In the central nervous system, the majority of excitatory synapses exist on small actin-enriched structures protruding from dendrites, known as dendritic spines. Actin cytoskeletal rearrangements drive dynamic changes in spine shape, size, and density depending on developmental stage and synaptic activity. Spines initially emerge from the dendritic shaft as dynamic protrusions known as filipodia-like spines, which serve as precursors to mature dendritic spines. The formation and maturation of dendritic spines facilitate information transfer in neural circuits, underlying cognitive processes, such as learning and memory formation, and altered spine development results in neurodevelopmental disorders. Within dendritic spines, signaling events are regulated by many synaptic receptors such as the ionotropic N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. However, only NMDA receptors are enriched in both immature filopodia-like spine precursors and mature dendritic spines, with AMPA receptors expressed later in development and coinciding with spine maturation. During embryonic development, most NMDA receptors contain GluN2B subunits, in contrast to mature synapses which predominantly contain GluN2A subunits. While many actin regulatory proteins, such as α-actinin-2, interact with NMDA receptor subunits, it remains unclear whether GluN2B vs. GluN2A-containing receptors exhibit differences in their preferential protein interactions that underly dendritic spine development. The following review highlights how preferential interactions between specific GluN2 isoforms and actin cytoskeletal regulators underlie synaptic development by balancing dynamic events of synaptic plasticity with competing events of synaptic strengthening and consolidation. We discuss how alterations in the expression of GluN2 isoforms and/or mutations that disrupt actin interactions contribute to neurological disorders, both developmental and degenerative.
Aging remains the predominant risk factor for Alzheimer's disease (AD) and other neurodegenerative disorders, yet the mechanisms linking systemic aging to brain dysfunction remain incompletely understood. Cellular senescence, a state of stable cell-cycle arrest coupled with metabolic and secretory reprogramming, has emerged as a pivotal and context-dependent driver of brain aging. Accumulation of senescent glial cells (astrocytes, microglia, and oligodendrocyte progenitors) and emerging evidence of "neurescence" in post-mitotic neurons contribute to neuroinflammation, impaired proteostasis, and synaptic dysfunction. This review synthesizes molecular, cellular, and translational findings that reframe senescence as an active process shaping brain vulnerability. We discuss SASP-mediated neurotoxicity, crosstalk among senescent glial subtypes, and context-specific pathways (NF-κB, p38 MAPK, mTOR, cGAS-STING) as therapeutic targets. Senomorphic and senolytic strategies, alongside emerging systemic interventions such as therapeutic plasma exchange with albumin replacement, are evaluated for their potential to mitigate senescence burden and restore homeostasis. Integrating evidence from fluid, imaging, and multi-omic biomarkers, we highlight how senescence can now be monitored in vivo and stratified across disease stages. Multi-omic and spatial transcriptomic data reveal that central and peripheral senescence signatures only partially overlap, suggesting bidirectional communication across the brain-body axis. This systemic dimension raises key questions about whether modifying peripheral senescence or proteostasis could reshape CNS trajectories. However, key uncertainties remain, particularly regarding the causal role of senescence in human neurodegeneration, the specificity of current biomarkers, and the distinction between adaptive versus maladaptive senescence responses. Notably, direct evidence linking senescent cells to functional alterations in the human brain microenvironment remains limited. This review distinguishes itself from prior literature by integrating a multi-scale brain-body axis perspective, combining molecular, cellular, and systemic evidence to propose senescence as a bidirectional and context-dependent driver of neurodegeneration rather than a purely cell-autonomous process.
