K777 promotes functional recovery after spinal cord injury via the PI3K/AKT signaling pathway.

Novel Neurotrophin-3 peptidomimetic synthetic neurotrophin promotes neurological recovery after spinal cord injury.

Neuronal polarization is a fundamental process in the formation of functional neural circuits, relying on the precise coordination between cytoskeletal regulatory signals and mechanisms that sustain cellular integrity. Disruption of these processes compromises neuronal differentiation and survival, and various neurotoxic compounds, including certain pesticides, have been associated with such dysfunctions. In this context, identifying molecules that counteract these detrimental effects is of significant therapeutic interest. Neuronal polarization is essential for the establishment of functional neural circuits and relies on coordinated regulation of actin cytoskeleton dynamics, RhoA/ROCK signaling, and mitochondrial function. Here, we investigated the neuroprotective and neurorestorative potential of the ganglioside GM1 and its oligosaccharide derivative, osGM1, in primary hippocampal pyramidal neurons derived from embryonic day 18 (E18) rat embryos exposed to the mitochondrial neurotoxin rotenone. Rotenone induced a marked arrest of neuronal development, impaired axonal elongation, and disrupted mitochondrial organization and functional status. Both GM1 and osGM1 promoted recovery of neuronal polarity and axonal growth, exerting protective and restorative effects even under continuous toxin exposure, with osGM1 showing superior efficacy. Notably, osGM1 also reversed axonal growth deficits caused by pathological actin stabilization. Mechanistically, osGM1 normalized rotenone-induced hyperactivation of the RhoA/ROCK pathway without altering basal signaling and partially restored mitochondrial network integrity and functional activity. Collectively, these findings identify osGM1 as a multi-target modulator of cytoskeletal and mitochondrial dysfunction and support its translational potential as a therapeutic strategy to counteract neurotoxin-induced neuronal damage.

Developmental electrophysiological changes in mouse mesencephalic trigeminal neurons.

Adolescent prefrontal and amygdala molecular signatures of perinatal morphine versus buprenorphine exposure in mice.

UPF3A and UPF3B shape the transcriptome cooperatively yet oppose cell function.

Tropomyosin receptor kinases family members TrkA, TrkB and TrkC mediate critical processes, such as neuronal growth, survival, and synaptic plasticity, and have been implicated in neuropsychiatric disorders. In this work, we characterized the pharmacokinetics of the novel positron emission tomography (PET) radioligand [18F]TRACK for in vivo quantification of TrkB/C in the human brain. Seven healthy volunteers (3 men; 20-61 years) underwent a 90 min PET scan following an intravenous bolus injection of [18F]TRACK. Arterial blood sampling was performed throughout image acquisition. [18F]TRACK was slowly metabolized, accounting for 60% of the plasma activity at 90 min, with two more polar radiometabolites observed. Regional time-activity curves (TACs) showed moderate uptake (SUV: 1-2) and good reversibility in gray matter regions. Across regions, the two-tissue compartment model (2TCM) yielded superior fits than the 1TCM for 98% of extra-striatal gray-matter TACs, whereas it improved fits for only 52% of striatal TACs. Total distribution volume (VT) ranged from 2.49±0.30 ml/cm3 (thalamus) to 1.94±0.21 ml/cm3 (hippocampus) showing good identifiability (%SE: 1-5%) and low inter-subject variability (%CoV<14%). Transient equilibrium between [18F]TRACK in tissue and plasma was reached at approximately 70 min. Shortening the scan duration to 60 min preserved VT accuracy and precision.

Molecular crosstalk between MAPK signaling and neuroprotective pathways in Parkinson's disease: from pathogenesis to therapeutic potential.

