Neuroscience[JOURNAL]
Sun
200 papers
Acetylcholine: a candidate substrate for hippocampal predictive learning?
de Cothi W, Shipley S, Barry C
Nat Rev Neurosci · 2026 Jun · PMID 42337376 · Publisher ↗
Acetylcholine release in the hippocampus has been associated with diverse neural functions in learning and memory, including novelty, uncertainty detection, error correction, arousal and hidden state inference, while als...
Acetylcholine release in the hippocampus has been associated with diverse neural functions in learning and memory, including novelty, uncertainty detection, error correction, arousal and hidden state inference, while also modulating theta oscillations. Confronted with this plurality of roles, a unifying framework for interpreting cholinergic function is lacking. Recently, predictive models have emerged as a normative lens for understanding neural function, viewing the brain as learning to predict environmental dynamics. Within this framework, we propose that hippocampal acetylcholine serves as a fundamental learning signal, encoding state transition prediction errors - the magnitude of mismatches between predicted and actual transitions in environmental states. We suggest that, analogously to how dopamine signals reward prediction errors to guide value learning, acetylcholine guides structural learning, signalling state transition prediction errors. By condensing behaviour onto timescales amenable to spike-timing-dependent plasticity, theta sequences provide a potential substrate for calculating state transition prediction errors and driving the synaptic updates that revise the internal world model. Within the septo-hippocampal circuit, we propose that theta sequences relay predictions to the septum for comparison against observed state transitions, with the resulting cholinergic feedback gating plasticity in proportion to the mismatch. Plausibly, this mechanistic account unifies the diverse roles of acetylcholine, from novelty detection to hidden state inference, as aspects of a single computational principle - learning predictive internal world models from precisely-timed neural sequences.
Astrocytes viewed through the lens of their proteomes and subproteomes.
Casha VH, Wu L, Wohlschlegel JA … +1 more , Khakh BS
Nat Rev Neurosci · 2026 Jun · PMID 42337375 · Publisher ↗
Astrocytes are morphologically complex and functionally diverse glial cells that play central roles in neural circuits and disease. Although transcriptomic and physiological analyses have advanced understanding of astroc...
Astrocytes are morphologically complex and functionally diverse glial cells that play central roles in neural circuits and disease. Although transcriptomic and physiological analyses have advanced understanding of astrocyte function, the intricacies of the relationship between gene expression and protein levels remains poorly understood. Proteins, rather than transcripts, execute the molecular processes that define astrocyte function, often within specialized subcellular compartments whose molecular composition has remained largely unresolved. Recent advances with genetically encoded proximity-dependent biotinylation have enabled mapping of astrocyte proteomes and subproteomes, revealing the spatial organization of protein networks that underpin astrocyte identity and function. In this Review we summarize strategies for defining astrocyte proteomes and subproteomes, emphasizing methodological innovations that permit cell-type-specific and spatially resolved proteomic profiling within intact neural tissue. The use of these approaches is shaping understanding of astrocyte biology by uncovering the molecular nature of their distributed physiology and the molecular basis of their interactions with neurons and other cells. Viewing astrocytes through a proteomic lens is beginning to help elucidate the molecular determinants of their morphology, signalling, and roles in homeostasis and disease. Such insights should enable detailed mechanistic understanding of astrocyte function and identify new avenues for targeting astrocytic contributions to brain disorders.
Author Correction: 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 42337099 · Publisher ↗
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Differential and compensatory roles for type I phosphatidylinositol-4-phosphate-5-kinase isoforms in retinal function and health.
He F, Long Y, Nichols RM … +2 more , Wu SM, Wensel TG
J Neurosci · 2026 Jun · PMID 42336665 · Publisher ↗
Phosphatidylinositol (4,5) bisphosphate (PI(4,5)P) plays important roles in development, signaling, intracellular trafficking and regulation throughout the nervous system. Using selective and combined gene ablation strat...
Phosphatidylinositol (4,5) bisphosphate (PI(4,5)P) plays important roles in development, signaling, intracellular trafficking and regulation throughout the nervous system. Using selective and combined gene ablation strategies, in mice of both sexes, we have determined the roles of this lipid and the kinase isoforms of the PIP5KI family primarily responsible for its synthesis in mouse retina. In rod cells, PI(4,5)P localizes predominantly to the plasma membrane of inner and outer segments and is enriched in membranes near the synaptic termini. Disruption of the gene encoding the γ PIP5KI isoform, , throughout the developing retina, using Cre expression driven by a Six3 transcription factor-dependent promoter, yields dramatic, but not complete, loss of the protein, with no apparent effects on morphology or function through the first 3-4 months after birth. Slowly progressing photoreceptor degeneration is observed at later ages. Complete loss of the γ isoform in rods, driven by the rhodopsin promoter-based iCre75 transgene, leads to no obvious developmental defects, but results in an earlier-onset rod degeneration. Germ-line ablation of neither the nor the gene leads to any observable morphological defects. Homozygous ablation leads to functional defects in photoreceptors as revealed by reduced a-wave and b-wave amplitudes in the electroretinograms. On the background of rod-specific ablation, deficiency greatly accelerates retinal degeneration. These results reveal a complex interplay among PIP5KI isoforms in ensuring proper photoreceptor function and health, with apparent partial redundancy in fulfilling their critical functions. They underscore the important role of PI(4,5)P in neuronal signaling and homeostasis. Phosphatidylinositol(4,5)P, PI(4,5)P, plays essential roles in nervous system development and function, but its roles in retina have been unknown. This study combines biochemistry, mouse genetics, light- and electron microscopy to reveal both specific and redundant functions for PIP formed by different kinase isoforms in the mammalian retina. It has implications for retinal function, disease and therapy, and for the broader field of phosphoinositide regulation.