Parkinson's disease is a progressive neurodegenerative condition, and unfortunately, there are currently no treatments available that can halt or slow down its progression. However, recent research on intensive and multidisciplinary rehabilitation shows great promise, indicating that vigorous exercise may offer benefits to patients. This study is a randomized, single-blind, controlled, two-arm trial comparing an intensive outpatient multidisciplinary rehabilitation program with a home-based self-administered stretching program in Persons with Parkinson's disease (PwPD). This study aims to assess the effects of an intensive rehabilitation program compared to a home-based self-treatment plan on the serum expression of four molecular biomarkers: brain-derived neurotrophic factor (BDNF), total α-synuclein, miR-223-3p, and miR-7-1-5p in PwPD. We enrolled seventy PwPD in mild-to-moderate stages (average age: 71.15 ± 16.19 years, disease duration: 7.67 ± 5.61 years; UPDRS: 38.06 ± 13.07). Out of these, 36 participants (19 males and 17 females) were assigned to an outpatient daily intensive multidisciplinary rehabilitation treatment (EXP-PwPD), while 34 (22 males and 12 females) participated in a home-based self-treatment stretching program (CTRL-PwPD). Serum samples were taken at baseline (T0), at the end of the intervention period (T1, 6 weeks after T0), and at T2 (3 months after T1). We measured the protein concentrations (BDNF and α-synuclein) and circulating miRNAs (miR-223-3p and miR-7-1-5p) in the serum, and compared results between the groups. The intensive rehabilitation program led to a significant increase in serum BDNF and α-synuclein expression. Notably, the rise in serum α-synuclein was dependent on exercise, returning to baseline concentration at T2, while serum BDNF remained significantly elevated even 2 months post-program completion (T2) (p = 0.03). Among the miRNAs studied, miR-7-1-5p reflected the pattern of BDNF, showing a notable increase after intensive rehabilitation (p = 0.05) and persistence at follow-up (p = 0.04). There were no significant changes for miR-223-3p. In conclusion, this study indicates that intensive rehabilitation can modify circulating biomarkers in PD. Our findings indicate that intensive exercise induces a sustained elevation of serum BDNF and miR-7-1-5p, reflecting enhanced neuroplastic and neurotrophic activity. ClinicalTrials.gov, identifier: NCT05452655.
Astrocytes regulate metabolic exchange between the vasculature and neurons in the central nervous system (CNS). In the retina of the eye, also a component of the CNS, astrocyte endfeet couple to vascular elements to mediate glucose uptake via the glucose transporter GLUT1 and shuttle metabolic resources to the axons of retinal ganglion cells (RGCs), which provide visual input to the brain. In addition to its own transcriptional regulation, GLUT1 is also modulated by signaling pathways that influence its subcellular localization at the astrocyte-vascular interface. For example, cyclic guanosine monophosphate (cGMP) signaling, a key regulator of vascular tone, is associated with changes in retinal astrocyte morphology and is implicated in age-related loss of RGCs, suggesting a potential role in astrocyte function within the neurovascular unit. Here, we tested this possibility directly by investigating the effects of 8-Br-cGMP on astrocyte morphology, vascular interactions, and GLUT1 localization in the retina. Using a transgenic mouse that allows resolution of individual astrocytes in great detail across the retina (the G-MORF mouse), we show that acute elevation of 8-Br-cGMP increases astrocyte coverage area without altering overall vascular structure. 8-Br-cGMP treatment was also associated with enhanced astrocyte-vascular association, reflected by increased endfoot coverage of blood vessels and altered scaling of astrocyte contact with vessel size. Treatment to increase cGMP signaling promoted redistribution of GLUT1 to astrocyte perivascular endfeet without changing overall levels of GLUT1. Together, these findings indicate that increased cGMP signaling induces coordinated structural and molecular remodeling of astrocytes at the vascular interface. These results provide important insight into how cyclic nucleotide signaling pathways may regulate astrocyte organization in the retina and suggests a potential role for cGMP in modulating astrocyte-vascular interactions within the neurovascular unit.
Traumatic spinal cord injury (SCI) has traditionally been regarded as a central nervous system injury mainly confined to the injured segment. However, increasing evidence indicates that SCI can also induce neuroinflammation, cognitive decline, and emotional disorders in remote brain regions, suggesting that its pathological impact is systemic rather than purely local. Remote brain dysfunction after SCI is unlikely to be driven by a single pathway, but may arise from the combined effects of systemic inflammation, autonomic imbalance, neuroendocrine dysregulation, and disruption of intestinal homeostasis. Unlike previous reviews that mainly discuss SCI-associated gut dysbiosis, neuroinflammation, or gut-brain communication separately, this review organizes SCI-related intestinal abnormalities around the concept of "gut-derived pathological signals" and further distinguishes direct SCI evidence from cross-disease mechanistic evidence and proposed mechanistic inference. Specifically, we summarize how intestinal dysmotility, microbial metabolic remodeling, abnormalities in short-chain fatty acids (SCFAs), barrier vulnerability, and mucosal immune imbalance after SCI may generate persistent pathological signals. We then analyze how these signals may affect the central nervous system through an immune-inflammatory main axis, a vagal neural relay branch, and a neuroendocrine modulatory branch, ultimately converging on a common downstream brain effector stage characterized by blood-brain barrier impairment, neuroinflammation, synaptic plasticity deficits, and dysfunction of key brain regions such as the hippocampus and medial prefrontal cortex (mPFC). Based on this cascade, we propose a stratified intervention framework involving upstream restoration of intestinal homeostasis, midstream regulation of interorgan transmission pathways, and downstream protection of brain effector mechanisms. Overall, this review provides an evidence-stratified gut-brain axis framework for understanding remote brain dysfunction after SCI and highlights the need for SCI-specific temporal mapping and pathway-selective causal validation.
