey A Fitzsimons, Larissa Staurengo-Ferrari, Eugen V Khomula, Oliver Bogen, Dionéia Araldi, Ivan J M Bonet, Paul G Green, Ethan E Jordan, Finn Sclafani, Connor E Nowak, Julie K Moulton, Geoffrey K Ganter, Jon D Levine, Kerry L Tucker","doi":"10.1523/JNEUROSCI.1265-24.2024","DOIUrl":"10.1523/JNEUROSCI.1265-24.2024","url":null,"abstract":"<p><p>The primary cilium, a single microtubule-based organelle protruding from the cell surface and critical for neural development, also functions in adult neurons. While some dorsal root ganglion neurons elaborate a primary cilium, whether it is expressed by and functional in nociceptors is unknown. Recent studies have shown the role of Hedgehog, whose canonical signaling is primary cilium dependent, in nociceptor sensitization. We establish the presence of primary cilia in soma of rat nociceptors, where they contribute to mechanical threshold, prostaglandin E₂ (PGE₂)-induced hyperalgesia, and chemotherapy-induced neuropathic pain (CIPN). Intrathecal administration of siRNA targeting <i>Ift88</i>, a primary cilium-specific intraflagellar transport (IFT) protein required for ciliary integrity, resulted in attenuation of <i>Ift88</i> mRNA and nociceptor primary cilia. Attenuation of primary cilia was associated with an increase in mechanical nociceptive threshold in vivo and decrease in nociceptor excitability in vitro, abrogation of hyperalgesia, and nociceptor sensitization induced by both a prototypical pronociceptive inflammatory mediator PGE₂ and paclitaxel CIPN, in a sex-specific fashion. siRNA targeting <i>Ift52</i>, another IFT protein, and knockdown of NompB, the <i>Drosophila Ift88</i> ortholog, also abrogated CIPN and reduced baseline mechanosensitivity, respectively, providing independent confirmation for primary cilia control of nociceptor function. Hedgehog-induced hyperalgesia is attenuated by <i>Ift88</i> siRNA, supporting the role for primary cilia in Hedgehog-induced hyperalgesia. Attenuation of CIPN by cyclopamine (intradermal and intraganglion), which inhibits Hedgehog signaling, supports the role of Hedgehog in CIPN. Our findings support the role of the nociceptor primary cilium in control of mechanical nociceptive threshold and inflammatory and neuropathic pain, the latter Hedgehog-dependent.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11580782/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142331452","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}

{"title":"Glutamine Oxidation in Mouse Dorsal Root Ganglia Regulates Pain Resolution and Chronification.","authors":"Md Mamunul Haque, Panjamurthy Kuppusamy, Ohannes K Melemedjian","doi":"10.1523/JNEUROSCI.1442-24.2024","DOIUrl":"10.1523/JNEUROSCI.1442-24.2024","url":null,"abstract":"<p><p>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. 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.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11580783/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142394789","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}

{"title":"Different Subregions of Monkey Lateral Prefrontal Cortex Respond to Abstract Sequences and Their Components.","authors":"Nadira Yusif Rodriguez, Aarit Ahuja, Debaleena Basu, Theresa H McKim, Theresa M Desrochers","doi":"10.1523/JNEUROSCI.1353-24.2024","DOIUrl":"10.1523/JNEUROSCI.1353-24.2024","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11580767/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142394787","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}

