Neuroscience[JOURNAL]
Sun
200 papers
The AMPA receptor life cycle: assembly, regulation and synaptic diversity.
Bowie D, Wang XT, Miguez-Cabello F … +1 more , Perozzo AM
Nat Rev Neurosci · 2026 Jun · PMID 42286176 · Publisher ↗
AMPA receptors (AMPARs) mediate the majority of fast excitatory neurotransmission in the mammalian brain. Recent structural, functional and proteomic advances have reshaped our understanding of how these receptors assemb...
AMPA receptors (AMPARs) mediate the majority of fast excitatory neurotransmission in the mammalian brain. Recent structural, functional and proteomic advances have reshaped our understanding of how these receptors assemble, gate and diversify within distinct synaptic environments. Notably, AMPAR function is governed by an interlocking set of regulatory layers that include alternative splicing and RNA editing within regions of the receptor subunits responsible for gating and permeation, and direct allosteric coupling with different families of auxiliary proteins. The assembly of AMPARs through a dedicated endoplasmic reticulum biogenesis pathway ensures accurate tetramer formation and provides a regulatory checkpoint for synaptic receptor abundance. Brain development introduces additional layers of control as editing, splicing and auxiliary-subunit expression shift from embryonic to adult states, whereas interactions with extracellular proteins contribute to the organization and diversification of synaptic architecture across circuits. Thus, AMPARs are dynamic macromolecular assemblies whose diversity underlies the breadth of glutamatergic signalling in health and disease. This Review synthesizes these emerging principles, highlighting how AMPARs transition from their molecular 'birth' to their deployment at functionally specialized synapses.
Extracellular vesicles MicroRNAs in stroke therapy: recent advances and translational potential.
Ding Y, Ma Y, Hu J … +5 more , Wei M, Liao H, Yang Y, Gu J, Tan R
Neuroscience · 2026 Jun · PMID 42285407 · Publisher ↗
Ischemic stroke accounts for ∼ 87% of all strokes. Existing reperfusion therapies are limited by narrow time windows. Small extracellular vesicles (sEVs) can cross the blood-brain barrier and deliver microRNAs (miRNAs) t...
Ischemic stroke accounts for ∼ 87% of all strokes. Existing reperfusion therapies are limited by narrow time windows. Small extracellular vesicles (sEVs) can cross the blood-brain barrier and deliver microRNAs (miRNAs) that modulate post-stroke inflammation, apoptosis, angiogenesis, and neurogenesis. However, most evidence is from preclinical studies (MCAO models), and no approved clinical protocols exist. This review summarizes ischemic stroke pathogenesis and critically evaluates preclinical advances in sEV-miRNA therapy. We highlight key translational barriers: lack of standardized sEV isolation (MISEV2023), miRNA cargo heterogeneity, dosing uncertainties, limited biodistribution data, off-target risks, regulatory bottlenecks, and absence of stroke-specific trials. We also evaluate exosomal miRNAs from various cell sources (e.g., bone marrow mesenchymal stem cells). This review provides a critical synthesis of preclinical evidence to establish a foundation for future translational research in precision stroke therapy.
Recent advances in neurodegenerative diseases therapeutics: The inhibition of monoacylglycerol lipase strategy.
Mendoza-Camacho DM, Espinoza-Gutiérrez HA, Viveros-Paredes JM … +2 more , Flores-Soto ME, Tejeda-Martínez AR
Neuroscience · 2026 Jun · PMID 42285406 · Publisher ↗
Neurodegenerative diseases share common pathophysiological mechanisms, including chronic neuroinflammation, glutamatergic excitotoxicity, oxidative stress, mitochondrial dysfunction, and disruptions in synaptic and lipid...
Neurodegenerative diseases share common pathophysiological mechanisms, including chronic neuroinflammation, glutamatergic excitotoxicity, oxidative stress, mitochondrial dysfunction, and disruptions in synaptic and lipid homeostasis. In this context, the endocannabinoid system has emerged as a key modulator of neuroimmune communication and neuronal survival. Within this system, Monoacylglycerol Lipase (MAGL) plays a central role by regulating the levels of the endocannabinoid 2-Arachidonoylglycerol (2-AG) while simultaneously contributing to the generation of arachidonic acid and pro-inflammatory eicosanoids. Pharmacological or genetic inhibition of MAGL increases 2-AG levels and concurrently reduces the biosynthesis of pro-inflammatory lipid mediators, thereby modulating microglial activation, astrocytic responses, and neuronal excitotoxicity. Preclinical studies in models of Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis consistently demonstrate that MAGL blockade attenuates neuroinflammation, preserves synaptic and neuronal integrity, improves motor and cognitive function, and, in some cases, delays disease progression. Although clinical evidence remains limited, the available data position MAGL as a metabolic convergence point between inflammation and neurodegeneration, suggesting that its modulation may represent a therapeutic strategy with disease-modifying potential.