Previous studies have demonstrated that phytochemicals present in Spondias mombin leaves possess neuro-regenerative and neuroprotective potentials. This study therefore evaluated the effects of ethanol leaf extract of Spondias mombin (ELESM) on the hippocampus of adult male Wistar rats with scopolamine-induced neurodegeneration using biochemical, behavioral, histological, and immunohistochemical assessments. This study was conducted for a period of 71 days. Forty-two adults male Wistar rats (200 ± 20 g) were randomly assigned into six groups (n = 7). Group I received normal saline (1 mL/kg) orally for 10 weeks. Neurodegeneration was induced in Groups II-VI by intraperitoneal administration of scopolamine (1 mg/kg) for two weeks. Twenty-four hours after induction, Group II received normal saline (1 mL/kg) orally, Group III received donepezil (5 mg/kg) orally, while Groups IV-VI received ELESM (200, 400, and 600 mg/kg) respectively for eight weeks. Result showed that scopolamine administration significantly increased acetylcholinesterase activity, reduced antioxidant status, and promoted inflammation. Behavioral assessments showed reduced locomotor activity, anxiety-like behavior accompanied with impaired working memory. Histological findings demonstrated features of neurodegeneration, including reduced neuronal density in the dentate gyrus and a decreased proportion of healthy neurons in the cornu ammonis subfields. White matter integrity in the alveus was compromised, appearing distorted and de-compacted. Immunohistochemical analysis further revealed astrocytic reactivity in response to oxidative stress. These findings indicate that scopolamine triggered molecular and structural alterations that persisted beyond the induction period. However, treatment with Donepezil and ELESM 200 mg/kg, 400 mg/kg and 600 mg/kg produced significant anticholinesterase, antioxidant, and anti-inflammatory effects, restoring these protein levels to near normal. Donepezil and ELESM improved cognitive and memory functions and attenuated anxiety-like behavior. Histological integrities of the hippocampus subfields were preserved, while immunohistochemistry showed modulation of astrocytic glial fibrillary acidic protein expression. Chronic scopolamine administration caused long term impairments, but ELESM demonstrated neuroprotective effects against scopolamine-induced neurodegeneration, likely mediated through its anticholinesterase, antioxidant, and anti-inflammatory properties in adult male Wistar rats.
Spinal cord injury (SCI) is a devastating neurological condition with limited regenerative capacity. Stem cell-based approaches have emerged as promising strategies due to their neuroprotective and immunomodulatory properties, largely mediated by small extracellular vesicles (sEVs) and their molecular cargo, including miRNAs. In this study, we aimed to evaluate the neuroprotective and anti-apoptotic potential of sEVs derived from SPC-01 and iMR-90 neural stem cell sources using an in vitro rat model of SCI. sEVs were isolated from SPC-01 and iMR-90 culture media and characterized by MADLS and Western blot. Spinal cord slices (SCS) were used as an in vitro SCI model with three groups: control, SCI, and SCI treated with sEVs. Injury was induced at 18-20 days in vitro, followed by immediate sEV application. After 72 h, tissue samples were collected and analyzed to assess proteins associated with apoptosis, cytoskeletal integrity, and survival signaling pathways. SCI induced cytoskeletal disruption and increased apoptotic markers. sEV treatment attenuated these changes, reducing injury-associated proteins toward baseline levels. Both SPC-01- and iMR-90-derived sEVs showed neuroprotective effects. This was associated with modulation of key pathways, including decreased PTEN, increased STAT3 phosphorylation, and elevated Bcl-xL. Reduced Nogo-A and normalized RhoA levels further indicate attenuation of inhibitory signaling and improved cytoskeletal stability. Overall, sEVs promoted early neuroprotective responses and reduced pathology-associated protein expression in the SCI model. Neural stem cell-derived sEVs promote neuroprotection in vitro by modulating PTEN/STAT3 signaling, reducing apoptosis, and stabilizing cytoskeletal dynamics. Although limited to early injury responses in an in vitro model, these findings support sEVs as a promising cell-free therapeutic strategy for SCI.