Quantifying changes in pain sensitivity using reproducible transcutaneous optogenetic stimulation in behaving mice.
Xie YF, Dedek C, Prescott SA
J Neurosci · 2026 Jun · PMID 42336664 · Publisher ↗
Optogenetics provides an unprecedented opportunity to delineate how different somatosensory afferents contribute to sensation, including pain. Afferents expressing channelrhodopsin-2 (ChR2) can be selectively activated b...
Optogenetics provides an unprecedented opportunity to delineate how different somatosensory afferents contribute to sensation, including pain. Afferents expressing channelrhodopsin-2 (ChR2) can be selectively activated by transcutaneous photostimuli applied to behaving mice. Despite targeting expression of ChR2 to specific cell types, imprecise photostimulation has hindered quantitative optogenetic-based behavioral testing. Here, we used a robot to reproducibly apply transcutaneous optogenetic stimuli to the hind paw of mice while measuring nocifensive withdrawal. Different photostimulus waveforms (pulses and ramps) and response metrics (threshold and latency) were compared in mice of either sex expressing ChR2 in all afferents (Advillin-ChR2) or preferentially in nociceptors (Na1.8-ChR2). Inflammation induced by complete Freund's adjuvant (CFA) caused withdrawal from ramped photostimuli to become faster relative to baseline and to vehicle-injected controls whereas pulsed photostimuli revealed a modest increase in threshold. Analgesia caused by Na1.7 and 1.8 channel blockade was evident in both testing protocols. Overall, ramp-based testing was more effective and more efficient (i.e. required less time and total stimulation) than pulse-based testing. Electrophysio-logical measurements confirmed that CFA increases nociceptor excitability without affecting photo-transduction, suggesting that withdrawal latency depends on the number of nociceptors activated rather than how strongly each nociceptor is activated. Consistent with changes described in nociceptor somata, the behavioral consequences of peripherally blocking different voltage-gated sodium (Na) channels showed that nociceptor axons normally rely on Na1.8 but upregulate Na1.7 after CFA, with important clinical implications for drug efficacy. Collectively, these results demonstrate the utility of optogenetic pain testing when reproducibly delivered and strategically designed photostimuli are used. Transcutaneous optogenetic stimulation in behaving mice has been used for over a decade to help delineate the contribution of various types of somatosensory afferents to sensation, especially pain. Such testing has typically involved applying light pulses via handheld fiber optic cables and scoring withdrawal responses by eye, but more quantitative testing is now possible thanks to new technology enabling reproducible photostimulation and precise withdrawal measurement. Our comparison of optogenetic pulse-based threshold measurements and ramp-based latency measurements shows the latter is better suited for measuring inflammation-induced hypersensitivity. We also demonstrate the utility of ramp-based latency measurements for quantifying analgesia by Na channel blockade. Links between the excitability of channelrhodopsin-expressing afferents and optogenetically evoked paw withdrawal are also highlighted.
GABAergic signaling from arginine vasopressin neurons in the suprachiasmatic nucleus is essential for maintaining the estrous cycle in mice.
Sugiyama M, Ono D, Miyazaki S … +6 more , Bentley GE, Ito H, Mieda M, Watanabe K, Nakamura W, Nakamura TJ
J Neurosci · 2026 Jun · PMID 42336663 · Publisher ↗
Reproductive function in female mammals is largely orchestrated by the hypothalamic-pituitary-gonadal axis, which generates rhythmic hormonal fluctuations underlying the estrous cycle. Part of this cycle, the preovulator...