{"title":"Optogenetic control of dopamine receptor 2 reveals a novel aspect of dopaminergic neurotransmission in motor function.","authors":"Hyunbin Kim, Geunhong Park, Hyo Geun Shin, Duwan Kwon, Heejung Kim, In-Yeop Baek, Min-Ho Nam, Il-Joo Cho, Jeongjin Kim, Jihye Seong","doi":"10.1523/JNEUROSCI.1473-24.2024","DOIUrl":"https://doi.org/10.1523/JNEUROSCI.1473-24.2024","url":null,"abstract":"<p><p>Dopaminergic neurotransmission plays a crucial role in motor function through the coordination of dopamine receptor (DRD) subtypes, such as DRD1 and DRD2, thus the functional imbalance of these receptors can lead to Parkinson's disease. However, due to the complexity of dopaminergic circuits in the brain, it is limited to investigating the individual functions of each DRD subtype in specific brain regions. Here, we developed a light-responsive chimeric DRD2, OptoDRD2, which can selectively activate DRD2-like signaling pathways with spatiotemporal resolution. OptoDRD2 was designed to include the light-sensitive component of rhodopsin and the intracellular signaling domain of DRD2. Upon illumination with blue light, OptoDRD2 triggered DRD2-like signaling pathways, such as Gαi/o subtype recruitment, a decrease in cAMP levels, and ERK phosphorylation. To explore unknown roles of DRD2 in glutamatergic cell populations of basal ganglia circuitry, OptoDRD2 was genetically expressed in excitatory neurons in lateral globus pallidus (LGP) of the male mouse brain. The optogenetic stimulation of OptoDRD2 in the LGP region affected a wide range of locomotion-related parameters, such as increased frequency of movement and decreased immobility time, resulting in the facilitation of motor function of living male mice. Therefore, our findings indicate a potential novel role for DRD2 in the excitatory neurons of the LGP region, suggesting that OptoDRD2 can be a valuable tool enabling the investigation of unknown roles of DRD2 at specific cell types or brain regions.<b>Significance Statement</b> We developed a light-responsive chimeric dopamine receptor type 2, OptoDRD2, by combining the blue-light sensing part of rhodopsin and intracellular functional regions of DRD2. OptoDRD2 can selectively trigger DRD2-like downstream signaling pathways upon illumination of blue light. To explore unknown roles of DRD2 in glutamatergic cell populations of basal ganglia circuitry, OptoDRD2 was genetically expressed in excitatory neurons at lateral globus pallidus (LGP) in the mouse brain. Optogenetic stimulation of OptoDRD2 in living mice suggested a potential novel function of DRD2 in the LGP that enhances motor outputs. Therefore, OptoDRD2 enabled the precise control of DRD2-like signaling in specific cell types and brain regions, allowing the exploration of potential novel DRD2 functions in living mice.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142677640","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}

{"title":"High-density recording reveals sparse clusters (but not columns) for shape and texture encoding in macaque V4.","authors":"Tomoyuki Namima, Erin Kempkes, Polina Zamarashkina, Natalia Owen, Anitha Pasupathy","doi":"10.1523/JNEUROSCI.1893-23.2024","DOIUrl":"https://doi.org/10.1523/JNEUROSCI.1893-23.2024","url":null,"abstract":"<p><p>Macaque area V4 includes neurons that exhibit exquisite selectivity for visual form and surface texture, but their functional organization across laminae is unknown. We used high-density Neuropixels probes in two awake monkeys (one female and one male) to characterize shape and texture tuning of dozens of neurons simultaneously across layers. We found sporadic clusters of neurons that exhibit similar tuning for shape and texture: ∼20% exhibited similar tuning with their neighbors. Importantly, these clusters were confined to a few layers, seldom 'columnar' in structure. This was the case even when neurons were strongly driven, and exhibited robust contrast invariance for shape and texture tuning. We conclude that functional organization in area V4 is not columnar for shape and texture stimulus features and in general organization maybe at a coarser stimulus category scale (e.g. selectivity for stimuli with vs without 3D cues), and a coarser spatial scale (assessed by optical imaging), rather than at a fine scale in terms of similarity in single neuron tuning for specific features. We speculate that this may be a direct consequence of the great diversity of inputs integrated by V4 neurons to build variegated tuning manifolds in a high-dimensional space.<b>Significance Statement</b> In the primary visual cortex of the macaque monkey, studies have demonstrated columnar functional organization, i.e. shared tuning across layers for stimulus orientation, spatial frequency, ocular dominance, etc. In mid and higher level visual form processing stages, where neurons exhibit high-dimensional tuning, functional organization has been harder to evaluate. Here, leveraging the use of the high-density Neuropixels probes to record simultaneously from dozens of neurons across cortical layers, we demonstrate that functional organization is not columnar for shape and texture tuning in area V4, a midlevel stage critical for form processing. Our results contribute to the debate about the functional significance of cortical columns providing support to the idea that they emerge due to one-to-many representational expansion.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142677568","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}