SCN2A, encoding the voltage-gated sodium channel Na V 1.2, is a high-risk gene associated with autism spectrum disorder (ASD) and has been linked to sensory hypersensitivity. Recent work indicates that Na V 1.2 loss-of-function produces developmental and compartment specific alterations in neuronal signaling. However, how SCN2A contributes to the maturation of subcortical auditory circuits that demand exceptional temporal precision remains unclear. In this study, using Scn2a haploinsufficient (Scn2a+/- ) mice, we investigated the functional contribution of Na V 1.2 to spike-generating mechanisms in the medial nucleus of the trapezoid body (MNTB), a fast inhibitory relay in the auditory brainstem organized along a medial-lateral tonotopic axis. In the pre-hearing period (P4-P6), Scn2a haploinsufficiency reduced transient Na+ current amplitude and eliminated a delayed onset inward Na+ current component observed in a subset of wild type neurons, providing functional evidence for Na V 1.2 dependent activity in developing MNTB neurons. Notably, Na V 1.2 dependent deficits were tonotopically patterned. Lateral (low frequency) MNTB neurons exhibited the largest reductions in both transient Na+ current and persistent Na+ current, whereas medial neurons were comparatively spared in peak current magnitude. In current clamp, Scn2a+/- neurons displayed altered action potential kinetics during the pre-hearing window (slower and broader spikes), but repetitive firing during prolonged depolarizing steps was largely preserved, indicating that Scn2a reduction impacts spike waveform maturation more than tonic spike count. After hearing onset, peak Na+ current amplitudes were comparable between genotypes (P14-P24), consistent with developmental reorganization of Na V channel contributions. Together, these findings identify a pre-hearing, tonotopically biased role for Scn2a in axon initial segment (AIS)-linked Na+ channel function and spike kinetics in the MNTB, providing a mechanistic framework for how Scn2a may influence early auditory brainstem development relevant to sensory phenotypes in ASD.
Spinal motor neurons are essential for translating neural activity into coordinated muscle contraction, yet defining their functional subtypes across development remains a persistent challenge. While embryonic patterning establishes the initial positional and molecular framework of motor neuron identity, substantial refinement continues during early postnatal life as intrinsic electrophysiological properties, synaptic connectivity, and neuromuscular interactions mature. A major limitation in the field is the lack of temporally stable and functionally validated molecular markers that can reliably distinguish motor neuron subtypes across developmental stages, particularly during neonatal maturation when subtype-specific physiological features are emerging. In this review, we synthesize classical developmental studies with recent advances in single-cell transcriptomics, chromatin accessibility profiling, and multimodal approaches linking gene expression with electrophysiological and anatomical features. Focusing on lumbar spinal motor neurons that underlie locomotor behavior, we discuss how transcriptional programs, activity-dependent mechanisms, and non-cell-autonomous signals converge to shape subtype-specific maturation trajectories. We propose that motor neuron subtype identity is best understood as a dynamic molecular and physiological state shaped by developmental timing, circuit context, and activity-dependent mechanisms, rather than as a fixed category defined by a single marker. From this perspective, early postnatal life represents a sensitive window of identity consolidation during which molecular programs and functional properties become aligned. Establishing temporally robust subtype markers and integrating molecular and physiological datasets will be essential for resolving motor neuron diversity and for improving our understanding of subtype-selective vulnerability in neuromuscular diseases. While this review emphasizes embryonic and early postnatal development, understanding how molecular subtypes stabilize in the adult spinal cord, despite ongoing activity-dependent physiological plasticity, remains an essential reference point for defining temporally robust motor neuron identities.
Early human development is characterized by sensitive periods which impact long-term cognitive and behavioral outcomes. While these windows of heightened plasticity are well documented, the cellular mechanisms that enable and regulate them remain incompletely understood. In this conceptual article, I propose that early-life shifts in cortical inhibitory-excitatory balance, driven by prolonged neurogenesis, migration, and maturation of GABAergic interneurons, play a central role in opening, shaping, and closing sensitive periods and thereby guide skill development. Drawing on evidence from human and animal studies, I synthesize findings showing that inhibitory interneurons are integrated into cortical circuits well into postnatal life, where they regulate intrinsic and sensory-driven activity, sculpt synaptic connectivity, coordinate interactions with glial cells, and progressively refine network dynamics. The developmental strengthening of inhibition alters excitation-inhibition ratios, drives the transition from highly synchronous early activity to decorrelated and efficient adult-like firing patterns, and gates critical period plasticity across cortical regions. I argue that these inhibitory processes are not merely stabilizing but actively facilitate learning by suppressing non-relevant activity and enabling the emergence of specialized functional networks. This framework highlights fundamental differences between infant and adult learning mechanisms and suggests that individual variability in inhibitory circuit development may underlie differences in cognitive trajectories and vulnerability to neurodevelopmental disorders. Together, this synthesis positions early inhibitory interneuron development as a key mechanistic substrate linking sensitive periods to lifelong skill acquisition and behavioral individuality.