Reproductive function in female mammals is largely orchestrated by the hypothalamic-pituitary-gonadal axis, which generates rhythmic hormonal fluctuations underlying the estrous cycle. Part of this cycle, the preovulatory LH surge, is tightly gated by the circadian system. The suprachiasmatic nucleus (SCN)-the central circadian clock-plays a critical role in this temporal regulation and among SCN-derived signals, neuropeptides such as arginine vasopressin (AVP) and vasoactive intestinal peptide (VIP) have been proposed to mediate this process. Notably, most SCN neurons are GABAergic; however, the contribution of SCN-derived GABAergic transmission in the female reproductive system remains unclear. To investigate the role of GABAergic output from the SCN, we first performed AAV-mediated SCN ablation in mice (; encoding the vesicular GABA transporter), resulting in disrupted estrous cycles. To assess GABAergic transmission from specific SCN populations, we next examined and mice, in which the gene is selectively deleted in AVP or VIP neurons. females showed regular cycles. However, females exhibited marked disruptions, and AAV-mediated rescue in AVP neurons in the SCN (SCN-AVP) restored normal estrous cycles. Anterograde tracing revealed dense SCN-AVP terminals in the anteroventral periventricular nucleus (AVPV), which contains kisspeptin neurons, but few projections to other major reproductive neuroendocrine populations. These findings suggest GABAergic output from SCN-AVP neurons stabilizes the estrous cycle, potentially via kisspeptin neurons in the AVPV, thereby highlighting that GABAergic signaling also contributes to female reproductive regulation alongside AVP and VIP. The circadian system must precisely coordinate the timing of ovulation, and is essential for maintaining a stable estrous cycle. Although most neurons in the master clock are GABAergic, their role in reproductive control remains unknown. Here, our study identifies GABAergic signaling from arginine vasopressin neurons in the master clock as a key regulator of the estrous cycle. Loss of this signaling disrupts estrous cyclicity, and its restoration rescues regular cycling. This finding highlights GABA release from arginine vasopressin neurons as an additional component of reproductive control, alongside established peptidergic regulators such as arginine vasopressin and vasoactive intestinal peptide. This work advances our understanding of how the brain's circadian system organizes complex reproductive physiology through multiple neural output pathways.
Trans-dimerization of Amyloid Precursor Protein family members induces pre- and postsynaptic differentiation through distinct signaling pathways.
Rajender R, Foth N, Eggert S … +13 more , Schilling S, Fäßler M, Ott C, Mühlhaus T, Sommer F, Schroda M, Maritzen T, Banicevic M, Bengelsdorff V, Kiss E, Buchholz CJ, Müller UC, Kins S
J Neurosci · 2026 Jun · PMID 42336662 · Publisher ↗
The amyloid precursor protein (APP), a key factor in Alzheimer's disease (AD) pathology, and its two mammalian homologues, amyloid precursor like proteins 1 and 2 (APLP1 and APLP2), are considered as members of the synap...
The amyloid precursor protein (APP), a key factor in Alzheimer's disease (AD) pathology, and its two mammalian homologues, amyloid precursor like proteins 1 and 2 (APLP1 and APLP2), are considered as members of the synaptic adhesion molecule (SAM) family. They are localized to the pre- and postsynapse, form trans-cellular dimers and have been shown to induce presynaptic differentiation in a heterologous synapse formation assay.We demonstrate that expression of all APP family members in non-neuronal cells also promotes dendritic excitatory postsynaptic differentiation in primary mouse neurons of either sex, similar to Neurexin1β and other SAMs. Synaptogenic activity was decreased by deletion of the E1 domain and increased upon inhibition of soluble APP (sAPP) generation, reinforcing that trans-cellular interaction of APP/APLPs can induce synaptogenesis. Consistent with this, the capacity of heterologously expressed APP to induce postsynaptic specializations in contacting dendrites was reduced by the absence of APP family members at the postsynaptic site and was lost in conditional triple knockout (cTKO) neurons. Pharmacological analyses revealed that heterologous formation of pre- and postsynapses relies on proper microtubule- and actin cytoskeleton dynamics, as well as the MAP kinase pathway, similar to what has been shown for Neurexin1β and Neuroligin1. However, inhibition of the PI3K/Akt pathway selectively impaired APP-induced postsynaptic differentiation, suggesting that distinct APP signaling pathways are required for pre- and postsynaptic differentiation. Collectively, our data highlight the role of all APP family members as SAMs in trans-synaptic signaling, providing key insights into their physiological function and advancing our understanding of AD-related synaptopathies. Our data show that all three amyloid precursor protein (APP) family members induce besides presynaptic also postsynaptic differentiation through distinct signaling pathways. Specifically, the c-Jun N-terminal kinase pathway is involved at pre- and postsynaptic sites, whereas the Akt pathway is selectively required for postsynaptic differentiation. Furthermore, mutagenesis studies demonstrate that pre- and postsynaptic differentiation is mediated independent of secreted APP. Finally, our analyses on knockout neurons lacking all APP family members strongly suggest that synaptogenic activity of APP is mostly mediated by APP or Amyloid precursor like proteins (APLPs) dimerization partner located at the opposing postsynaptic site. Together, these data support the hypothesis that synaptogenic activity of APP/APLPs is predominantly driven by heterotypic trans-cellular interaction as synaptic adhesion molecules.
Managing Gaze Competition during Simultaneous Manual Action Control and Environment Monitoring.
Fooken J, Johansson RS, Flanagan JR
J Neurosci · 2026 Jun · PMID 42336661 · Publisher ↗
Research on visually guided object manipulation has shown that participants fixate goal locations-including objects to be grasped and locations where they are placed-prior to hand arrival, with gaze serving two primary f...
