Journal of Neuroscience最新文献

{"title":"Retinoid-X-Receptor as a Mediator of Poststroke Recovery by Reversing Age-Associated Phenotypes of Microglia/Hematogenous Macrophages.","authors":"Shun-Ming Ting, Xiurong Zhao, Guanghua Sun, Mercedes Ricote, Jaroslaw Aronowski","doi":"10.1523/JNEUROSCI.0248-25.2025","DOIUrl":"10.1523/JNEUROSCI.0248-25.2025","url":null,"abstract":"<p><p>After stroke, microglia and hematogenous macrophages, together referred to as MΦ, clear dead cells and cellular debris in the infarcted brain through phagocytosis as an essential part of the recovery process. However, the phagocytic capability of MΦ declines with age. Furthermore, aged MΦ become overactivated in response to stroke, enhancing secondary brain injury. In this study, we demonstrated that by reversing the age-related dysfunctions in MΦ through activating the retinoid X receptor (RXR), the recovery after stroke in the aged brain could be improved. Using RNA-sequencing, we compared the transcriptomes between MΦ isolated from the brains of young and aged male mice. We observed higher levels of proinflammatory genes and lower levels of phagocytosis-facilitating genes (<i>Cd206</i> and <i>Cd36</i>) expressed by aged MΦ. Meanwhile, the treatment with RXR agonist bexarotene (BEX) reversed the signature genes of microglia aging in the aged MΦ. With the in vivo phagocytosis model, we showed that BEX enhanced the phagocytic ability of aged MΦ. Using the MCAo stroke model and male and female mice, we established that BEX improved sensorimotor and cognitive recovery after MCAo in a myeloid-RXRα-specific and myeloid-RXRα-dependent manner. In conclusion, we showed that activating RXRα partially restores age-related MΦ dysfunctions and that RXRα deficiency in MΦ limits the therapeutic effect of RXR in improving poststroke recovery in the aged brain.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12424960/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144849522","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":"Stereoelectroencephalography reveals neural signatures of multisensory integration in the human superior temporal sulcus during audiovisual speech perception.","authors":"Yue Zhang,John F Magnotti,Xiang Zhang,Zhengjia Wang,Yingjia Yu,Kathryn A Davis,Sameer A Sheth,H Isaac Chen,Daniel Yoshor,Michael S Beauchamp","doi":"10.1523/jneurosci.1037-25.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.1037-25.2025","url":null,"abstract":"Human speech perception is multisensory, integrating auditory information from the talker's voice with visual information from the talker's face. BOLD fMRI studies have implicated the superior temporal gyrus (STG) in processing auditory speech and the superior temporal sulcus (STS) in integrating auditory and visual speech, but as an indirect hemodynamic measure, fMRI is limited in its ability to track the rapid neural computations underlying speech perception. Using stereoelectroencephalograpy (sEEG) electrodes, we directly recorded from the STG and STS in 42 epilepsy patients (25 F, 17 M). Participants identified single words presented in auditory, visual and audiovisual formats with and without added auditory noise. Seeing the talker's face provided a strong perceptual benefit, improving perception of noisy speech in every participant. Neurally, a subpopulation of electrodes concentrated in mid-posterior STG and STS responded to both auditory speech (latency 71 ms) and visual speech (109 ms). Significant multisensory enhancement was observed, especially in the upper bank of the STS: compared with auditory-only speech, the response latency for audiovisual speech was 40% faster and the response amplitude was 18% larger. In contrast, STG showed neither faster nor larger multisensory responses. Surprisingly, STS response latencies for audiovisual speech were significantly faster than those in the STG (50 ms vs. 64 ms), suggesting a parallel pathway model in which the STG plays the primary role in auditory-only speech perception, while the STS takes the lead in audiovisual speech perception. Together with fMRI, sEEG provides converging evidence that STS plays a key role in multisensory integration.Significance Statement One of the most important functions of the human brain is to communicate with others. During conversation, humans take advantage of visual information from the face of the talker as well as auditory information from the voice of the talker. We directly recorded activity from the brains of epilepsy patients implanted with electrodes in the superior temporal sulcus (STS), a key brain region for speech perception. These recordings showed that hearing the voice and seeing the face of the talker evoked larger and faster neural responses in STS than the talker's voice alone. Multisensory enhancement in the STS may be the neural basis for our ability to better understand noisy speech when we can see the face of the talker.