BACKGROUND: This study examined the long-term effects of polyinosinic:polycytidylic acid (poly I:C), a synthetic double-stranded RNA and Toll-like receptor 3 (TLR3) agonist, on behavioral and immune outcomes in chronical...BACKGROUND: This study examined the long-term effects of polyinosinic:polycytidylic acid (poly I:C), a synthetic double-stranded RNA and Toll-like receptor 3 (TLR3) agonist, on behavioral and immune outcomes in chronically stressed mice. METHODS: Male C57BL/6J mice were exposed to 21 days of wet bedding stress followed by a poly I:C injection. Post viral fatigue syndrome (PVFS)-like symptoms were evaluated over 7 days post-injection using grip strength testing, the forced swim test, von Frey filament testing, the Morris water maze, the open field test, and the social interaction test. Body temperature and locomotor activity were continuously monitored via intraperitoneally implanted dataloggers. Serum concentrations of interleukin-6 (IL-6), IL-10, and C-X-C motif chemokine ligand 10 (CXCL10) were quantified. In separate cohorts, minocycline (a microglial activation inhibitor) or RU486 (a glucocorticoid receptor antagonist) was administered prior to poly I:C injection. RESULTS: Following IP injection of poly I:C, body temperatures in both stressed and unstressed mice were significantly elevated, indicating a polyphasic febrile response. At 7 days post-injection, stressed mice treated with poly I:C exhibited persistent fatigue, mechanical allodynia, depressive-like behavior, impaired spatial memory, increased anxiety-like behavior, and reduced social interaction. Serum levels of IL-6 and CXCL10 remained elevated and correlated with behavioral outcomes. Pretreatment with minocycline partially attenuated both the behavioral and immune responses, whereas RU486 pretreatment did not. CONCLUSION: These findings demonstrate that TLR3-mediated systemic inflammation induced by poly I:C produces persistent, multi-domain PVFS-like symptoms in chronically stressed mice. The attenuation by minocycline implicates neuroinflammation as a possible mechanism.
AbstractAccurate gaze control - coordinating head and eye orientation - is essential for effective movement, yet during locomotion the self-generated, phasic head motions accompanying each step destabilize the visual sce...AbstractAccurate gaze control - coordinating head and eye orientation - is essential for effective movement, yet during locomotion the self-generated, phasic head motions accompanying each step destabilize the visual scene. The vestibular system acts to counter these disturbances by sensing head motion and generating rapid reflexes that stabilize posture and vision, but its specific contribution to gaze stabilization during locomotion is not well understood. To directly test the vestibular system's contribution during walking, we compared gait and gaze kinematics in male and female rhesus macaques with normal vestibular function and those with chronic bilateral vestibular loss (BVL) during treadmill walking at multiple speeds and during overground locomotion. We identified systematic differences in gait kinematics between normal and BVL animals, including markedly increased gait variability in BVL animals across all conditions. Gaze-stabilization deficits were equally pronounced: normal monkeys effectively stabilized gaze across conditions, whereas BVL animals exhibited reduced and more variable eye movements that failed to compensate for head motion. Vestibular loss increased the magnitude of reorienting eye movements, consistent with an increased tolerance for gaze-position error. Extending established oculomotor models to incorporate intrinsic noise and elevated error thresholds reproduced these behavioral signatures, revealing that chronic vestibular loss drives a fundamental recalibration of gaze-control strategies. Together, these findings demonstrate that vestibular input provides a central scaffold for stabilizing gaze and gait during natural locomotion and establish essential behavioral benchmarks for future neural, rehabilitative, and prosthetic interventions. Locomotion generates rhythmic head movements that can destabilize vision, yet the specific contribution of vestibular signals to gaze stabilization during natural primate locomotion has not been established. Here, we quantified gaze and gait behavior in rhesus macaques with chronic bilateral vestibular loss during treadmill and overground walking. Vestibular loss increased stride-to-stride gait variability, reduced the consistency of compensatory eye-head coupling, and altered the magnitude of gaze-reorienting movements. Computational modeling further showed that these behavioral changes are consistent with the presence of sensorimotor noise and elevated gaze-error tolerance. Together, these findings demonstrate that vestibular signals provide a central scaffold for stabilizing gaze during locomotion and reveal how oculomotor strategies reorganize following sensory loss.