Identification of traumatic intracerebral hemorrhage associated metabolites using untargeted metabolomics.
Wang W, Zheng W, Lu X
Int J Neurosci · 2026 Jun · PMID 42283270 · Publisher ↗
Traumatic intracerebral hemorrhage (TICH) is a severe neurological emergency whose metabolic mechanisms remain largely unresolved. This study used serum metabolomics analysis to compare the metabolic profiles of TICH pat...
Traumatic intracerebral hemorrhage (TICH) is a severe neurological emergency whose metabolic mechanisms remain largely unresolved. This study used serum metabolomics analysis to compare the metabolic profiles of TICH patients ( = 10) with non-TICH controls ( = 10). LC-MS/MS analysis identified a total of 3183 metabolites. The relative abundances of benzene and its derivatives, organic acids and their derivatives were significantly increased in the serum of ICH patients, while fatty acid, glycerophospholipid, and sphingomyelin metabolites were generally decreased. Multidimensional statistical methods were used to screen for significantly differentially expressed metabolites. Metabolite regulatory networks revealed the potential roles of amino acid metabolism, lipid metabolism (GP/SP/FA), and aromatic compounds (benzenes) in regulating TICH metabolism. Enrichment analysis revealed that these metabolites were highly enriched in lipid metabolism, amino acid metabolism, and neural signaling pathways, and were significantly associated with inflammatory drug pathways. The differentially expressed metabolites were further mapped to the Human Metabolite Database (HMDB) and subjected to metabolic-disease association analysis, suggesting that these metabolites may be closely related to the pathogenesis of TICH. ROC analysis demonstrated good diagnostic performance of five key metabolites in both discovery and validation cohorts (AUC > 0.70), with hypoxanthine and L-histidine showing the highest accuracy (AUC > 0.93). Correlation analysis indicated that key metabolites were associated with hematoma volume, NIHSS and GCS scores. experiments further confirmed that, under conditions of neuronal injury, the changes in these metabolites exhibit consistency. This study provides a theoretical basis for the development of potential biomarkers and precise intervention strategies.
Taurine reverses long-term memory deficits caused by LPS induced neuroinflammation.
Haskel MVL, da Silva Vequi LS, Flauzino MWP … +6 more , da Silva Correa V, Oliveira CS, Pereira ME, de Gregório E, Bonini JS, da Silva WC
BMC Neurosci · 2026 Jun · PMID 42277642 · Full text
BACKGROUND: Despite neuroinflammation being an initially protective response made by the central nervous system (CNS), as it becomes chronic, it can lead to neuronal damage since the cytokines which are released by micro...
BACKGROUND: Despite neuroinflammation being an initially protective response made by the central nervous system (CNS), as it becomes chronic, it can lead to neuronal damage since the cytokines which are released by microglia potentialize cellular death due to excitotoxicity, and this, in turn, promotes the release of pro-inflammatory mediators, feeding this way a self-sustaining cycle of neuroinflammatory response, which favor subsequent neurodegeneration. Given the fact that until this moment, there are not any therapeutic alternatives able to stop the neurodegeneration, the objective of the present work was to evaluate the putative neuroprotector effect of taurine, a partial glycinergic ionotropic receptor agonist, and also a GABA receptor agonist, in a neuroinflammation animal model. METHOD: For this intent, the oral taurine administration was evaluated on mnemonic impairing caused by LPS induced neuroinflammation in male Wistar rats. Such effects were investigated on recent and late spatial long-term memory and aversive memory in the behavioural tasks Morris water maze (MWM) and context fear conditioning (CFC), respectively. In addition, we investigated the effect of orally administered taurine on hippocampal neuronal density and on hippocampal levels of TNF-α and IL-4. RESULTS: Taurine, when orally administered for 30 days, in the doses of 20 and 200 mg/kg, was able to reverse the mnemonic impairment caused by neuroinflammation on recent and remote spatial long-term memory, and in the dose of 200 mg/kg, it also was able to do the same on aversive long-term memory. In the doses of 20 and 200 mg/kg, taurine was also able to reverse the LPS-induced increase in hippocampal TNF-α levels. CONCLUSION: Taurine, when orally administered in a pathological context characterized by neuroinflammatory background, as it was induced in this work, can perform a dose-dependent neuroprotective effect, probably by acting in an excitotoxic scenario in which the activation of hyperpolarizing receptors can be welcomed.