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"14 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145031956","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 Beta Power in the Ventrolateral Prefrontal Cortex Indexes Human Approach Behavior: A Case Study.","authors":"Nicole R Provenza, Sameer V Rajesh, Gabriel Reyes, Kalman A Katlowitz, Lokesha S Pugalenthi, Raphael A Bechtold, Nabeel Diab, Sandesh Reddy, Anthony K Allam, Ajay D Gandhi, Katherine E Kabotyanski, Kasra A Mansourian, Jonathan H Bentley, Jordan R Altman, Saurabh Hinduja, Nisha Giridharan, Garrett P Banks, Mohammed Hasen, Ben Shofty, Sarah R Heilbronner, Jeffrey F Cohn, David A Borton, Eric A Storch, Jeffrey A Herron, Benjamin Y Hayden, Mary L Phillips, Wayne K Goodman, Sameer A Sheth","doi":"10.1523/JNEUROSCI.1321-24.2025","DOIUrl":"10.1523/JNEUROSCI.1321-24.2025","url":null,"abstract":"<p><p>Deep brain stimulation (DBS) of the ventral capsule and ventral striatum (VC/VS) is an effective therapy for treatment-resistant obsessive-compulsive disorder (trOCD). DBS initiation often produces acute improvements in mood and energy. These acute behavioral changes, which we refer to as \"approach behaviors,\" include increased social engagement and talkativeness. We investigated the relationship between stimulation amplitude, spectral power in the ventrolateral prefrontal cortex (vlPFC), and speech rate in one male patient with trOCD implanted with bilateral VC/VS DBS leads and subdural electrodes adjacent to the orbitofrontal cortex and vlPFC. Several times over the first 24 weeks of therapy, we conducted experiments where we recorded data during epochs of high-amplitude or zero-/low-amplitude stimulation. We found that both the speech rate and vlPFC power in a high beta frequency band (31 ± 1.5 Hz, 1/<i>f</i> activity removed) increased during high-amplitude as compared with low-amplitude periods. The speech rate correlated with vlPFC high beta power. These effects were more consistent across time points in the left hemisphere than the right. At Week 24, we performed an experiment where stimulation was held constant, while the patient was asked to speak or remain silent. We showed that the presence or absence of speech was not sufficient to increase the vlPFC high beta power, suggesting stimulation is a key driver of the observed neurobehavioral phenomenon. Our results suggest vlPFC high beta power is a biomarker for approach behaviors associated with VC/VS DBS.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12424958/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143076177","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":"Phasic alertness impairs cognitive control by amplifying competition between evidence accumulators.","authors":"Jeshua Tromp,Franz Wurm,Federica Lucchi,Roy de Kleijn,Sander Nieuwenhuis","doi":"10.1523/jneurosci.1595-24.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.1595-24.2025","url":null,"abstract":"Although phasic alertness generally benefits cognitive performance, it often increases the impact of distracting information, resulting in impaired decision-making and cognitive control. However, it is unclear why phasic alertness has these negative effects. Here, we present a novel, biologically-informed account, according to which phasic alertness generates a transient, evidence-independent input to the decision process. This shortens overall response times, but also amplifies competition between evidence accumulators, thus slowing down decision-making and impairing cognitive control. The key hypotheses of this account are supported with pupil measurements and electrophysiological data from human decision-makers of either sex performing an arrow flanker task. We also show that a computational model of the flanker task that incorporates a transient, evidence-independent input can reproduce the behavioral effects of phasic alertness, but only when the evidence accumulators compete with each other through lateral inhibition. Our results reveal a close interplay between dynamic changes in alertness, cognitive control and evidence accumulation.Significance Statement The human attention system is thought to consist of three fundamental components: alerting, orienting, and cognitive control, which shields goal-directed mental activity from distracting information. Although these attentional components are thought to be subserved by distinct brain systems, they seemingly work in concert to produce complicated patterns of behavior. Here, we focus on an interaction between alertness and cognitive control that has puzzled cognitive psychologists for two decades: although increased alertness generally benefits cognitive performance, it disrupts cognitive control. We propose a neurobiologically plausible mechanistic account of how alertness impairs control, and support this account with pupil and EEG measurements, as well as computer simulations.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"100 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145025467","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":"Layer 6 corticothalamic neurons induce high gamma oscillations through cortico-cortical and cortico-thalamo-cortical pathways.","authors":"Simone Russo, Elaida D Dimwamwa, Garrett B Stanley","doi":"10.1523/JNEUROSCI.0094-25.2025","DOIUrl":"10.1523/JNEUROSCI.0094-25.2025","url":null,"abstract":"<p><p>Layer 6 corticothalamic (L6CT) neurons project to both cortex and thalamus, inducing multiple effects including the modulation of cortical and thalamic firing, and the emergence of high gamma oscillations in the cortical local field potential (LFP). We hypothesize that the high gamma oscillations driven by L6CT neuron activation reflect the dynamic engagement of intracortical and cortico-thalamo-cortical circuits. To test this, we optogenetically activated L6CT neurons in NTSR1-cre mice (both male and female) expressing channelrhodopsin-2 in L6CT neurons. Leveraging