Neocortical synapses are highly dynamic during brain development, undergoing formation, elimination, and maturation before acquiring properties that support adult cognition. Individual neocortical regions develop at diff...Neocortical synapses are highly dynamic during brain development, undergoing formation, elimination, and maturation before acquiring properties that support adult cognition. Individual neocortical regions develop at different ages and individual layers within these regions contain distinct neuronal subtypes that process unique patterns of local and long-range synaptic input. To better understand the development of the cortical hierarchy we explored the laminar maturation of glutamatergic synapses across cortical regions of male and female mice. Synapse maturation was associated with the upregulation of the postsynaptic density protein PSD95. This maturation occurred in a region- and layer-specific manner - layers associated with feedforward pathways develop earlier, while layers associated with higher-order circuits develop later. Our findings highlight adolescence as an important period for the cortex-wide maturation of synapses in cortical layer 1, synapses known to receive top-down feedback from higher-order cortices. We propose that this delayed adolescent maturation of top-down input represents a global signature of cortical development and seemingly acts as the final stage of outside-in brain maturation. Our findings provide a high-throughput analysis of the postnatal development of glutamatergic synaptic proteins across the neocortical hierarchy. We highlight key differences in the maturation of higher cognitive areas and sensory motor areas. We also observe the delayed and protracted maturation of cortical layer 1, which develops in a neocortex-wide manner during adolescence. Using analysis of synaptic puncta and computational modelling we explore the synaptic mechanisms that underlie these changes. This work highlights adolescence as an important period for the maturation of top-down inputs to layer 1, which may play an important role in the emergence of adult-like cognition during this developmental stage.
We previously reported "true" deviance detection in rat frontal and parietal cortex, reflected in amplified evoked frontal and parietal local field potential (eLFP) responses to rare deviant tones, a likely neural mechan...We previously reported "true" deviance detection in rat frontal and parietal cortex, reflected in amplified evoked frontal and parietal local field potential (eLFP) responses to rare deviant tones, a likely neural mechanism of bottom-up auditory attention. These amplified cortical responses could not be accounted for by stimulus-specific adaptation (SSA) mechanisms alone, implying that they reflect prediction errors calculated by comparing stored expectations to current stimuli. The cholinergic system is well-known to be involved in attention, but the contributions of different acetylcholine receptor (AChR) types in bottom-up as opposed to top-down attention are not fully understood. To test the role of muscarinic receptors in amplifying the neural response to rare tones, we recorded LFPs from the medio-dorsal frontal and posterior parietal cortices of awake male rats exposed to sequences of frequent standard and rare oddball (deviant) tones and compared eLFPs under 0.75 mg/kg of the muscarinic receptor blocker scopolamine vs vehicle injection. We analyzed the amplitudes of specific eLFP components called N1, P2, N2, P3E (early), and P3L (late) to identify the contribution of muscarinic receptors to the oddball amplification at each peak. Administration of scopolamine was associated with a significant reduction of the rare-tone amplification at the frontal N1 and P2 peaks and the parietal N2 peak. In contrast, the frontal P3L oddball amplification was significantly larger in the scopolamine condition. We also observed a reduction in stimulus-induced gamma power under scopolamine. These results suggest that muscarinic receptors contribute to the cortical prediction error response to rare auditory events.