Hierarchical Reconfiguration of Neurocognitive Task Set Representations Mediates Cognitive Flexibility.
Leach SC, Chen X, Hwang K
J Neurosci · 2026 Jun · PMID 42276789 · Publisher ↗
Cognitive control organizes abstract contexts, stimuli, and actions into hierarchically structured representations. This organization supports flexible behavior but requires updating at multiple levels of the hierarchy,...
Cognitive control organizes abstract contexts, stimuli, and actions into hierarchically structured representations. This organization supports flexible behavior but requires updating at multiple levels of the hierarchy, a process reflected in task switch costs. However, it remains unclear how updating differs across levels of abstraction and how these differences relate to behavior and neural representations. Here, we investigated the behavioral and neural sources of switch costs using fMRI and behavioral data from healthy adult participants (male and female). We employed a hierarchical control task that dissociates abstract context reconfiguration from more concrete task-set reconfiguration of stimulus-response mappings. We predicted that task sets, which incorporate sensory-motor mappings, would be more strongly influenced by feedforward inputs than higher-level contextual goals, which are more abstracted from immediate perceptual and motor demands. As predicted, subordinate rule switches were faster and were more strongly influenced by task-irrelevant perceptual changes, whereas context switches were slower and relatively insensitive to such interference. To characterize the neural basis of these effects, we quantified trial-to-trial reconfiguration of multivoxel activity patterns. Across the brain, larger pattern shifts predicted larger RT switch costs, linking representational reorganization to behavioral performance. Importantly, representational reconfiguration differed across hierarchical levels and anatomical systems. Subordinate rule updating was modulated by task-irrelevant perceptual features and expressed in distributed perceptual and motor networks, whereas context reconfiguration engaged the mid-lateral frontal cortex and was comparatively insulated from interference. Our results reveal how the hierarchical structure of neural representations supports flexible updating with interference-shielded contextual representations subserving behavioral control. Daily activities often require simultaneously updating different tasks and thoughts. Driving requires maintaining a stable destination goal while rapidly updating motor plans (brake, accelerate, turn, etc.) in response to changing perceptual information (traffic lights, pedestrians, etc.). Although people perform such tasks with ease, it remains unclear how neural and cognitive representations are structured to respond to these flexibility demands. The present study suggests that sensory-motor plans prioritize flexibility by allowing greater influence from sensory inputs, which can create interference across brain networks when that input is task-irrelevant. Contextual information is insulated from this interference by representing contexts as distinctly as possible in the lateral prefrontal cortex, resulting in slower but more stable context switching.
Disrupted maternal care alters neural-microglia interactions in the primate paralaminar (PL) nucleus of the amygdala.
King DP, Khan M, Majewska AK … +2 more , Cameron JL, Fudge JL
J Neurosci · 2026 Jun · PMID 42276788 · Publisher ↗
Prolonged postnatal maturation of the primate amygdala is thought to be driven, at least partially, by continued neural maturation within the paralaminar nucleus (PL). At birth, the PL is densely populated with post-mito...