Research on visually guided object manipulation has shown that participants fixate goal locations-including objects to be grasped and locations where they are placed-prior to hand arrival, with gaze serving two primary functions: the hand (or object in hand) to the vicinity of the goal using peripheral vision and gaze related signals, and the hand using central vision as it approaches the goal. However, real world manipulation tasks are often performed while concurrent monitoring of the environment, resulting in competition for gaze. We examined gaze-hand coordination under such conditions. Human participants of either sex performed a manipulation task, that involved grasping balls and placing them at target locations, while concurrently monitoring a display to detect probabilistically occurring visual events, which required central vision. Participants managed gaze competition in two main ways. First, fixations allocated to the action task were brief and prioritized the hand towards the goal (object or target location); participants then relied on tactile feedback to complete the action (grasping or placing the object). When tactile feedback was reduced-by using a tool instead of the fingertips to perform the task-gaze additionally served the function. Second, participants reduced gaze competition by exploiting temporal regularities of events in the monitoring task. Specifically, they adjusted both gaze allocation and hand movement timing to reduce the likelihood that action task fixations would coincide with visual events. These findings demonstrate how individuals flexibly integrate sensorimotor control with analysis of environmental statistics to manage competing visual demands. In everyday behaviour, we often perform manual tasks while simultaneously monitoring the environment, creating competition for gaze. How the brain resolves this competition remains poorly understood. Using a novel paradigm combining an object manipulation task with visual event monitoring, we show that participants integrate knowledge of sensorimotor demands and temporal regularities in the monitoring task to manage gaze. Specifically, we found that participants preferentially allocated gaze to the action task when it is most critical for sensorimotor control and when the likelihood of a visual event was low. Additionally, participants adjusted their hand movement timing based on event statistics to reduce gaze competition. These findings reveal how the brain dynamically allocates gaze resources across competing sensorimotor and visual task demands.
Endoplasmic reticulum proteins MCTP-1 and ESYT-2 support presynaptic function during sustained activity in Caenorhabditis elegans.
Tovilla-Loza FI, Téllez-Arreola JL, Martínez-García I … +5 more , Pimentel-Domínguez R, Avila R, Seidenthal M, Gottschalk A, Martínez-Torres A
Neuroscience · 2026 Jun · PMID 42336263 · Publisher ↗
The presynaptic terminal has a complex molecular organization where numerous proteins are involved in various processes, including vesicle trafficking and neurotransmitter release. Calcium ions play a central role in pre...
The presynaptic terminal has a complex molecular organization where numerous proteins are involved in various processes, including vesicle trafficking and neurotransmitter release. Calcium ions play a central role in presynaptic function by triggering neurotransmitter release and synaptic vesicle recycling. Here, we investigated the role of two calcium binding proteins, MCTP-1 and ESYT-2, in the synaptic vesicle cycle of Caenorhabditis elegans. Both proteins are widely expressed in the nervous system and colocalize in endoplasmic reticulum subdomains, consistent with membrane contact sites. Loss-of-function mutants for both genes displayed slight defects in motility and similar resistance to acetylcholinesterase inhibition. Recordings of pharyngeal electrical activity revealed that aged (day 6 adult) esyt-2 and mctp-1 single mutants and mctp-1; esyt-2 double mutants exhibit significantly shorter muscle contraction events, but increased pumping rates compared to wild type, indicating altered age-dependent regulation of pharyngeal activity. We also found in an all-optical assay of synaptic transmission and synaptic vesicle recycling, that the endocytic rate was similarly reduced in mctp-1, esyt-2, and mctp-1; esyt-2 loss-of-function worms. Together, these findings show that MCTP-1 and ESYT-2 participate in similar and/or complementary roles, acting within a shared pathway to support efficient synaptic vesicle recycling and to maintain presynaptic function during sustained activity.
Bromodomain protein 4 (BRD4) as a central epigenetic regulator in neuropsychiatric and neurodegenerative disorders.
Bhagat PP, Sharma TG, Shirasath KR … +2 more , Goyal SN, Awathale SN
Neuroscience · 2026 Jun · PMID 42336262 · Publisher ↗
Bromodomain-containing protein 4 (BRD4), a member of the bromodomain and extra-terminal (BET) family, is a central epigenetic regulator that links histone acetylation-dependent chromatin remodelling to transcriptional co...
Bromodomain-containing protein 4 (BRD4), a member of the bromodomain and extra-terminal (BET) family, is a central epigenetic regulator that links histone acetylation-dependent chromatin remodelling to transcriptional control. Through recognition of acetylated lysine residues and recruitment of transcriptional machinery, it is increasingly recognised as a critical regulator of neuronal and glial functions, influencing synaptic plasticity, neuroinflammation, learning, memory, and behavioural adaptation. A wide range of neurological, neurodevelopmental, and neuropsychiatric diseases are linked to abnormal BRD4 signalling. BRD4 coordinates common pathogenic pathways, such as dysregulated transcriptional networks, by binding to acetylated histones and recruiting positive transcription elongation factor b to stimulate RNA polymerase II-dependent transcription of genes associated with central nervous system (CNS) diseases such as Alzheimer's and post-traumatic stress disorder. These convergent roles of BRD4 positioned it as a molecular hub that connects CNS dysfunction and epigenetic control. In this review, we focus on the involvement of BRD4 in various CNS disorders and provide a thorough overview of its structure, transcriptional mechanisms, and physiological and pathogenic functions in the CNS. Here, the emphasis is on common BRD4-dependent mechanisms that span multiple neurological conditions and the therapeutic opportunities and challenges associated with targeting BRD4. Collectively, current evidence supports BRD4 as a promising target for precision epigenetic therapies aimed at restoring neuronal homeostasis and modifying disease progression.