the vibrissal pathway in awake, head-fixed mice, we presented ramp-and-hold light at different intensities while recording neural activity in the primary somatosensory barrel cortex (S1) and the ventral posteromedial nucleus (VPm) of the thalamus using silicon probes. We found that the activation of S1 L6CT neurons induces high-frequency LFP oscillations in S1 that are modulated in frequency, but not in amplitude, across light intensities and over time. To identify which neuronal classes contribute to these oscillations, we examined the temporal evolution of firing rate in S1 and VPm. While most S1 neurons were steadily suppressed, VPm and S1 Layer 4 fast spiking (L4 FS) neurons evolved from being suppressed to facilitated within 500 ms, suggesting differential recruitment of the intracortical vs cortico-thalamo-cortical pathways. Finally, we found that LFP frequency selectively correlates with VPm firing rate. Taken together, our data suggests that L6CT neurons sculpt the frequency of S1 LFP oscillations through cortico-thalamo-cortical circuits, linking the recurrent interactions mediated by L6CT neurons to the high gamma oscillations observed across physiological and pathological conditions.<b>Significance Statement</b> Layer 6 corticothalamic (L6CT) neurons are strategically positioned to modulate the cortex and the thalamus allowing them to engage distinct, yet interlocked, circuits. Here we show that the activation of L6CT neurons in the mouse primary somatosensory cortex induces fast cortical oscillations through the coordinated engagement of cortico-thalamo-cortical and intracortical pathways. Our work reveals that these two L6CT-mediated pathways exert competing effects: while intracortical connections suppress cortical spiking, the activity of the cortico-thalamo-cortical loop rapidly evolves, facilitating cortical spiking. We demonstrate that the cortico-thalamo-cortical pathway operates on a faster timescale than the intracortical pathway and critically shapes cortical oscillation frequency. These findings reveal how the unique position of corticothalamic neurons allows them to flexibly and dynamically modulate the thalamocortical network.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145031069","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":"Presenilin loss impairs synaptic transmission and causes axonal degeneration through ryanodine receptor dysfunction, independent of γ-secretase activity.","authors":"Xinran Du,Longgang Niu,Michal Ragan,Zuzanna Fracz,Zhao-Wen Wang","doi":"10.1523/jneurosci.1052-25.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.1052-25.2025","url":null,"abstract":"Presenilin mutations are the most common cause of familial Alzheimer's disease (FAD), but the mechanisms by which they disrupt neuronal function remain unresolved, particularly in relation to γ-secretase activity. Using C. elegans, we show that the presenilin ortholog SEL-12 supports synaptic transmission and axonal integrity through a pathway involving the ryanodine receptor RYR-1. Loss-of-function mutations in either sel-12 or ryr-1 reduce neurotransmitter release and cause neuronal structural defects, with no additional impairment in double mutants, suggesting a shared pathway. Transgenic expression of a γ-secretase-inactive SEL-12 variant or human presenilin 1 restores normal synaptic transmission in sel-12 mutants. Notably, sel-12 loss does not alter ryr-1 transcript or protein levels. These findings define a novel γ-secretase-independent role for presenilin in maintaining neuronal function via ryanodine receptor signaling, providing new mechanistic insight into presenilin-linked neurodegeneration and pointing to potential therapeutic strategies for FAD.Significance Statement Mutations in presenilins are the major cause of familial Alzheimer's disease and are commonly associated with impaired synaptic transmission and neurodegeneration. However, the molecular mechanisms underlying these effects remain poorly understood. This study shows that loss of presenilin in C. elegans impairs neurotransmitter release and causes axonal degeneration through dysfunction of ryanodine receptors (RyRs), independent of presenilin's γ-secretase activity. Notably, RyR expression remains unchanged, suggesting that presenilins likely regulate RyR function. These findings uncover a γ-secretase-independent pathway linking presenilin dysfunction to synaptic and neuronal deficits. The findings of this study offer new insight into the pathogenesis of Alzheimer's disease.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"11 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145025466","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":"Competition between tool and hand motion impairs movement planning in limb apraxia.","authors":"Simon Thibault, John B Yates, Laurel J Buxbaum, Aaron L Wong","doi":"10.1523/JNEUROSCI.0692-25.2025","DOIUrl":"10.1523/JNEUROSCI.0692-25.2025","url":null,"abstract":"<p><p>Tool use is a complex motor planning problem. Prior research suggests that planning to use tools involves resolving competition between different tool-related action representations. We therefore reasoned that competition may also be exacerbated with tools for which the motions of the tool and the hand are incongruent (e.g., pinching the fingers to open a clothespin). If this hypothesis is correct, we should observe marked deficits in planning the use of