Prolonged postnatal maturation of the primate amygdala is thought to be driven, at least partially, by continued neural maturation within the paralaminar nucleus (PL). At birth, the PL is densely populated with post-mitotic glutamatergic neurons that gradually mature throughout postnatal life. This active process is likely supported by microglia, which promotes synaptic maturation. Our previous work showed that maternal separation alters microglia development across the infant to adolescent transition (n=19 females, 4 males). Here, in the same cohort, we examined whether morphologic microglial changes are associated with alterations in the numbers of pre-synaptic terminals (SYN1+ puncta), post-synaptic terminals (PSD95+ puncta), and putative excitatory contacts (SYN1-PSD95 colocalization), and whether these synaptic elements are engulfed by phagocytic microglia. In maternally reared macaques, SYN1+ puncta, PSD95+ puncta, and putative synaptic contacts decreased, while microglial (IBA1+) volume, CD68+ content, and engulfment of synaptic elements increased between infancy and adolescence. These findings suggest greater pruning of all synaptic elements by adolescence. Maternal separation altered this trajectory, resulting in increased phagocytic activity and engulfment of synaptic elements primarily during infancy. Maternal separation also resulted in a 50% reduction in mature PL neurons by adolescence, suggesting maturational failure, cell loss, or both by adolescence. These findings demonstrate that early life stress disrupts normative synaptic pruning and microglia-synapse interactions in the developing primate PL. Increased synaptic engulfment in infants with disrupted care is associated with premature, aberrant pruning and highlights a potential cellular mechanism through which early environmental insults could change PL neural development by adolescence. The paralaminar nucleus (PL) of the amygdala is an important substrate for the delayed post-natal development of the amygdala in human and nonhuman primates. Gradually maturing glutamatergic neurons in this region, and the microglia that support them, are exposed to life events that may shape their development. We recently found that maternal separation in infants produces aberrant hyper-ramified microglia in the PL beginning in infancy and persisting into adolescence. Examining neuron-microglial interactions in the same cohort, we now find increased phagocytic engulfment of synaptic elements by microglia after maternal separation in infancy only, with a reduction in PL mature neurons that is apparent by adolescence. Together, these data suggest a mechanism for altered PL maturation, instigated by disrupted maternal care.
Downregulation of Nrf2 and upregulation of TXNIP/NLRP3 signaling Induce postoperative cognitive dysfunction via oxidative stress and pyroptosis in the hippocampus.
Sun J, Cao J, Yang C … +4 more , Gao L, Li N, Xu J, Liu C
Neuroscience · 2026 Jun · PMID 42276292 · Publisher ↗
Postoperative Cognitive Dysfunction (POCD) is a neurocognitive complication after anaesthesia and surgery, with oxidative stress as a key pathological driver. Nuclear factor erythroid-related factor 2 (Nrf2) and Thioredo...
Postoperative Cognitive Dysfunction (POCD) is a neurocognitive complication after anaesthesia and surgery, with oxidative stress as a key pathological driver. Nuclear factor erythroid-related factor 2 (Nrf2) and Thioredoxin-Interacting Protein (TXNIP) are critical regulators of oxidative stress and inflammation, and TXNIP directly facilitates NLRP3 inflammasome activation. Using an 18-month-old mouse model of POCD established by tibial fracture surgery, we investigated the changes in the expression of TXNIP and the regulatory mechanism of the Nrf2/TXNIP/NLRP3 signaling pathway. Cognitive function was assessed by the Morris water maze test, and hippocampal samples were analyzed for protein levels(Nrf2, TXNIP, and NLRP3 inflammasome-related protein), pro-inflammatory factors (IL-1β and IL-18), Reactive Oxygen Species (ROS), and neuronal apoptosis. Anesthesia/surgery significantly upregulated TXNIP expression. Inhibiting TXNIP with verapamil attenuated oxidative stress, neuronal injury, and NLRP3 inflammasome activation, thereby ameliorating cognitive impairment. Similarly, sulforaphane (SFN)-mediated upregulation of Nrf2 suppressed TXNIP expression, decreased NLRP3 inflammasome-related proteins and pro-inflammatory factors, and alleviated cognitive deficits. These findings demonstrate thatthe Nrf2/TXNIP/NLRP3 axis mediates hippocampal oxidative stress and pyroptosis in POCD pathogenesis, highlighting this pathway as a potential therapeutic target.
Cerebellar aging is spatially heterogeneous and supports cognitive resilience in later life.
d'Oleire Uquillas F, Sefik E, Seidlitz J … +10 more , Daniel Hertz E, Romero-Garcia R, Warrier V, Bethlehem RAI, Alexander-Bloch AF, Cohen JD, Wang SS, Sepulcre J, Vannini P, Gomez J
Nat Neurosci · 2026 Jun · PMID 42271047 · Publisher ↗
The cerebellum contains most of the brain's neurons and supports many functions, yet how it changes with age remains unclear. Here we used three brain imaging studies spanning 47,000 adults and examined how different par...