Recurrence associated IGFBP2 promotes malignant progression and epithelial mesenchymal transition in glioma cells via the AKT mTOR pathway.
Que Y, Zhao W, He B
Int J Neurosci · 2026 Jun · PMID 42334226 · Publisher ↗
BACKGROUND: Glioma recurrence and progression are major causes of poor prognosis and death. Although surgery can provide short-term benefit, long-term outcomes remain limited because effective targets for preventing recu...
BACKGROUND: Glioma recurrence and progression are major causes of poor prognosis and death. Although surgery can provide short-term benefit, long-term outcomes remain limited because effective targets for preventing recurrence and progression are lacking. METHODS: Differentially expressed genes between primary and recurrent gliomas were identified using the CGGA and TCGA databases. The effects of IGFBP2 knockdown on glioma cell proliferation, colony formation, migration, and invasion were assessed by CCK-8, colony formation, migration, and invasion assays. Western blotting was used to investigate the underlying molecular mechanisms. RESULTS: Bioinformatics analysis identified IGFBP2 as a recurrence-associated candidate gene in glioma. High IGFBP2 expression was associated with recurrence status and shorter overall survival. experiments showed that IGFBP2 knockdown suppressed glioma cell proliferation, colony formation, migration, and invasion. Mechanistically, IGFBP2 knockdown was accompanied by changes in EMT-related markers and reduced AKT/mTOR signaling activity. CONCLUSION: IGFBP2 may serve as a recurrence-associated candidate biomarker and potential therapeutic target in glioma. Further validation using clinical specimens, patient-derived models, orthotopic animal models, and mechanistic rescue experiments is required to confirm its biological and translational significance.
Decreased miR-1305 expression is associated with tumour invasiveness and poor prognosis in glioma patients.
Wang Y, Guo M
Int J Neurosci · 2026 Jun · PMID 42333465 · Publisher ↗
INTRODUCTION: Gliomas are highly prevalent and lethal primary malignant tumours of the central nervous system. MicroRNA plays a tumour-suppressive role in various tumours, including glioma. This study aims to elucidate t...
INTRODUCTION: Gliomas are highly prevalent and lethal primary malignant tumours of the central nervous system. MicroRNA plays a tumour-suppressive role in various tumours, including glioma. This study aims to elucidate the expression profile, clinical relevance, biological roles, and underlying mechanisms of miR-1305 in glioma. METHODS: Tumour tissues alongside their matched normal counterparts were acquired from 105 individuals with glioma. The expression of miR-1305 was quantified using RT‑qPCR. The relationship between miR-1305 expression, clinicopathological characteristics, and prognosis was assessed through Kaplan‑Meier analysis and Cox regression. The proliferative, migratory, and invasive capacities of glioma cells following miR-1305 modulation were assessed using CCK‑8 and Transwell assays. Potential target genes of miR-1305 were predicted bioinformatics analysis, and the direct targeting interactions were subsequently confirmed by dual-luciferase reporter assays. RESULTS: A significant downregulation of miR-1305 was observed in glioma tissues. Low expression of miR-1305 was associated with increased tumour size, poorer KPS score, and higher WHO tumour grade ( < 0.05). Patients exhibiting low miR-1305 levels experienced decreased overall survival; multivariate analysis identified this marker as an independent prognostic factor. Functional assays showed miR-1305 overexpression inhibited glioma cell proliferation, migration, and invasion. Mechanistically, WNK3 was a direct target of miR-1305, exhibited inverse correlation in glioma, and its overexpression rescued miR-1305-mediated suppression of malignant phenotypes. CONCLUSION: Low miR-1305 expression is associated with an adverse prognosis in glioma; it exerts tumour-suppressive effects by targeting WNK3 and inhibiting disease progression.
mA in RNA: a key regulator of brain development, function and disease.
Sivasudhan E, Meyer KD
Nat Rev Neurosci · 2026 Jun · PMID 42332080 · Publisher ↗
Epitranscriptomic regulation of cellular RNAs is a major mechanism of gene expression control in the brain. N-Methyladenosine (mA) is installed on thousands of mRNAs and non-coding RNAs, where it functions as a context-d...
Epitranscriptomic regulation of cellular RNAs is a major mechanism of gene expression control in the brain. N-Methyladenosine (mA) is installed on thousands of mRNAs and non-coding RNAs, where it functions as a context-dependent regulator of RNA-protein interactions to control the amplitude and kinetics of gene expression. In the nervous system, mA is critical for neurodevelopment, synaptic plasticity and adaptive responses to physiological stimuli, and its dysregulation has been linked to various brain disorders. In this Review, we present a comprehensive synthesis of how mA is deposited, interpreted and dynamically regulated, and integrate recent advances to present a unified framework for its function in neural cells. We discuss how mA coordinates RNA stability, translation, localization and chromatin-associated processes across developmental and adult contexts and how disruption of these pathways contributes to neurological disease. Finally, we explore challenges and future directions for the field.
Low-intensity transcranial ultrasound stimulation improves motor behavior and modulates cortical functional network connectivity in mice with ischemic stroke.