{"title":"Activity-Dependent Internalization of Glun2B-Containing NMDARS Is Required For Synaptic Incorporation of Glun2A And Synaptic Plasticity.","authors":"Granville P Storey, Raul Riquelme, Andres Barria","doi":"10.1523/JNEUROSCI.0823-24.2024","DOIUrl":"https://doi.org/10.1523/JNEUROSCI.0823-24.2024","url":null,"abstract":"<p><p>NMDA-type glutamate receptors are heterotetrameric complexes composed of two GluN1 and two GluN2 subunits. The precise composition of the GluN2 subunits determines the channel's biophysical properties and influences its interaction with postsynaptic scaffolding proteins and signaling molecules involved in synaptic physiology and plasticity. The precise regulation of NMDAR subunit composition at synapses is crucial for proper synaptogenesis, neuronal circuit development, and synaptic plasticity, a cellular model of memory formation.In the forebrain during early development, NMDARs contain solely the GluN2B subunit, which is necessary for proper synaptogenesis and synaptic plasticity. In rodents, GluN2A subunit expression begins in the second postnatal week, replacing GluN2B-containing NMDARs at synapses in an activity- or sensory experience-dependent process. This switch in NMDAR subunit composition at synapses alters channel properties and reduces synaptic plasticity. The molecular mechanism regulating the switch remains unclear.We have investigated the role of activity-dependent internalization of GluN2B-containing receptors in shaping synaptic NMDAR subunit composition. Using molecular, pharmacological, and electrophysiological approaches in cultured organotypic hippocampal slices from rats of both sexes, we show that the process of incorporating GluN2A-containing NMDARs receptors requires activity-dependent internalization of GluN2B-containing NMDARs. Interestingly, blockade of GluN2A synaptic incorporation was associated with impaired potentiation of AMPA-mediated synaptic transmission, suggesting a potential coupling between the trafficking of AMPARs into synapses and that of GluN2A-containing NMDARs.These insights contribute to our understanding of the molecular mechanisms underlying synaptic trafficking of glutamate receptors and synaptic plasticity. They may also have implications for therapeutic strategies targeting NMDAR function in neurological disorders.<b>Significance statement</b> NMDARs play a critical role in synaptogenesis, synaptic stability, and activity-dependent regulation of synaptic strength. The developmental switch in their GluN2 subunits composition is part of normal synapse development and crucial for proper synaptic physiology, plasticity, and the formation of functional neuronal circuits, though the mechanisms governing it remain unclear. We show that internalization of GluN2B-containing NMDARs is required for synaptic incorporation of GluN2A-containing receptors. This process can be induced by long-term potentiation and requires Ca⁺² Notably, GluN2A trafficking to synapses is linked to the incorporation of AMPA-type glutamate receptors, suggesting a shared pathway for synaptic incorporation. These findings provide greater insight into the molecular mechanisms behind glutamate receptor trafficking and synaptic plasticity, potentially informing therapeutic strategies for neurological disorders.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142677529","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}

{"title":"Synapse-to-nucleus ERK-CREB transcriptional signaling requires dendrite-to-soma Ca²⁺propagation mediated by L-type voltage-gated Ca²⁺ channels.","authors":"Katlin H Zent, Mark L Dell'Acqua","doi":"10.1523/JNEUROSCI.1216-24.2024","DOIUrl":"https://doi.org/10.1523/JNEUROSCI.1216-24.2024","url":null,"abstract":"<p><p>The cAMP-response element binding protein (CREB) transcription factor controls the expression of the neuronal immediate early genes <i>c-Fos</i>, <i>Arc</i>, and <i>Bdnf</i> and is essential for long-lasting synaptic plasticity underlying learning and memory. Despite this critical role, there is still ongoing debate regarding the synaptic excitation-transcription (E-T) coupling mechanisms mediating CREB activation in the nucleus. Here we employed optical uncaging of glutamate to mimic synaptic excitation of distal dendrites in conjunction with simultaneous imaging of intracellular Ca²⁺ dynamics and transcriptional reporter gene expression to elucidate CREB E-T coupling mechanisms in hippocampal neurons cultured from both male and female rats. Using this approach, we found that CREB-dependent transcription was engaged following dendritic stimulation of N-methyl, D-aspartate receptors (NMDARs) only when Ca²⁺ signals propagated to the soma via subsequent activation of L-type voltage-gated Ca²⁺ channels resulting in activation of Extracellular signal-Regulated Kinase (ERK) MAP kinase signaling to sustain CREB phosphorylation in the nucleus. In contrast, dendrite-restricted Ca²⁺ signals generated by NMDARs failed to stimulate CREB-dependent transcription. Furthermore, Ca²⁺-CaM-dependent kinase (CaMK)-mediated signaling pathways that may transiently contribute to CREB-phosphorylation following stimulation were ultimately dispensable for downstream CREB-dependent transcription and c-Fos induction. These findings emphasize the essential role that L-type Ca²⁺ channels play in rapidly relaying signals over long distances from synapses located on distal dendrites to the nucleus to control gene expression.<b>Significance Statement</b> The transcription factor CREB controls gene expression programs required for long-lasting synaptic plasticity and learning and memory, yet the synapse-to-nucleus signaling mechanisms mediating CREB activation are still unclear. Using glutamate uncaging to mimic synaptic input to dendrites, this study shows that Ca²⁺ signals propagated to the soma by L-type voltage-gated Ca²⁺ channels engage the ERK MAP kinase cascade to mediate CREB phosphorylation and CREB-dependent transcription. In contrast, dendrite-restricted Ca²⁺ signals generated primarily by NMDARs failed to effectively engage this signaling pathway or CREB-dependent transcription. In addition, we found that while ERK and CaMK pathways may both contribute to increased CREB phosphorylation immediately following neuronal stimulation, sustained ERK signaling to CREB was necessary to effectively drive CREB-dependent transcription.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142677644","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}