We characterized in vitro and in vivo responses to the antioxidant N-acetyl cysteine (NAC), which in the 22q11.2 Deletion Syndrome LgDel mouse model restores growth and connectivity of developing upper layer cortical projection neurons (Layer 2/3 PNs) and improves cognitive performance. NAC ameliorates L 2/3 PN developmental pathology without restoring wild type (WT) growth patterns or expression levels of downstream targets of 22q11-deleted genes. Instead, novel neuronal growth and antioxidant defense genes are differentially expressed compared to LgDel or WT: some generally NAC-regulated, others responsive only in the context of 22q11 deletion. NAC also elicits novel growth and antioxidant defense gene expression in differentiating 22q11-deleted L 2/3 PNs in postnatal LgDel mouse cortex rather than restoring 22q11 downstream targets to WT levels; however, these L 2/3 PN-selective in vivo changes differ substantially from those in primary culture. Thus, the NAC therapeutic response that diminishes oxidative stress-related L 2/3 PN developmental circuit and behavioral pathology due to 22q11 deletion has a distinct in vivo signature.

Neuroimmunology has garnered significant attention due to its role in immune regulation, particularly in cancer, where infiltrating neurons can influence antigen presentation, T-cell activation, and cancer metastasis, ultimately leading to an inadequate immune response. Here, we integrate manganese-doped titanium-based metal-organic framework (MOF) piezoelectric materials (MT), coated with neuron-derived membranes from dorsal root ganglia, into microneedles (MN) to create a piezoelectric microneedle (MT MN) patch designed to disrupt neuron-immune crosstalk in melanoma. A single administration of MT via microneedle patch stably deposits the MT at the melanoma site in female mice to accelerate the nociceptor neurons targeting. Upon moderate ultrasound stimulation, the MT facilitates the internalization of TRPV1 and activates the cGAS-STING pathway, resulting in the reduction of Ca2+ influx in nociceptor neurons. This ultimately limits the production of calcitonin gene-related peptide (CGRP) and substance P (SP). Consequently, to rescue the tumor immune microenvironment damaged by infiltrated neurons, MT MN is utilized to inhibit the growth and infiltration of nociceptor neurons, highlighting a promising manner for interfering neuron-immune crosstalk in melanoma to enhance cancer immunotherapy.

Ayurvedic Herbs as neurogenesis modulators: Current understanding on their potential therapeutic relevance in enhancing neuroplasticity and cognition in aging and neurodegeneration.

Serotonergic psychedelics (e.g., psilocybin, LSD) have potential to treat psychiatric disorders, with therapeutic effects lasting days to weeks after a single dose. Prominent theories suggest that psychedelics have a lasting effect on hierarchical brain circuits, reducing top-down influence on information processing to facilitate an unbiased, bottom-up reassessment of the world, but direct and concrete evidence for such an effect is lacking. Here we directly tested this hypothesis in both humans and mice, assessing predictive processing in the fronto-visual system in the days after a single psychedelic exposure. Individuals who recently (<3 weeks) used 5-HT 2A Receptor agonist psychedelics (psilocybin, LSD) were assessed via electroencephalography (EEG) and electrooculography recordings during a saccadic prediction task and compared to age- and sex-matched non-users. Compared to non-users, recent psychedelic users produced fewer fast saccades and less suppression of EEG delta/theta power to predictively presented stimuli, pointing to a disruption of predictive processing. These changes correlated with time since psychedelic use and were replicated in a second cohort taking a different serotonergic psychedelic (5-MeO-DMT). Direct recordings of primary visual cortex (V1) in mice administered psilocybin (1 mg/kg) evinced a similar loss of predictive suppression 24-hrs after the dose. This coincided with weakened top-down modulation of V1 from anterior cingulate area (ACa), a subregion of medial prefrontal cortex, along with clear spine growth in ACa neurons that project to V1. These results suggest that psychedelic-induced neural plasticity serves to reorganize feedback circuits in the cortex and relax top-down influence on bottom-up sensory processing - an effect that persists beyond the acute exposure period and may underlie a therapeutic window.