This study aims to investigate the characteristic brain abnormalities in Southern Chinese patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis and to explore their association with blood-brain barrier (BBB) disruption and clinical implications. This study retrospectively analyzed 80 cases of anti-NMDAR encephalitis. Patients were divided into a group with abnormal brain MRI (n = 35) and a group with normal brain MRI (n = 45). The extent of BBB disruption was assessed using the albumin quotient (Qalb), defined as the cerebrospinal fluid (CSF)-to-serum albumin ratio. Disease severity was evaluated using the modified Rankin Scale (mRS). Patients were further categorized into a relapse group and a non-relapse group based on post-discharge relapse status. Key predictive factors were identified through multivariate regression analysis. Brain MRI abnormalities were observed in 43.75% (35/80) of the anti-NMDAR encephalitis patients. Among these, typical MRI findings of anti-NMDAR encephalitis abnormalities were present in 26 patients (32.5% of the total cohort). Brain MRI abnormalities were significantly associated with abnormal BBB permeability (42.9% vs. 13.3%, p = 0.003). Multivariate logistic regression analysis identified two independent predictive factors for brain MRI abnormalities: BBB dysfunction (OR = 4.088, 95% CI: 1.031-16.213, p = 0.045) and time from symptom onset to first-line immunotherapy (OR = 1.041, 95% CI: 1.001-1.083, p = 0.045). Furthermore, receiver operating characteristic (ROC) curve analysis demonstrated that the combined model of BBB dysfunction and time from symptom onset to first-line immunotherapy exhibited favorable predictive performance, with an area under the curve (AUC) of 0.745 (95% CI: 0.634-0.857). BBB dysfunction was closely associated with multi-regional cerebral involvement (p = 0.002). Further Spearman correlation analysis showed that impaired BBB integrity correlated with greater MRI lesion severity and broader lesional distribution (p = 0.003). In binary logistic regression analysis adjusting for mRS score, positive oligoclonal bands (OCBs) were identified as a potential predictor of relapse, with an OR of 7.991 (95% CI: 1.242-51.411, p = 0.029). The AUC was 0.730 (95% CI: 0.542-0.918), indicating moderate predictive performance. Abnormal BBB permeability is an independent risk factor for structural abnormalities on brain MRI and is positively correlated with the extent of MRI abnormalities. CSF OCB positivity is a risk factor for disease relapse. These findings may inform brain injury assessment, relapse risk stratification, and individualized treatment in patients with anti-NMDAR encephalitis.
The emergence of novel experimental techniques such as dendritic patch-clamp recordings or genetically-encoded Ca2+-indicators have made the activity of the dendritic tree considerably more tractable, challenging the old postulate that dendrites serve mainly to connect neurons and to convey information with no specific role in synaptic plasticity. Hence, how the dendritic tree transforms synaptic input into neuronal output and defines the relationships between active synapses is now a leading question in neuroscience. To understand the specific role of dendrites, dendritic spines and dendritic tree geometry in shaping neuronal signal, a crucial first step is to understand precisely voltage and ionic dynamics in such small neuronal compartments. For this purpose, we use the Poisson-Nernst-Planck (PNP) model, which is the recognized standard for modeling voltage dynamics and ionic electrodiffusion in electrolytes at the scale now reached by experimental techniques. This non-linear model presents significant challenges for both modeling and simulation due to its high concentration gradients and sensitivity to boundary conditions, making it difficult to simulate on complex geometries. We resolve these issues here by using a state-of-the-art finite volume method, the Discrete-Duality Finite Volume method, which we previously developed to simulate the PNP system of equations on various two-dimensional geometries representing neuronal compartments. Using this method, we investigate the propagation and attenuation of an ionic influx coming from a synapse near a dendritic branch bifurcation and at a dendritic spine, as well as signal invasion in the nearby branches and spines. By connecting these compartments to an ionic reservoir representing the dendritic shaft, we observe that the distance to the shaft strongly influences signal propagation. Notably, a spine positioned close to a large branch behaves as an isolated compartment, while a distant spine is susceptible to signal invasion. Our numerical results therefore suggest that the local geometry of the dendritic tree has a major influence on spine behavior. Consequently, this study proposes that signal integration rules would differ depending on the location of the spine on the dendritic tree. This means that modifications to neuronal structure and organization following activity are not limited to the spine morphology but depend on the entire dendritic tree architecture.