Wan S, Wang Q, Wang Y … +5 more , Huang D, Yan J, Jiao H, Zhang X, Yuan Y
J Neurosci · 2026 Jun · PMID 42331631 · Publisher ↗
The recovery of motor function in patients with ischemic stroke is closely related to the plastic remodeling of cortical functional networks. Low-intensity transcranial ultrasound stimulation (TUS) has been shown to impr...
The recovery of motor function in patients with ischemic stroke is closely related to the plastic remodeling of cortical functional networks. Low-intensity transcranial ultrasound stimulation (TUS) has been shown to improve motor behavior in patients with ischemic stroke and modulate cortical functional networks in healthy individuals. However, whether motor improvement after TUS is associated with cortical functional network reorganization remains unclear. Therefore, in this study, we constructed a mouse model of ischemic stroke using male C57BL/6 mice and simultaneously recorded the local field potential and gait behavior data of the whole-brain cortex of mice in a free-walking state before and after ultrasound intervention. Gait parameters, cortical functional network connectivity, and topology were systematically analyzed, and the correlations between behavioral indicators and network connectivity were explored. Our findings revealed that TUS significantly improved motor function in the mouse model, modulated cortical functional network connectivity to restore it to a healthy state, enhanced global information integration ability, optimized local separation efficiency, and restored gait phase transition control. Furthermore, the TUS-induced changes in the cortical functional network were positively correlated with behavioral improvement. This study confirmed that motor improvement after low-intensity TUS is accompanied by cortical functional network reorganization, and that such reorganization may contribute to post-stroke functional recovery. Stroke disrupts the neural networks essential for maintaining gait coordination. Although low-intensity TUS stimulation can improve post-stroke motor performance, how it remodels and restores cortical functional network connectivity during natural behavior remains unclear. This study combined free-walking gait with simultaneous acquisition of cortical local field potentials to conduct a 7-day targeted ultrasound modulation intervention in the infarct area in ischemic stroke mice. Results showed that TUS significantly improved gait and induced gait-phase-specific cortical functional network connectivity reconnection. This study provides evidence for the neural mechanisms by which ultrasound promotes post-stroke motor function recovery and offers a theoretical basis for the translational application of TUS in stroke treatment.
Faster but less precise: expectation enhances response speed while reducing sensory fidelity.
Hu Z, Tran DMD, Rideaux R
J Neurosci · 2026 Jun · PMID 42331630 · Publisher ↗
The brain's remarkable ability to process continuous sensory inputs with - balancing flexibility while minimizing metabolic cost - is thought to rely on predictive mechanisms that generate and update internal models tha...
The brain's remarkable ability to process continuous sensory inputs with - balancing flexibility while minimizing metabolic cost - is thought to rely on predictive mechanisms that generate and update internal models that leverage statistical regularities in the environment. However, it remains unclear whether this efficiency arises from prioritizing reliable, expected events or informative, unexpected ones, as they offer complementary adaptive advantages. To isolate genuine expectation effects, we combined electroencephalography (EEG), pupillometry, and behavioural measures in a paradigm that independently manipulated task relevance (selective attention) and stimulus predictability, while minimizing stimulus repetition at identical spatial locations to control for low-level adaptation. Human participants (both sexes) responded faster and more accurately to expected events, which was enhanced when attention was engaged; however, these events were reproduced with lower precision, independent of attention. Feature-specific neural decoding revealed pre-stimulus effects of attention and post-stimulus effects of expectation, with no interaction between the two. Attention increased decoding accuracy, while expectation reduced accuracy. The reduced representational fidelity for expected events appeared rapidly (∼100-200 ms after stimulus onset) and correlated with individual differences in perceptual precision. Collectively, our findings indicate two complementary processes that define how the brain leverages redundancy in the environment: an early (pre-stimulus) mechanism, which supports rapid motor responses to expected events and is mediated by attention, and a later (post-stimulus) process, which dampens sensory responses to expected events and is unaffected by attention. The brain must process vast amounts of sensory information efficiently while remaining flexible enough to detect important changes. Competing theories propose that the brain saves energy either by prioritizing expected events or by enhancing responses to surprising ones, but experimental evidence has been inconsistent. Our findings show that the brain uses both strategies, each serving a different purpose. Expected events are processed quickly to support rapid, accurate actions, whereas expected events are also encoded with reduced precision, prioritising unexpected events to update internal models and guide future behaviour. By cleanly separating expectation from attention and low-level adaptation, we provide a unified explanation of how the brain balances efficiency with adaptability across multiple timescales.
Establishment and validation of the NEX-RiboTag system for profiling the excitatory neuronal translatome in the postnatal mouse forebrain.
Zheng K, Liu M, Jin B … +9 more , Chai G, Wang S, Yang Y, Li K, Huang H, Lu C, Zhang X, Wang J, Zhang C
Neuroscience · 2026 Jun · PMID 42324055 · Publisher ↗
Excitatory neurons are the principal neurons of the mammalian cortex and hippocampus and are essential for postnatal circuit maturation. Although single-cell RNA sequencing has refined their molecular taxonomy, dissociat...