During early postnatal development, γ-aminobutyric acid (GABA) signaling undergoes a functional switch from excitation to inhibition, driven by age-dependent shifts in intracellular chloride concentrations ([Cl⁻]). In th...During early postnatal development, γ-aminobutyric acid (GABA) signaling undergoes a functional switch from excitation to inhibition, driven by age-dependent shifts in intracellular chloride concentrations ([Cl⁻]). In the retina, starburst amacrine cells (SACs) are pivotal for establishing direction-selective circuitry. However, the molecular mechanisms and the precise timing of the reversal potential of GABA-induced currents (E) shift in mouse SACs remain to be fully elucidated. We investigated the maturation of GABA responsiveness and chloride homeostasis in mouse SACs during the neonatal period. Ca imaging in dissociated retinal neurons revealed that the application of GABA markedly increased intracellular Ca concentrations in SACs on postnatal day (P) 0-P2, whereas these excitatory responses were largely absent by P7-P9. Gramicidin-perforated patch recordings showed that E underwent a significant hyperpolarizing shift with development, accompanied by a marked decrease in [Cl⁻]. Immunohistochemical analyses demonstrated a developmental decline in Na-K-2Cl⁻ co-transporter (NKCC1) expression and the concomitant up-regulation of K-Cl⁻ co-transporter (KCC2) in SACs. Consistent with these expression patterns, the pharmacological inhibition of NKCC1 or KCC2 selectively changed E in a stage-dependent manner. Collectively, these results demonstrate a developmentally regulated GABAergic switch in SACs orchestrated by coordinated changes in chloride transporter expression, providing insights into the physiological maturation of the retinal circuitry underlying direction selectivity.
Electroencephalography (EEG) slowing and reduced functional connectivity are markers of Alzheimer's disease (AD) and Lewy body dementia (DLB), but the significance of epileptiform discharges to these changes remains unkn...Electroencephalography (EEG) slowing and reduced functional connectivity are markers of Alzheimer's disease (AD) and Lewy body dementia (DLB), but the significance of epileptiform discharges to these changes remains unknown. To investigate whether epileptiform discharges are associated with EEG slowing or decreased functional connectivity over time. In this longitudinal observational exploratory study, we included a total of 15 healthy controls, 25 patients with AD, and 10 patients with DLB. The patients underwent conventional resting-state EEG up to three times over 6 months. A baseline ear-EEG recording was used to quantify the number of epileptiform discharges per 24 h. We found that compared to healthy controls, DLB and AD patient groups showed a pattern of slowing and decreased alpha coherence. Epileptiform discharges were not associated with slowing or coherence at baseline. In longitudinal analyses, patients with DLB and epileptiform discharges demonstrated an increase in relative theta power over six months compared with patients with DLB without epileptiform discharges. No significant longitudinal theta-power changes were observed in patients with AD. These findings suggest that while EEG slowing is a characteristic feature of neurodegenerative diseases, epileptiform discharges are not directly associated with baseline EEG theta activity but may be linked to a distinct longitudinal trajectory of theta activity in DLB. Given the small group sizes and unbalanced subgroups analysis, these observations should be considered exploratory and require confirmation in larger longitudinal studies.
OBJECTIVE: In addition to a gap detection threshold, an auditory gap detection task also provides information on response time. This study investigated the association of response time from an adaptive gap detection task...OBJECTIVE: In addition to a gap detection threshold, an auditory gap detection task also provides information on response time. This study investigated the association of response time from an adaptive gap detection task with two validated measures of cognitive processing speed as well as scores from a cognitive screener, while accounting for the effects of age, peripheral hearing ability, and HIV status. DESIGN: Participants (age 17-45 years) were from a prospective cohort study in Dar es Salaam, Tanzania with normal hearing ability and no reported neurological diseases. The final sample included 283 unique subjects (158 living with HIV, 125 without HIV) matched on age and sex. Multiple linear regression models were employed to assess the relationship between gap response time and cognitive processing speed scores from the Tests of Variables of Attention, Cogstate test battery, and Montreal Cognitive Assessment. RESULTS: Regression analysis showed significant relationships between gap response time and all processing speed scores, except one. Age showed varying degrees of association with different processing speed measures, but peripheral hearing ability did not show any significant relationship with speed measures. CONCLUSIONS: This study identifies a link between cognitive processing speed and gap detection response times. With further validation, gap detection response times could emerge as a straightforward yet informative measure of cognitive processing speed and would expand the clinical usefulness of the gap test. In the audiology clinic, this measure may hold promise as a tool for detecting and monitoring cognitive decline.