{"title":"Neural bases of proactive and predictive processing of meaningful sub-word units in speech comprehension.","authors":"Suhail Matar, Alec Marantz","doi":"10.1523/JNEUROSCI.0781-24.2024","DOIUrl":"https://doi.org/10.1523/JNEUROSCI.0781-24.2024","url":null,"abstract":"<p><p>To comprehend speech, human brains identify meaningful units in the speech stream. But whereas the English '<i>She believed him.</i>' has 3 word-units, the Arabic equivalent '<i>ṣaddaqathu.</i>' is a single word-unit with 3 meaningful sub-word units, called morphemes: a verb stem ('<i>ṣaddaqa</i>'), a subject suffix ('-<i>t</i>-'), and a direct object pronoun ('-<i>hu</i>'). It remains unclear whether and how the brain processes morphemes, above and beyond other language units, during speech comprehension. Here, we propose and test hierarchically-nested encoding models of speech comprehension: a naïve model with word-, syllable-, and sound-level information; a bottom-up model with additional morpheme boundary information; and predictive models that process morphemes before these boundaries. We recorded magnetoencephalography (MEG) data as 27 participants (16 female) listened to Arabic sentences like '<i>ṣaddaqathu.</i>'. A temporal response function (TRF) analysis revealed that in temporal and left inferior frontal regions predictive models outperform the bottom-up model, which outperforms the naïve model. Moreover, verb stems were either length-ambiguous (e.g., '<i>ṣaddaqa</i>' could initially be mistaken for the shorter stem '<i>ṣadda</i>'='<i>blocked</i>') or length-unambiguous (e.g., '<i>qayyama</i>'='<i>evaluated</i>' cannot be mistaken for a shorter stem), but shared a uniqueness point, beyond which stem identity is fully disambiguated. Evoked analyses revealed differences between conditions before the uniqueness point, suggesting that, rather than await disambiguation, the brain employs proactive predictive strategies, processing accumulated input as soon as any possible stem is identifiable, even if not uniquely. These findings highlight the role of morphemes in speech, and the importance of including morpheme-level information in neural and computational models of speech comprehension.<b>Significance statement</b> Many leading models of speech comprehension include information about words, syllables and sounds. But languages vary considerably in the amount of meaning packed into word units. This work proposes speech comprehension models with information about meaningful sub-word units, called morphemes (e.g., '<i>bake-</i>' and '<i>-ing</i>' in '<i>baking</i>'), and shows that they explain significantly more neural activity than models without morpheme information. We also show how the brain predictively processes morphemic information. These findings highlight the role of morphemes in speech comprehension and emphasize the contributions of morpheme-level information-theoretic metrics, like surprisal and entropy. Our findings can be used to update current neural, cognitive, and computational models of speech comprehension, and constitute a step towards refining those models for naturalistic, connected speech.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142677571","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}