Excitatory neurons are the principal neurons of the mammalian cortex and hippocampus and are essential for postnatal circuit maturation. Although single-cell RNA sequencing has refined their molecular taxonomy, dissociation-induced stress artifacts and the disconnect between transcript abundance and translational output can limit functional interpretation. Bulk proteomics lacks cell-type specificity, while single-cell proteomics remains constrained by limited sensitivity and throughput. These limitations leave a gap between transcriptional identity and cell-type-resolved translational output. Because translation directly governs the selective recruitment of mRNAs for protein synthesis, defining excitatory neuron-specific translatome in vivo is valuable to bridge this gap. Here, we established and validated a NEX-RiboTag mouse line for targeted profiling of ribosome-associated mRNAs in cortical and hippocampal excitatory neurons. By crossing Neurod6 (NEX)-Cre mice with RiboTag reporter mice, we achieved Cre-dependent ribosomal tagging in excitatory neurons of the cortex and the hippocampus. RNA sequencing analysis at the 1-week postnatal stage demonstrated enrichment of excitatory neuronal markers and depletion of inhibitory neuronal and glial transcripts. Comparative analysis revealed a clear separation between the whole-tissue transcriptome and the ribosome-associated fractions, with enrichment of synaptic and metabolic pathways characteristic of excitatory neurons. Together, these datasets provide a valuable resource for investigating translational regulation in postnatal excitatory neurons and for studying molecular programs underlying neuronal maturation and synapse formation.
Brain kappa opioid receptor availability across stress and social buffering conditions: A positron emission tomography study in coppery titi monkeys.
Manca C, Paulus JP, Almeida AJ … +6 more , Caceres A, Sosnowski MJ, Hobson BA, Ferrer E, Chaudhari AJ, Bales KL
Neuroscience · 2026 Jun · PMID 42324054 · Publisher ↗
Social connectedness strongly influences health and longevity, and adult pair bonds provide psychological benefits distinct from other social relationships. Oxytocin (OT), corticotropin-releasing hormone (CRH), and opioi...
Social connectedness strongly influences health and longevity, and adult pair bonds provide psychological benefits distinct from other social relationships. Oxytocin (OT), corticotropin-releasing hormone (CRH), and opioids play an important role in pair bond formation and maintenance. OT modulates the stress response via the hypothalamic-pituitary-adrenal (HPA) axis, while the kappa (κ) opioid system may modulate OT signaling in contexts of stress and separation. Here, 20 male and female coppery titi monkeys (Plecturocebus cupreus), a unique non-human primate model for the study of pair bonding and social buffering, were exposed to a physical stressor under three social conditions: baseline (no stressor, partner present), stress (stressor, no partner) and buffering (stressor, partner present). We predicted stress would engage the dynorphin/κ-opioid receptor system, reflected in reduced κ-opioid receptor (KOR) availability measured via [C]GR103545 Positron Emission Tomography (PET) and lower cerebrospinal fluid (CSF) OT, whereas partner presence would attenuate this response. The social buffering effect was successfully replicated: cortisol was significantly elevated during stress relative to baseline in both sexes, with no significant difference between the buffering and baseline conditions. PET imaging revealed condition- and sex-specific differences in [C]GR103545 binding potential across limbic regions, including the amygdala, hippocampus, and hypothalamus. Females exhibited lower CSF OT levels during stress than at baseline and Spearman correlations revealed no significant associations between plasma and CSF OT. These findings highlight the complex interactions among κ-opioid signaling, OT, and HPA axis activity during social buffering and provide preliminary evidence for region- and sex-specific KOR modulation in a pair-bonded primate model.
Visual motion processing in substance addiction: an ERP study of heroin and methamphetamine groups.
Liu H, Wang X, Li Q … +6 more , Zheng Y, Li D, Sun Q, Liu Y, Wang C, Lyu S
Neuroscience · 2026 Jun · PMID 42324053 · Publisher ↗
OBJECTIVE: The present study employed event-related potential (ERP) technique combined with random dot kinetograms (RDK) tasks to investigate visual motion processing in methamphetamine group, heroin group, and healthy c...
OBJECTIVE: The present study employed event-related potential (ERP) technique combined with random dot kinetograms (RDK) tasks to investigate visual motion processing in methamphetamine group, heroin group, and healthy controls. METHODS: Two RDK conditions with 80% and 100% motion consistency were used to record transient ERP components (N1, N2, P2) and analyze group differences in visual motion processing. RESULTS: ① No significant group differences were found in N1 amplitude or latency (all p > 0.05); ② Heroin group showed significantly different N2 amplitudes from healthy controls at occipital O1/O2 electrodes (F (1, 49) = 4.534, p = 0.038, η = 0.085), while no N2 differences were observed in methamphetamine group; after controlling for smoking frequency as a covariate, the main effect of group became non-significant (F (1, 45) = 2.660, p = 0.110, η = 0.056); ③ Methamphetamine-dependent individuals exhibited significantly reduced P2 amplitude relative to healthy controls at fronto-central electrodes including Fz and FCz (F (1, 43) = 4.713, p = 0.036, η = 0.099). A similar reduction in P2 amplitude was observed for heroin-dependent individuals at frontal and fronto-central electrodes including Fz, FCz, and FC4 (F (1, 45) = 5.988, p = 0.018, η = 0.117). A Mixed-design repeated-measures ANOVAs further revealed a significant main effect of group on P2 latency at frontal sites (F7, F3, Fz, F4, F8, FC3, FCz) (F (2, 64) = 9.087, p < 0.001, η = 0.221) and at central sites (C3, Cz) (F (2, 64) = 4.837, p = 0.011, η = 0.131). Post hoc comparisons indicated that P2 latency was significantly shorter in the healthy control group than in the two addiction groups. CONCLUSION: Chronic methamphetamine and heroin use impairs visual motion processing, with distinct neural mechanisms possibly mediating the effects of different addictive substances on fronto-parietal visual integration networks. SIGNIFICANCE STATEMENT: The research team used event-related potential (ERP) technology to explore the sensory and perceptual brain functions of individuals with substance addiction (including methamphetamine group and heroin addicts); based on the random dot kinematogram (RDK) experimental paradigm, the study revealed that the abuse of psychoactive substances impairs not only the frontal lobe but also the parietal cortex, thereby providing a new brain region-based basis for intervention in subsequent treatment.