Exposure to alcohol (ethanol) is the most common toxic insult during human development and is a teratogenic agent associated with abnormalities ranging from behavioral disorders to fetal alcohol syndrome. Ethanol disrupts gene regulatory programs crucial for neuronal identity, including alternative splicing. A distinctive feature of developing neuronal transcriptomes is the high prevalence of microexon inclusion, which consists of short exonic sequences ranging from 3 to 51 nucleotides. However, the impact of ethanol on microexon inclusion remains poorly understood. In this study, we investigated whether ethanol exposure disrupts neuron-specific alternative splicing programs during neuronal differentiation. To this end, PC12 cells were exposed to 50 mM ethanol throughout five days of NGF-induced differentiation, alongside undifferentiated control cells, to analyze mRNA and protein expression dynamics of key splicing regulators and neurodevelopmental targets. Our data show that in undifferentiated cells, ethanol exposure resulted in a significant reduction in Srrm4 expression, while concomitantly increasing Srrm3 mRNA levels, consistent with reduced neuron-specific microexon inclusion of the intersectin 1 (Itsn1) mRNA. While undifferentiated PC12 cells primarily express the canonical variants of lysine-specific demethylase 1 (LSD1) and PHD finger protein 21A (PHF21A), differentiation triggers the inclusion of microexons 8a and 14, generating the neuron-specific isoforms neuronal LSD1 and PHF21A, respectively. Under differentiated conditions, ethanol exposure increased neurite length but did not affect the mRNA levels of the neuronal variants of Lsd1, Phf21a, or Itsn1. Notably, ethanol exposure significantly increased the levels of LSD1 protein and its associated histone substrate, H3K4me2, in differentiated PC12 cells. Taken together, these findings suggest that ethanol exposure modulates post-transcriptional and chromatin-based mechanisms during neuronal commitment and differentiation. This selective disruption highlights distinct molecular pathways that may contribute to persistent neurodevelopmental alterations relevant to alcohol use disorder, providing new insights into the teratogenic mechanisms of ethanol on the developing nervous system.
Women exhibit sex-specific differences in their responses to nicotine, with sex hormones like estrogen and progesterone playing key roles in nicotine addiction among women. Nicotine disrupts neuronal firing in the brain's reward system, an effect regulated by estrogen. In this study, we hypothesized that exposing human female neurons to both nicotine and estrogen would activate distinct signaling pathways. We treated human female SH-SY5Y neurons with nicotine and estrogen, and compared these to treatments with each substance alone or vehicle control. Using PamGene PamStation technology, we created an atlas of over 500 kinase activities per sample. We found that nicotine modulates MAP kinase pathways in a dichotomous manner. Estrogen showed unique kinase effects, and in combination with nicotine, elicited diverse pathway responses-some kinases becoming hyperactive and others hypoactive. Bioinformatics analysis highlighted several kinases as central to this combined signaling, including PKCɩ and TAO, which showed higher kinase activity only with combined treatment and have known links to behavior in rodent models. Conversely, kinases such as the insulin receptor (INSR), HER2, FAK1, and ABL1 exhibited decreased activity under combined treatment. These findings reveal nicotine-specific kinase mechanisms and suggest potential targets for pharmacotherapy aimed particularly at females with high estrogen levels and nicotine use disorder.