Neuronal activation within the fronto-parietal network (FPN) exhibits distinct time windows during bottom-up and top-down attention. Previous studies have shown that transcranial magnetic stimulation (TMS) applied to the...Neuronal activation within the fronto-parietal network (FPN) exhibits distinct time windows during bottom-up and top-down attention. Previous studies have shown that transcranial magnetic stimulation (TMS) applied to the FPN can have inhibitory effects on attention performance. However, whether the timing of TMS over the FPN differentially inhibits bottom-up and top-down behaviors requires further investigation. Here, we examined how the timing of TMS delivery to (FPN) nodes affects visual selective attention. The single-pulse TMS was applied to the right dorsolateral prefrontal cortex (rDLPFC) and right superior parietal lobule (rSPL) in both active and sham groups, with different timings (early: 33 ms, 50 ms, 66 ms, 83 ms; late: 216 ms, 233 ms, 250 ms, 266 ms) of TMS pulses after stimulus onset. Behavioral results showed that late TMS over the rDLPFC impaired top-down attention by decreasing accuracy and prolonged reaction times (RTs). Late TMS over the rSPL enhanced top-down attention by increasing accuracy and reducing the RT/Accuracy index. Late TMS over the rDLPFC and rSPL respectively enhanced and reduced the cognitive load difference between bottom-up and top-down attention. Voxel-based morphometry further revealed that RTs in the active group were correlated with gray matter volume (GMV) in the fronto-parietal cortex. Predictive analysis confirmed the stability of the associations between regional GMV and attention. These findings provide causal behavioral evidence that the FPN contributes to visual selective attention during the late time window, and the brain structure results further support the relationship between fronto-parietal structure and the behavioral regulation of visual selective attention.
This study investigated the effects of manipulating tuberomammillary nucleus (TMN) histidine decarboxylase (HDC)-lineage neurons, which constitute the major source of central histaminergic neurons, on motion sickness-lik...This study investigated the effects of manipulating tuberomammillary nucleus (TMN) histidine decarboxylase (HDC)-lineage neurons, which constitute the major source of central histaminergic neurons, on motion sickness-like behaviors in mice. Using a transgenic mouse line and a cyclic rotational stimulation paradigm, we found that rotational stimulation significantly upregulated Fos expression in the TMN. Silencing of TMN HDC-lineage neurons did not affect conditioned flavor avoidance but significantly reduced retching-like episodes following rotational stimulation. However, mice with TMN HDC-lineage neuron silencing exhibited lower baseline locomotor activity and impaired motor coordination compared to controls, which complicates interpretation of the retching-like behavior. These findings provide preliminary evidence that TMN HDC-lineage neurons may contribute to the expression of motion sickness-induced retching-like behavior, while their role in motion sickness-induced malaise-related responses and motor impairments remains to be further clarified.
Distinct cortical inputs to the ventrolateral periaqueductal gray (vlPAG) have been implicated in pain modulation, however, the effect of their simultaneous activation on pain and anxiety remains unclear. Here, we examin...Distinct cortical inputs to the ventrolateral periaqueductal gray (vlPAG) have been implicated in pain modulation, however, the effect of their simultaneous activation on pain and anxiety remains unclear. Here, we examined the roles of medial prefrontal cortex (mPFC) and ventrolateral orbitofrontal cortex (vlOFC) projections to the vlPAG in a neuropathic pain model. Using optogenetic stimulation in spared nerve injury (SNI) mice, activation of either mPFC or vlOFC inputs to the vlPAG partially reduced mechanical hypersensitivity, whereas simultaneous activation produced a complete analgesic effect. c-Fos analysis revealed increased neuronal activation across all conditions following activation of the respective circuits, with glutamatergic neurons predominating over GABAergic neurons within the c-Fos + population. Anatomical tracing showed that mPFC and vlOFC projections target distinct subregions within the vlPAG. In addition, the mPFC-vlPAG pathway appears to primarily drive the anxiolytic effect. These findings demonstrate that the mPFC and vlOFC inputs to the vlPAG differentially regulate pain and anxiety related behaviors and provide new insight into cortical control of these processes.