The cerebellum contains most of the brain's neurons and supports many functions, yet how it changes with age remains unclear. Here we used three brain imaging studies spanning 47,000 adults and examined how different parts of the cerebellum age and their relation to cognition. We characterized cerebellar aging using volumetry and the T1-weighted/T2-weighted ratio, and corroborated these findings with quantitative magnetic resonance imaging in an independent sample. We show a spatially heterogeneous pattern of aging in which specific association and motor-related regions show steeper relationships with age than other lobules. Greater cerebellar volume was associated with higher cognitive scores with increasing age, suggesting that cerebellar structure may provide brain reserve that helps maintain function despite aging. In patients with Alzheimer's disease, cerebellar volume was linked to cognition in individuals with lower amyloid burden, especially in those carrying two copies of the APOE-ε4 risk gene. This supports a threshold-reserve model, in which the cerebellum helps sustain cognition until pathology becomes widespread. These results show that the cerebellum has an active role in healthy cognitive aging and resilience.
Triple-N dataset: large-scale fMRI-guided dense recordings of nonhuman primate neural responses to natural scenes.
Li Y, Liu X, Li W … +8 more , Yang J, Gong B, Jin W, Gong Z, Wang K, Luo J, Zhao Z, Bao P
Nat Neurosci · 2026 Jun · PMID 42271046 · Publisher ↗
Understanding high-level visual processing requires data that capture both fine-grained neuronal activity and large-scale cortical organization. We present the Triple-N dataset, which extends the Natural Scenes Dataset (...
Understanding high-level visual processing requires data that capture both fine-grained neuronal activity and large-scale cortical organization. We present the Triple-N dataset, which extends the Natural Scenes Dataset (NSD) framework to macaques by combining functional magnetic resonance imaging with dense Neuropixels recordings in the inferotemporal cortex and early visual areas during the viewing of 1,000 NSD images. Neuropixels probes provide high-resolution population sampling, capturing hundreds of simultaneously isolated units with millisecond temporal precision. Using these data, we show that inferotemporal category-selective regions exhibit robust tuning for their preferred categories, and dense sampling further reveals diverse temporal response patterns and image-dependent latency variations that reflect both intrinsic neuronal properties and stimulus features. Aligning macaque electrophysiology with human NSD functional magnetic resonance imaging demonstrates cross-species correspondences and divergences in representational geometry. Overall, the Triple-N dataset lays a foundation for unifying single-neuron dynamics, cortical representations and cross-species comparisons, helping to shape a more comprehensive understanding of primate visual processing.
Cerebrovascular vulnerability and fibrosis in human brain aneurysms.
Wang JC, Kim CN, Bhalla S … +31 more , Scherschinski L, Gopinadhan A, Arul S, Sanchez D, Schriber TD, Apolonio ACM, Gülsuyu B, Öztürk MM, Andrews JP, Kim J, Jahromi BR, Niemelä M, Lehecka M, Poddar A, Wälchli T, Catapano JS, Sen RD, Levitt MR, Cooke DL, Narsinh K, Jha RM, Hashimoto T, Oh SP, Huang EJ, Chang EF, Lim DA, Abla AA, Yang AC, Nowakowski TJ, Lawton MT, Winkler EA
Nat Neurosci · 2026 Jun · PMID 42271045 · Publisher ↗
Brain aneurysms are a cerebrovascular disease that results in a severe type of stroke. The cell-specific molecular pathology underlying their formation and rupture is unknown. Here we profile 227,663 neurovascular cells,...
Brain aneurysms are a cerebrovascular disease that results in a severe type of stroke. The cell-specific molecular pathology underlying their formation and rupture is unknown. Here we profile 227,663 neurovascular cells, including 52,946 aneurysmal cells, from a total of 14 adult human brain aneurysms and 11 control vessels. Our atlas of human brain aneurysms, as well as cell-resolution spatial transcriptomics, revealed that pathological cerebrovascular remodeling occurs with the loss of structurally supportive smooth muscle cells and the emergence of activated perivascular fibroblasts, which re-populate the vascular wall and express multiple genes linked to aneurysm risk. Fibrotic changes coincide with fibroblast-myeloid cell signaling pathways and an influx of specialized macrophages that are rarely detected in non-aneurysmal cerebrovasculature and that express destabilizing vascular cell programs. Thus, we reveal an unrecognized interplay between cerebrovascular fibrosis and myeloid inflammation during disease progression, substantially advancing our understanding of the cellular drivers and mechanisms underlying this devastating cerebrovascular disease that will inform translational development.