Ischemic stroke remains a leading cause of death and long-term disability, yet effective treatments that promote recovery beyond the acute phase are lacking. Neuregulin-1 (NRG-1) has shown potent neuroprotective and anti-inflammatory properties in preclinical stroke models, with evidence of enhanced neuronal regeneration when administered after injury. To investigate the spatial mechanisms underlying its neuroregenerative therapeutic effects, we examined brain proteomic responses to post-ischemic NRG-1 treatment in mice using NanoString Digital Spatial Profiling (DSP). Adult C57BL/6 mice were subjected to photothrombotic middle cerebral artery occlusion (MCAO) and treated with NRG-1β (5 μg/kg/day) or vehicle at 24- and 48-h post-stroke. Brains were collected at 3 days post-ischemia for spatial proteomic analysis of 68 neural proteins across the ischemic core, peri-infarct tissue, and peri-infarct normal tissue (PiNT). While NRG-1 did not significantly alter overall neuronal death, it markedly reshaped the neuroregenerative milieu, upregulating myelin basic protein (MBP) and synaptophysin and attenuating inflammatory mediators (SPP1, P2RX7, and CD39). NRG-1 also enhanced expression of autophagy and mitophagy markers (ULK1, LC3B, ATG5, PINK1, and Park7), suggesting restoration of cellular clearance and mitochondrial quality control. Pathway and network analyses revealed activation of neuroregeneration, autophagy, and lysosomal biogenesis pathways, while suppressing neuroinflammatory signaling. These findings demonstrate that delayed NRG-1 therapy, even when initiated 24 h after stroke, induces early molecular programs that prime an anti-inflammatory and neuroregenerative environment. The results support further development of NRG-1 as a clinically translatable, multimodal therapy for extending the post-stroke treatment window and promoting functional recovery.
This study describes the distribution of non-reactive brain-resident microglia densely populated along the borders of the lateral ventricles and choroid plexus in premature rabbit pups during early forebrain development. Following intraventricular hemorrhage (IVH) injury, activated microglia expand by proliferation, and migrate deeper into parenchymal regions. During this process, activated microglia exhibit a disproportionate elevation of the proinflammatory microglia phenotype (M1 nomenclature) from the total IBA-1+ microglia cell population along with tissue iron accumulation; this shift was reduced by sulforaphane (SFN; Nrf2-antioxidant response element [ARE] activator of anti-inflammatory pathways) plus deferoxamine (DFN; iron chelator) treatment. A separate DFN monotherapy transcriptome analysis identified over expression of pro-inflammatory calcium-binding proteins S100A8 and S100A12 (intracellular damage signals), as well as chemokines CXCL8 and CXCL10 by microglia and other cells, along with upregulated ferroptosis interactive network genes in IVH including: HMOX1, CTSB, FTL, PRM2, LPCAT1, and CDK1. Importantly, the expression of multiple key genes involved in iron metabolism and transport function included: ACSL4, TFRC, SLC7A11 and ABCA4 which were all downregulated in IVH and this trend was reversed after DFN treatment. Taken together, in the developing postnatal brain, the combination treatment of SFN-DFN mitigated M1 infiltration, reduced iron deposition in the tissue and in the CSF, suppressed the magnitude of inflammation and reduced cell death after IVH. Moreover, DFN monotreatment reversed most dysregulated genes in inflammation and iron homeostasis networks, revealing potential molecular targets for additional pharmacologic interventions after IVH. We speculate that reducing the toxic microcellular environment will attenuate injurious inflammatory responses and improve recovery of the trajectory toward normal brain development.
Insulin resistance, a major component of metabolic syndrome (MetS), is involved in phosphorylated tau and beta amyloid buildup, linking MetS to neurodegenerative processes, e.g., Alzheimer's disease. One of the initial signs of neurodegeneration, in diseases such as Parkinson's and Alzheimer's, is olfactory dysfunction. Accordingly, in previous reports we found that high carbohydrate diet based on 30% sucrose in drinking water, increased visceral fat and insulin resistance, leading to an augment of oxidative stress and reduced brain energy metabolism, upregulating amyloidogenic genes (APP and BACE1) in hypothalamus and hippocampus. Thus, herein we comparatively evaluated the effect of sucrose induced MetS on episodic memory, olfaction, protein expression in amyloidogenic and insulin pathways, lipoperoxidation, antioxidant and BACE1 enzymatic activity between the hippocampus and olfactory bulb in male Wistar rats. Also, cellular structure of the olfactory bulb was analyzed. After 24 weeks of 30% sucrose consumption, we found preserved performance in a memory test; decreased hippocampal expression of APP and hyperactivation of the insulin pathway, low levels of lipoperoxidation, and high activity of antioxidant and BACE1 enzymes. Olfactory dysfunction was present in MetS rats, accompanied by morphological alterations in the olfactory bulb along with BACE1 increased activity. Thus, chronic high-sucrose consumption may prime the brain for neurodegenerative processes by modulating insulin signaling, oxidative stress homeostasis and amyloidogenic pathways in a region-dependent manner, with the olfactory system emerging as an early and sensitive target of metabolic dysfunction.