Zhao F, Quan W, Zhang Q
… +9 more, Yin Y, Jiang Y, Zhang X, Li H, Zhang C, Li L, Hu S, Li F, Hu R
BMC Neurosci
· 2026 Jul · PMID 42393564
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Full text
Intracerebral hemorrhage (ICH) is a health challenge resulting in death or disability. Iron overload has been identified as one of post-ICH damaging factors. However, the impact of iron overload, as well as the underlyin...Intracerebral hemorrhage (ICH) is a health challenge resulting in death or disability. Iron overload has been identified as one of post-ICH damaging factors. However, the impact of iron overload, as well as the underlying mechanisms, on neural stem/progenitor cells (NSPCs) remains unknown. In this study, we found that iron overload induced significant NSPC death in a dose-dependent manner. Interestingly, iron overload increased the number of early and late apoptotic cells and the expression of caspase-3 in NSPCs. Moreover, iron overload was highly correlated with enhanced intracellular reactive oxygen species (ROS) generation and loss of mitochondrial integrity. Further, iron overload activated mTOR signaling and downregulated AMP-activated protein kinase (AMPK) phosphorylation. Importantly, drugs that eliminate ROS or activate AMPK prevented this event, as well as apoptosis of NSPCs. These results indicate that post-ICH iron overload in the brain induces excessive ROS generation and leads to NSPC death by regulating mTOR and AMPK signaling.
Neural activity fluctuates over a wide range of timescales within and across brain areas. Experimental observations suggest that diverse neural timescales reflect information in dynamic environments. However, the definit...Neural activity fluctuates over a wide range of timescales within and across brain areas. Experimental observations suggest that diverse neural timescales reflect information in dynamic environments. However, the definitions and measurements of timescales derived from brain recordings vary across the literature. Moreover, these observations do not specify the mechanisms that underlie variations in timescales or whether specific timescales are necessary for neural computation and brain function. Here we synthesize three directions in which computational approaches can distill the broad set of empirical observations into quantitative and testable theories. We review (1) how different data analysis methods quantify timescales across distinct behavioral states and recording modalities; (2) how biophysical models provide mechanistic explanations for the emergence of diverse timescales; and (3) how task-performing networks and machine learning models uncover the functional relevance of neural timescales. This integrative computational perspective complements experimental investigations, providing a holistic view of how neural timescales reflect the relationships among brain structure, dynamics and behavior.
Hirschsprung disease (HSCR) is a congenital malformation characterized by the absence of the enteric nervous system (ENS) in the distal colon, resulting from defective colonization of enteric neural crest cells (ENCCs)....Hirschsprung disease (HSCR) is a congenital malformation characterized by the absence of the enteric nervous system (ENS) in the distal colon, resulting from defective colonization of enteric neural crest cells (ENCCs). The underlying pathogenesis of HSCR remains incompletely understood. Here, we report that c-Cbl-associated protein (CAP), also known as sorbin and SH3 domain-containing protein 1 (SORBS1), is upregulated in the aganglionic colon tissues of children with HSCR. Functional studies revealed that CAP overexpression suppresses ENCC colonization by binding the lipid raft protein flotillin-1 through its sorbin homology (SoHo) domain, followed by recruitment of the focal adhesion protein vinculin via its SH3 domain. Using mass spectrometry, we identified an endogenous CAP-derived peptide, termed PDCAP, in aganglionic colon tissues. ELISA further revealed reduced PDCAP levels in the diseased colon tissues of HSCR children. Mechanistically, PDCAP exerts a protective role by competing with its precursor protein, CAP, for binding to flotillin-1, thereby reversing CAP-mediated inhibition of ENCC colonization. This protective function was further validated in as well as mouse models of either sex, where PDCAP promoted ENCC colonization and ENS development. Collectively, our findings establish PDCAP as a functional antagonist of its precursor CAP, providing a rationale for exploring peptide-mediated interventions in HSCR. This study identifies a novel pathogenic mechanism in Hirschsprung disease (HSCR), showing that upregulated c-Cbl-associated protein (CAP) suppresses enteric neural crest cell (ENCC) colonization through interactions with flotillin-1 and vinculin. We further characterize an endogenous peptide derived from c-Cbl-associated protein (PDCAP) that competitively binds flotillin-1 and thereby counteracts CAP-mediated inhibition of ENCC colonization. By demonstrating the protective role of PDCAP in promoting ENCC colonization and enteric nervous system (ENS) development, our findings suggest a potential biological strategy to support ENS formation and provide a new direction for future therapeutic exploration.