Spatiotemporal Divergence Between Intrinsic And Evoked Cortical Activity Predicts Visual Detection.
Jensen D, Davis ZW
J Neurosci · 2026 Jun · PMID 42270430 · Publisher ↗
The threshold for sensory detection varies with fluctuations in intrinsic cortical activity. When stimulus-encoding cortical populations are more excitable, stimuli elicit stronger neural responses that are more likely t...
The threshold for sensory detection varies with fluctuations in intrinsic cortical activity. When stimulus-encoding cortical populations are more excitable, stimuli elicit stronger neural responses that are more likely to be detected. However, the detection of a stimulus is also more likely when cortical populations are less excitable because there is less background "noise". Therefore, it is unclear how the variable states of cortical activity interact to impact sensory detection. We hypothesize the answer depends on the spatiotemporal structure of intrinsic activity states across stimulus encoding and non-encoding populations. To test this, we examined intrinsic and target-evoked population activity across cortical Area MT in common marmosets (Callithrix jacchus; one male and one female) while they performed a threshold visual detection task. We compared detection performance based on target-evoked responses and the state of intrinsic activity in the larger surrounding population. We find that the intrinsic activity in the surrounding, non-encoding population predicted trial-by-trial detection performance better than the population encoding the target-evoked response. Furthermore, we find that the detection performance of the monkey was best predicted by the divergence in activity between the encoding and surrounding non-encoding population. These findings suggest that, rather than a source of noise or irrelevant to sensory processing, the distributed spatiotemporal state of intrinsic activity directly influences how sensory signals are represented in cortical populations and can influence perceptual thresholds in visual detection. Prior research into how variability in neural activity impacts perception has often focused on neural populations that encode relevant sensory information. However, the role of variable intrinsic activity in nearby, non-encoding populations and their contribution to sensory representations is less well understood. We found that the state of intrinsic activity in non-encoding populations was a better predictor of performance on a threshold visual detection task than the evoked-response magnitude. These results suggest that the state activity in broader neural populations plays a larger role in sensory computations relevant to perceptual decisions than previously regarded.
Distinct hippocampal subfield representational shifts underlie category exception learning.
Xie Y, Mack ML
J Neurosci · 2026 Jun · PMID 42270429 · Publisher ↗
When we encounter an exception to our prior category knowledge, such as a leaf-like butterfly that perceptually diverges from the butterflies we commonly see, we must update our knowledge to reconcile this exception item...
When we encounter an exception to our prior category knowledge, such as a leaf-like butterfly that perceptually diverges from the butterflies we commonly see, we must update our knowledge to reconcile this exception item and generalize it to similar instances. Category knowledge updating has been suggested to rely on flexible representational modulation by the hippocampus, which involves two critical operations - pattern differentiation and integration. Yet, how separate hippocampal subfields carry out these operations has remained an outstanding puzzle in the exception learning domain. Here, we used functional magnetic resonance imaging (fMRI) to investigate the specific hippocampal subfield operations during which human participants (28 females and 25 males) learned exceptions that violated previously acquired regularities in two visual categories. We found that learning drove representations of exception and regular items towards differentiation in DG and integration in CA1, especially when the exception was confusable with members of the competing category instead of being a distinct oddball. Moreover, learning-related pattern differentiation and integration within DG, CA2/3, and CA1 were associated with participants' abilities to reconcile and generalize the confusable exception post-learning. Finally, the representational space in each subfield was distinctively reorganized in successful exception learners. Altogether, our findings provide fresh and nuanced insights into the hippocampal representational shifts over exception learning, contributing to a more complete picture of the hippocampal circuits in knowledge updating. Not all things in the world can be categorized using rigid rules. We sometimes encounter exceptions that contradict our category knowledge, and to acquire these exceptions, we may rely on flexible hippocampal operations that differentiate and integrate category item representations to update the knowledge structures. To characterize such operations, we examine changes in hippocampal representations before and after exception learning. We show that, over learning, anatomically separate hippocampal subfields engage in different representational shifts. Importantly, these shifts depend on exceptions' properties and are linked to learners' categorization performance. Overall, our findings help delineate the flexible hippocampal mechanisms that underlie knowledge updating in the face of exceptions.
Erratum: Jing and Wu et al., "Neddylation E1 Obligatory Subunit Nae1 Is Critical to Neuromuscular Junction Development and Maintenance".