incongruent as compared to congruent tools in individuals with limb apraxia following left-hemisphere stroke (LCVA), a disorder associated with abnormal action competition. We asked 34 individuals with chronic LCVA (14 females) and 16 matched neurotypical controls (8 females) to use novel tools in which the correspondence between the motions of the hand and tool-tip were either congruent or incongruent. Individuals with LCVA also completed background assessments to quantify apraxia severity. We observed increased planning time for incongruent as compared to congruent tools as a function of apraxia severity. Further analysis revealed that this impairment predominantly occurred early in the task when the tools were first introduced. Lesion-symptom mapping analyses revealed that lesions to posterior temporal and inferior parietal areas were associated with impaired planning for incongruent tools. A second experiment on the same individuals with LCVA revealed that the ability to gesture the use of conventional tools was impaired for tools rated as more incongruent by a normative sample. These findings suggest that tool-hand incongruence evokes action competition and influences the tool-use difficulties experienced by people with apraxia.<b>Significance Statement</b> Prior research indicates that competition between different representations associated with moving or using tools must be resolved to enable tool use. We demonstrated that competition may be exacerbated when tool and hand motions are incongruent (e.g., pinching the hand opens a clothespin), resulting in tool-use impairments particularly for individuals with greater severity of limb apraxia, a disorder known to be associated with action competition abnormalities. Lesions in posterior portions of the brain's tool use network were associated with impairments in planning incongruent tool actions. This study thus demonstrates that tool-hand incongruence may invoke competition between motions of the hand and tool-tip, which individuals with limb apraxia have difficulty resolving to properly use tools.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145031062","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":"Convergence and segregation of excitatory and inhibitory afferents in the paraventricular thalamic nucleus.","authors":"László Biró,Zsolt Buday,Kata Kóta,Szabolcs Lőrincz,László Acsády","doi":"10.1523/jneurosci.0539-25.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.0539-25.2025","url":null,"abstract":"The paraventricular thalamic nucleus (PVT) integrates subcortical signals related to arousal, stress, addiction, and anxiety with top-down cortical influences. Increases or decreases in PVT activity exert profound, long-lasting effects on behavior related to motivation, addiction and homeostasis. Yet the sources of its subcortical excitatory and inhibitory afferents, their distribution within the PVT, and their integration with layer-specific cortical inputs remain unclear. Using transgenic male and female mice selective for GABAergic and glutamatergic neurons, or for different cortical layers we found that the input organization of PVT is unique among thalamic nuclei. PVT received subcortical GABAergic and glutamatergic inputs from multiple, distinct hypothalamic and brainstem regions. Most regions provided either excitatory or inhibitory afferents however subcortical inputs with dual components have also been found. Most of these subcortical inputs selectively targeted the core region of the PVT that contained large number of densely packed calretinin-positive (CR+) neurons. Cortical afferents to PVT displayed layer specific segregation. Layer 5 neurons of the medial prefrontal cortex preferentially innervated the CR+ core, whereas layer 6 input was more abundant in the transition zone between PVT and the mediodorsal nucleus. These findings demonstrate extensive convergence of excitatory and inhibitory inputs from diverse subcortical sources, selectively, in a sharply delineated CR+ core region of PVT which is also under strong top-down control from layer 5. This unique organization may explain why the CR+ PVT core serves as a critical bottleneck in the subcortex-cortex communication involved in affective behavior.Significance Statement The paraventricular thalamic nucleus (PVT) is a critical hub that integrates diverse neural signals controlling arousal, emotion, and motivation. This integration depends on which brain regions excite or inhibit PVT and whether these inputs converge or segregate. The present study reveals that the PVT receives distinct excitatory and inhibitory inputs from multiple subcortical and cortical regions. Most afferents converge in a sharply delineated core region of PVT. The work offers new insights into how structural organization of thalamus can explain its influence on behavior like stress adaptation, craving or affective behavior. These findings can lead to novel understanding of PVT's function and guide future research to study therapeutic strategies aimed at restoring balanced neural dynamics in neuropsychiatric disorders.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"24 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145025468","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":"Sphingosine-1-phosphate signaling through Müller glia regulates neuroprotection, accumulation of immune cells, and neuronal regeneration in the rodent retina.","authors":"Olivia Taylor,Lisa E Kelly,Heithem M El-Hodiri,Andy J Fischer","doi":"10.1523/jneurosci.0150-25.