Spinal muscular atrophy (SMA) has traditionally been described as a motor neuron disorder; however, increasing evidence suggests a broader neurodevelopmental involvement, particularly in the era of disease-modifying therapies. As survival and motor outcomes improve, cognitive and behavioral trajectories have become clinically relevant but remain inconsistently characterized. To systematically synthesize current evidence on cognitive and neurodevelopmental outcomes in children and adults with SMA, with particular focus on differences across phenotypes and therapeutic eras. A scoping review was conducted including observational studies, clinical cohorts, and case series reporting cognitive, language, behavioral, or executive outcomes in individuals with SMA. Studies were analyzed qualitatively with attention to disease severity, age, and treatment status. Twenty-three studies were included. Global intellectual functioning was generally preserved, particularly in SMA types II and III. Nevertheless, selective vulnerabilities were frequently reported in processing speed, executive functioning, and language development. Behavioral and socio-emotional challenges were described in pediatric populations. Neurodevelopmental outcomes in early-onset SMA showed substantial heterogeneity, ranging from global developmental delay to relatively preserved cognitive trajectories, especially in pre-symptomatically treated patients. Methodological variability and motor-related testing limitations were common across studies. Cognitive functioning in SMA appears largely preserved in milder phenotypes but domain-specific vulnerabilities in processing speed, working memory, and language are consistently identified across phenotype groups and represent clinically relevant targets for monitoring and intervention. Systematic neurodevelopmental monitoring and standardized assessment protocols are needed to better define long-term outcomes as treatment modifies disease trajectories.
Macrophage activation is closely associated with age-related hearing loss (ARHL), and Siglec-1 may be involved in modulating macrophage activation. This study aimed to investigate the immunological mechanisms underlying spiral ganglion neuron (SGN) degeneration in ARHL, with a focus on the roles of the immune regulatory gene Siglec-1 and immune regulatory cells, macrophages. Combined transcriptomic sequencing of SGNs from ARHL mice and peripheral blood samples from ARHL patients identified significant upregulation of Siglec-1 in aged groups. Auditory brainstem response (ABR) testing and histological analysis confirmed that hearing thresholds increased and SGN density decreased significantly with age, exhibiting a strong negative correlation. Subsequently, both immunofluorescence and Western blot analyses revealed a notable upregulation of Siglec-1 expression within the spiral ganglion of aged mice. Further RT-PCR analysis revealed that the expression levels of both pro-inflammatory cytokines (including IL-6, TNF-α, and IFN-γ) and the anti-inflammatory cytokine IL-10 were significantly elevated in the aging spiral ganglion tissue. Meanwhile, notable macrophage activation was observed within the spiral ganglion, particularly involving M1 pro-inflammatory macrophages. These findings suggest that Siglec-1 may play a role in the inflammatory response. Finally, we also confirmed a positive correlation between Siglec-1 mRNA expression in human blood samples with age and severity of hearing loss. These findings suggest that Siglec-1 may promote SGN degeneration in ARHL by modulating macrophage-mediated neuroinflammation and represents a potential blood immune biomarker and therapeutic target.
Single-cell sequencing and multi-omics technologies are revolutionizing research on central nervous system (CNS) diseases by enabling high-resolution analysis of cellular heterogeneity and molecular dynamics. Traditional technologies (e.g., bulk sequencing, routine histology) often lack cellular resolution, fail to capture heterogeneity among individual cells, and struggle to reveal subtle molecular changes in early pathogenesis, limiting their ability to clarify complex CNS disease mechanisms and develop precise diagnostic tools. This review comprehensively summarizes the latest advances in single-cell multi-omics methodologies, including genomics, transcriptomics, proteomics, metabolomics, and spatial omics, and their applications in elucidating the pathogenesis, diagnosis, and treatment of common CNS disorders. Representative diseases such as ischemic stroke, Alzheimer's disease, Parkinson's disease, viral meningitis, bacterial meningitis, multiple sclerosis, autism spectrum disorder, and depression are used as examples to discuss the current status and future prospects of single-cell multi-omics technologies in CNS disease research. Currently, these technologies have enabled the identification of rare pathogenic cell subsets, the mapping of cell-specific molecular pathways, and the discovery of potential diagnostic biomarkers in several common CNS disorders, though their clinical translation is still hindered by technical costs and standardization issues. In the future, the integration of single-cell multi-omics with spatial transcriptomics, artificial intelligence, and clinical data is expected to further decode the complex pathogenesis of CNS disorders, accelerate the development of targeted therapies, and promote the shift toward personalized medicine in CNS disease management-aligning with translational goals of neuropsychopharmacology.