J Neurosci · 2026 Jun · PMID 42270428 · Full text
Abstract loading — click title to view on PubMed.
Erratum: "Behavioral and Neural Mechanisms of Face-Specific Attention during Goal-Directed Visual Search".
J Neurosci · 2026 Jun · PMID 42270427 · Full text
Abstract loading — click title to view on PubMed.
Striatal cAMP Is Regulated by a Local Clock-Gene-Dependent Mechanism.
McCarthy JM
J Neurosci · 2026 Jun · PMID 42270379 · Full text
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Cerebral hypoperfusion and the vascular-metabolic-immune-glymphatic network in Alzheimer's disease: mechanisms, diagnosis, and therapy.
Yao M, Liu A, Song J … +3 more , Xing L, Zi M, Li H
Neuroscience · 2026 Jun · PMID 42269809 · Publisher ↗
Alzheimer's disease (AD), characterized by progressive cognitive decline, represents a major public health challenge in aging societies. Since the proposal of the amyloid cascade hypothesis, Aβ-targeted therapeutic strat...
Alzheimer's disease (AD), characterized by progressive cognitive decline, represents a major public health challenge in aging societies. Since the proposal of the amyloid cascade hypothesis, Aβ-targeted therapeutic strategies have dominated this field for over three decades. Although recent anti-Aβ antibodies have shown modest promise, their limited clinical benefits coupled with safety concerns underscore the necessity of re-evaluating the pathological mechanisms underlying AD. Cerebral hypoperfusion (CH), a detectable alteration emerging in the preclinical stage of AD, has garnered increasing attention for its potential driving role in disease pathogenesis. This review proposes a "vascular-metabolic-immune-glymphatic" (VMIG) pathological network model originating from CH: CH induces pericyte damage, astrocyte end-feet impairment, and extracellular matrix degradation, thereby resulting in neurovascular unit dysfunction; reduces oxygen and glucose delivery, precipitating mitochondrial energy failure and reactive oxygen species overproduction, which in turn initiates neuroinflammatory cascades; and attenuates arterial pulsation-driven flow while disrupting perivascular space architecture, culminating in glymphatic system clearance dysfunction. These mechanisms are intricately interconnected, establishing a self-perpetuating pathological loop. Building upon the VMIG framework, this review integrates multimodal neuroimaging techniques (ASL-MRI, Aβ/tau-PET, DTI-ALPS) with peripheral biomarkers (VEGF/Ang-2, sTREM2/GFAP, sPDGFRβ/Aβ42 ratio) to establish a comprehensive system for early diagnosis and stratified assessment of AD. Furthermore, we advocate for temporally sequenced combinatorial therapeutic strategies targeting the pathological network and discuss the translational potential of nanoparticle-based co-delivery systems. The VMIG model offers an integrative framework for understanding the multi-system dysregulation inherent to AD, facilitating a paradigm shift from single-target intervention toward network-based restoration.
Prognostic role of admission neutrophil-to-lymphocyte ratio in acute ischemic stroke: a systematic review and updated meta-analysis of 31,835 patients.
Sabet H, Abbas A, Abo-Elnour DE … +18 more , Hasan MT, Elshahat A, Samir A, Abouelmagd ME, Amin AM, Mansour A, Mohamed HM, Youssef RA, Elmashad A, Naghani IM, Soldozy S, Lashin B, Elshahat A, Meshref M, Elfil M, Kaur G, Gandhi CD, Al-Mufti F
Int J Neurosci · 2026 Jun · PMID 42267389 · Publisher ↗
OBJECTIVE: To evaluate the association of admission neutrophil-to-lymphocyte ratio (NLR) with functional outcomes, intracranial hemorrhage (ICH), and mortality in patients with acute ischemic stroke (AIS). METHODS: We se...