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.0150-25.2025","url":null,"abstract":"The purpose of this study was to investigate how Sphingosine-1-phosphate (S1P) signaling regulates glial phenotype, neuroprotection, and reprogramming of Müller glia (MG) into neurogenic MG-derived progenitor cells (MGPCs) in the adult male and female mouse retina. We found that S1P-related genes were dynamically regulated following retinal damage. S1pr1 (S1P receptor 1) and Sphk1 (sphingosine kinase 1) are expressed at low levels by resting MG and are rapidly upregulated following acute damage. Overexpression of the neurogenic bHLH transcription factor Ascl1 in MG downregulates S1pr1, and inhibition of Sphk1 and S1pr1/3 enhances Ascl1-driven differentiation of bipolar-like cells. Treatments that activate S1pr1 or increase retinal levels of S1P initiate pro-inflammatory NFκB-signaling in MG, whereas treatments that inhibit S1pr1 or decreased levels of S1P suppress NFκB-signaling in MG. Conditional knock-out (cKO) of S1pr1 in MG, but not Sphk1, enhances the accumulation of immune cells in damaged retinas. cKO of S1pr1 promotes the survival of ganglion cells, whereas cKO of Sphk1 promotes the survival amacrine cells in damaged retinas. Consistent with these findings, pharmacological treatments that inhibit S1P receptors or inhibit Sphk1 had protective effects upon inner retinal neurons. We conclude that the S1P-signaling pathway is activated in MG after damage and this pathway acts secondarily to restrict the accumulation of immune cells, impairs neuron survival and suppresses the reprogramming of MG into neurogenic progenitors in the adult mouse retina.Significance Statement Understanding the mechanisms of retinal neuron survival and regeneration is fundamental for the development of therapeutic strategies of retinal repair. Here, we show that Sphingosine-1-phosphate signaling kick-starts the glial pro-inflammatory response, restricts immune cell recruitment, and exacerbates neuron cell death after acute retinal injury. Importantly, blocking sphingosine-1-phosphate activity enhances Ascl1-driven neurogenesis in the mouse retina, highlighting a potential therapeutic target for retinal regeneration.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"2 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145025470","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":"Reduction in reward-driven behaviour depends on the basolateral but not central nucleus of the amygdala in female rats.","authors":"Belinda P P Lay,Guillem R Esber,Mihaela D Iordanova","doi":"10.1523/jneurosci.0288-25.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.0288-25.2025","url":null,"abstract":"Adaptive behavior depends on a dynamic balance between acquisition and extinction memories. Male and female rodents differ in extinction learning rates, suggestion potential sex-based differences in this balance. In males, deletion of extinction-recruited neurons in the central nucleus (CN) of the amygdala impairs extinction retrieval, shifting behavior toward acquisition (Lay et al., 2023). Here, we tested whether this mechanism also operates in females. In contrast to previously reported findings in males, deleting extinction-recruited CN neurons after single or extended extinction training had no effect on extinction retrieval in female rats. This lack of behavioral impact was not due to sex differences in CN activation during extinction. However, during early extinction, females showed greater activity in the basolateral amygdala (BLA) than males. Deletion of this BLA ensemble produced a more substantial reduction in conditioned approach than in non-deletion controls. These findings uncover a potential interplay between the CN and BLA in regulating conditioned approach in females. While ablation of extinction-recruited CN neurons do not modulate extinction retrieval in females, targeted BLA neuronal ablation during early extinction shifts behavior toward low, extinction-level responding. Thus heightened BLA activation during early extinction may prevent the emergence of extinction-like behavior in females. These findings, taken together with those reported by Lay et al. (2023) offer new insights into potential sex-based differences in the neural mechanisms underlying extinction and may inform the development of sex-based treatments for cue-triggered appetitive behaviors.Significance Statement This manuscript uncovers a neural mechanism that explains why females take longer to inhibit previously learned behavior. Together with findings reported in Lay et al. (2023), we uncover that the BLA and CN play complementary roles in balancing acquisition and extinction memories-BLA supports acquisition-based responses, which dominate during the early stages of extinction in females, while CN facilitates extinction-based responding, which develops faster in males. The CN-dependent extinction process, however, was not obtained in the females. This novel mechanism may account for the observed sex differences in disorders where competing memories influence behavior, such as drug abuse versus abstinence or anxiety versus cue-exposure therapy.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"57 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145025469","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}