Fluctuations in alertness shape perception and behaviour, yet how they affect the brain's ability to integrate information across senses remains poorly understood. Here we investigated whether multisensory integration is...Fluctuations in alertness shape perception and behaviour, yet how they affect the brain's ability to integrate information across senses remains poorly understood. Here we investigated whether multisensory integration is preserved as humans transition from wakefulness to sleep. Participants (18 females, 8 males) performed an audio-tactile detection task while electroencephalography tracked spontaneous declines in alertness. Behaviourally, multisensory stimulation continued to facilitate responses during drowsiness, despite slowing and increased omissions. Although race-model predictions were consistent with preserved evidence for multisensory integration, event-related signatures of multisensory interactions were attenuated or no longer detectable during drowsiness. Crucially, multivariate decoding showed that multisensory neural representations remained detectable, although less temporally stable, and early cross-state generalization revealed shared representational structure across alertness levels, indicating preserved core multisensory computations. These findings show that multisensory integration remains functional but dynamically altered as alertness declines, revealing how the brain maintains adaptive behaviour during the wake-to-sleep transition. Multisensory integration has often been described as a stable and automatic perceptual process. However, growing evidence indicates that it can be modulated by ongoing brain states and cognitive demands. Here, we ask whether this computation remains invariant as alertness declines. We show that multisensory integration is neither abolished nor fully invariant during drowsiness. Instead, behavioural benefits are maintained despite less stable neural dynamics. Although event-related responses are attenuated, core multisensory representations remain shared across levels of alertness. These findings indicate that multisensory integration is preserved across fluctuations in alertness, while their neural dynamics are flexibly altered as alertness decreases.
Developmental and epileptic encephalopathies (DEEs) are a group of neurological disorders primarily affecting young children and are characterized by severe seizures. DEEs are challenging to manage, with some patients ex...Developmental and epileptic encephalopathies (DEEs) are a group of neurological disorders primarily affecting young children and are characterized by severe seizures. DEEs are challenging to manage, with some patients experiencing severe side effects or not responding to frontline therapies. The CACNA1E gene, which encodes the voltage-gated calcium channel Cav2.3 (R-type), has recently been associated with DEEs. More than fifteen different variants in CACNA1E have been identified in patients with DEEs; however, the mechanisms by which these variants affect channel function and, thus, their relationship to DEEs, remain largely unknown. Previous research has begun to characterize the functional effects of R-type channel variants on channel biophysics, but only a handful of them have been studied functionally to date. Here, we transiently expressed Cav2.3 channels in a tsa-201 cell expression system and used whole-cell patch-clamp to examine the biophysics of one specific disease-associated R-type channel variant in which leucine 228 is substituted with a proline (L228P). Compared to wild-type, the L228P mutant did not present altered peak current density, inactivation kinetics, or recovery from inactivation, but showed a significant shift towards hyperpolarized voltages in both voltage-dependent activation and steady-state inactivation. This resulted in a broader window current shifted towards more hyperpolarized potentials, which predicts increased channel availability and activity at subthreshold voltages relative to wild-type channels. Our results contribute to the ongoing characterization of R-type variants, with the long-term goal of informing mechanism-specific therapies for DEEs.
Successful spatial navigation requires rapid evaluation of potential future trajectories. Hippocampal 'theta sweeps', the sequential activation of place cells within individual theta cycles, exhibit predictive dynamics w...Successful spatial navigation requires rapid evaluation of potential future trajectories. Hippocampal 'theta sweeps', the sequential activation of place cells within individual theta cycles, exhibit predictive dynamics within the ideal timeframe for this role. However, whether these sequences reflect movement-related variables, perceptual targets or more cognitive goal-directed planning remains unresolved. Using data from the 'Honeycomb' maze, which dissociates head, movement and goal directions, we found that theta sweeps form vectors toward remembered goal locations independent of the rat's movement or heading directions. Stronger goal modulation preceded correct navigational choices, establishing the relevance of theta sweeps for spatial planning. A hierarchical continuous attractor network with goal-oriented directional inputs reproduced these findings and made several nontrivial predictions, which we confirmed empirically. Sequential activity during immobility-related sharp-wave ripples was also goal directed and, therefore, more aligned with theta sweeps than with previously experienced trajectories. Our findings identify hippocampal theta sweeps as neural substrates for online goal-directed planning.