OBJECTIVE: To evaluate the association of admission neutrophil-to-lymphocyte ratio (NLR) with functional outcomes, intracranial hemorrhage (ICH), and mortality in patients with acute ischemic stroke (AIS). METHODS: We searched PubMed, Scopus, Web of Science, Cochrane CENTRAL, and Embase from inception until December 17, 2024. Studies examining admission NLR as a predictor for functional outcomes, ICH, and mortality in AIS patients were included. A meta-analysis was performed using pooled odds ratios (ORs) with 95% confidence intervals (CIs). Subgroup analyses were conducted based on treatment modality, time of measurement, hemorrhage type, and ethnicity. Heterogeneity was assessed using I statistics, and publication bias was evaluated using Egger's test. RESULTS: Sixty observational studies (31,853 patients), including 59 cohort studies and one cross-sectional study, were included. Higher admission NLR was significantly associated with unfavorable functional outcomes (OR: 1.10, 95% CI: [1.07, 1.14]), ICH (OR: 1.06, 95% CI: [1.03, 1.09]), and mortality (OR: 1.06, 95% CI: [1.04, 1.08]). Subgroup analysis indicated that NLR was associated with poor outcomes in AIS patients receiving mechanical thrombectomy and intravenous thrombolysis. CONCLUSION: Admission NLR is significantly associated with unfavorable functional outcomes, ICH, and mortality in AIS patients. Its predictive value remained evident in the MT and Asian subgroups; however, the association with unfavorable functional outcomes was not significant in the non-Asian subgroup, and the association with mortality in the IVT subgroup was also not significant. Given its accessibility and cost-effectiveness, NLR holds promise as a routine biomarker for stroke prognosis.
Human learning of noninvasive brain-computer interfaces via manifold geometry.
Busch EL, Fincke EC, Lajoie G … +2 more , Krishnaswamy S, Turk-Browne NB
Nat Neurosci · 2026 Jun · PMID 42265352 · Full text
Brain-computer interfaces (BCIs) promise to restore and enhance human capabilities. Yet, their adoption has been limited by slow and inconsistent learning across users. We show that BCI learning is accelerated by leverag...
Brain-computer interfaces (BCIs) promise to restore and enhance human capabilities. Yet, their adoption has been limited by slow and inconsistent learning across users. We show that BCI learning is accelerated by leveraging the naturally occurring geometry, or intrinsic manifold, of brain activity, extracted using data diffusion. Participants were trained with real-time functional magnetic resonance imaging to control an avatar in a video game by self-modulating activity in brain regions supporting spatial navigation. We perturbed the mapping between brain activity and avatar movement to test how neural manifolds constrain human BCI learning. When new mappings relied on directions of significant variance on the intrinsic manifold, participants successfully gained control by realigning brain activity along these directions. When new mappings did not follow the intrinsic manifold, participants could not learn to control the avatar. These findings show how manifold geometry in higher-order brain regions guides human learning of complex cognitive tasks, identifying a principle for improving future neurotechnologies.
Sex differences in the effects of chronic stress and oxycodone associative learning on glial markers in rat hippocampus.
Hirschkorn M, Kim A, Sommer G … +6 more , Warwick S, Gregoire L, Zhou Y, Kogan J, Gray JD, Milner TA
Neuroscience · 2026 Jun · PMID 42263838 · Full text
Prior studies revealed significant sex differences in hippocampal opioid neuronal networks especially after chronic immobilization stress (CIS) that have important implications for opioid associative learning. Besides ne...
Prior studies revealed significant sex differences in hippocampal opioid neuronal networks especially after chronic immobilization stress (CIS) that have important implications for opioid associative learning. Besides neurons, glia play important roles in hippocampal associated learning and can be affected by sex and environmental conditions. Here, we examined the relationship of sex and CIS on microglia (ionized calcium binding adapter molecule, Iba1) and astrocyte (glial fibrillary acidic protein, GFAP) densities in rat hippocampus following conditioned place preference (CPP) to saline (Sal) or oxycodone (Oxy). Although baseline glial densities were few, Sal females compared to Sal males had lower CA3b Iba1 and CA1. Following Oxy CPP, only females had increased Iba1 densities in CA3b and CA2/3a and GFAP densities in CA1, but both sexes had increased GFAP densities in CA3b. Moreover, compared to Sal counterparts, GFAP densities were lower in dentate gyrus (DG) in Oxy females and in CA1 in Oxy males. CIS females and males compared to unstressed counterparts had decreased CA3b Iba1 and GFAP densities and DG GFAP densities, however, these decreases were more extensive in males. Oxy CIS females, which acquired Oxy CPP, primarily had increased Iba1 and GFAP densities in CA1 and CA3 and decreased GFAP densities in DG. In contrast, Oxy CIS males, which did not acquire Oxy CPP, primarily exhibited increases in GFAP densities in the DG. These studies, together with our prior studies, reveal significant sex differences in the hippocampal glial densities, especially after CIS, which have important implications for Oxy associated learning processes.
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