Structural MRI and mild behavioral impairment as complementary predictors of conversion from amnestic MCI to Alzheimer's disease.
Tomyshev A, Cherkasov N, Panikratova Y … +3 more , Bozhko O, Kolykhalov I, Lebedeva I
Neuroscience · 2026 Jun · PMID 42324052 · Publisher ↗
Mild Behavioral Impairment (MBI) and amnestic Mild Cognitive Impairment (aMCI) are complementary early markers of Alzheimer's disease (AD), yet their combined neuroanatomical correlates and predictive value for conversio...
Mild Behavioral Impairment (MBI) and amnestic Mild Cognitive Impairment (aMCI) are complementary early markers of Alzheimer's disease (AD), yet their combined neuroanatomical correlates and predictive value for conversion remain underexplored. In this study of 72 community-dwelling older adults (49 aMCI, 23 healthy controls), we retrospectively classified aMCI participants into non-converters (aMCI-NC, n = 31) and converters (aMCI-C, n = 18) based on longitudinal follow-up. Baseline structural MRI revealed that aMCI-C patients exhibited bilateral atrophy in the hippocampus, amygdala, and nucleus accumbens, alongside cortical thinning in temporal-limbic and parietal regions compared to both aMCI-NC and controls. Notably, in the non-converter group, MBI-Checklist scores correlated negatively with temporal-parietal cortical thickness, while Montreal Cognitive Assessment scores correlated positively with subcortical volumes. Cox proportional-hazards regression with supervised principal component analysis revealed that while MBI symptoms alone did not independently predict conversion, they demonstrated significant conditional predictive value when combined with structural MRI markers. Model robustness was confirmed via rigorous internal validation using nested leave-one-out cross-validation with bootstrap aggregation. Furthermore, time-varying analysis indicated that the protective effect of larger medial temporal-limbic subcortical volumes was strong initially but attenuated over follow-up, consistent with a depletable brain reserve. Given the limited conversion events, which constrained statistical power for smaller independent effects and restricted model complexity, replication in larger prospective cohorts is warranted. Despite this limitation, our results underscore the conditional utility of integrating MBI assessment with structural MRI to enhance early detection and risk stratification in memory clinic settings.
Moyamoya disease and angiogenesis: a quantitative analysis of key angiogenic markers.
Gupta T, Bharti R, Kumar M … +2 more , Devi V, Aggarwal A
Neuroscience · 2026 Jun · PMID 42323005 · Publisher ↗
Moyamoya disease (MMD) is a cerebrovascular condition characterized by progressive narrowing of the internal carotid arteries and their adjacent branches. Aberrant angiogenesis plays a crucial role in its pathogenesis, c...
Moyamoya disease (MMD) is a cerebrovascular condition characterized by progressive narrowing of the internal carotid arteries and their adjacent branches. Aberrant angiogenesis plays a crucial role in its pathogenesis, contributing to both ischemic and hemorrhagic complications. This study aimed to identify potential biomarkers with prognostic value by investigating angiogenic markers in MMD patients. Paired blood and dura mater tissue samples were collected from MMD patients and healthy controls. Using quantitative reverse transcription-polymerase chain reaction, we analysed the expression levels of various angiogenic markers, including vascular endothelial growth factor, Transforming growth factor-β1, Basic fibroblast growth factor, Hypoxia-inducible factor 1-alpha, Platelet-derived growth factor, and Angiopoietin-1. VEGF and TGF-β1 expression were validated at the transcript level (qRT-PCR) in a separate cohort of MMD patients with VEGF further confirmed at the protein level using Enzyme-Linked Immunosorbent Assay. We observed significant increase in expression levels of VEGF, HIF-1α, TGF-β1, bFGF, PDGF and ANG-1 in the dura samples of MMD patients compared to controls. However, in serum samples, only VEGF, TGF-β1, and bFGF were found to be up-regulated. Validation revealed significant upregulation of VEGF and TGF-β1 at the transcript level, with VEGF also markedly elevated at protein level. Study highlights the upregulation of key angiogenic markers in MMD, with VEGF and TGF-β1 showing consistent elevation across tissue and serum samples. These findings suggest their potential role in MMD pathophysiology and as possible biomarkers for disease progression.
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