The clinical translation of electroactive nerve conduits is often hindered by the trade-off between electrical performance and biodegradability, as well as the rapid clearance of neurotrophic factors which limits their ability to act in concert with long-term electrical stimulation. In this study, we engineered a fully biodegradable, self-powered multifunctional conduit by integrating piezoelectric poly(l-lactic acid) (PLLA) matrix with conductive reduced graphene oxide (rGO) within a flexible poly(l-lactide-co-ε-caprolactone) (PLCL) scaffold. This unique piezoelectric-conductive hybrid enabled efficient charge generation under mechanical stress and rapid signal transmission, creating an intrinsic electroactive microenvironment without external power sources. A polydopamine coating was further employed to enable sustained NGF release, extending the bioactive window of the scaffold. In vitro cell experiments demonstrated this dual-electroactive platform synergistically enhanced Schwann cells myelination, and promoted neuronal differentiation and neurite outgrowth in PC12 cells. Mechanistically, the in situ generated electrical activity amplified NGF-induced intracellular Ca2+ influx, leading to sustained mitochondrial activation and elevated ATP production, providing the bioenergetic foundation for enhanced regeneration. In a rat 10 mm sciatic nerve defect model, the conduit effectively accelerated functional recovery, reduced muscle atrophy, and promoted axonal regeneration and remyelination, achieving outcomes comparable to autografts. This work demonstrated that maintaining sustained copresence of self-generated electrical cues and neurotrophic support within a fully resorbable platform effectively enhances peripheral nerve regeneration.

Female Drosophila melanogaster undergo a dynamic transition in sexual behavior, shifting from high receptivity to active rejection of courting males. While this post-mating switch is well characterized, the molecular mechanisms governing this plasticity remain incompletely understood. Here, we identify the conserved microRNA, miR-9a, as a critical regulator of this process. We show that miR-9a mutant females exhibit a premature rejection phenotype, mimicking the behavior of mated females, which is correlated with an aberrant overgrowth of adult body wall sensory neurons. We demonstrate that this neuronal phenotype is governed by a dual regulatory system. First, in a noncell autonomous mechanism, miR-9a expression in the epidermis is required to constrain sensory neuron dendrite growth, indicating that an epithelial-derived signal patterns the underlying neuron. Second, miR-9a interacts genetically with the transcription factor senseless (sens) and the novel RNA-binding protein bruno2 (bru2). Reducing the dosage of either sens or bru2 rescues both the neuronal and behavioral defects of miR-9a mutants. Our findings reveal an integrated, inter-tissue signaling axis where epithelial miR-9a orchestrates a noncell autonomous cue that modulates a cell-intrinsic network to ensure the precise development of sensory neurons, thereby calibrating behavioral responses critical for reproductive success.

Aquaporin 4 knockdown alleviates traumatic brain edema and reduces neuronal axonal growth cone collapse via the RhoA/ROCK pathway.

Peripheral nerve repair requires biomaterials capable of dynamically guiding neural cells. While stiffness-tunable hydrogels hold promise, how their mechanical properties translated into pro-regenerative intracellular signals remains poorly understood. To address gap, we developed a library of polyacrylamide/chitosan hydrogels with tunable stiffness (1.5∼39 kPa) to mimic the native neural microenvironment. Using this platform, we identified an optimal stiffness (∼13.75 kPa) that maximizes PC12 cell adhesion, spreading, neurite outgrowth, and migration. When fabricated into nerve guidance conduits and implanted in rat sciatic nerve defects, hydrogels with this optimal stiffness promoted axonal regeneration and functional recovery to a significantly greater extent than their softer or stiffer counterparts. Transcriptomic analysis further revealed coordinated upregulation of lysosomal and focal adhesion-related genes, with the lysosomal α-mannosidase Man2b1 identified as a core mechanosensitive regulator. We demonstrated that Man2b1 converts optimal matrix stiffness into enhanced lysosomal activity and stable nanoscale adhesion complexes (e.g., FAK, Vinculin). Importantly, genetic ablation of Man2b1 disrupted this mechano-transduction cascade and abolished the pro-regenerative effects of the optimized hydrogel both in vitro and in vivo. Collectively, this study establishes stiffness-engineered hydrogels as a robust platform for peripheral nerve repair and uncovers a fundamental mechano-transduction axis-the Man2b1-lysosome-adhesion signaling cascade-that governs neural regeneration. Our findings highlight how rational biomaterial design can precisely modulate cellular machinery to advance functional tissue engineering. STATEMENT OF SIGNIFICANCE: Peripheral nerve injuries often lead to permanent disability due to the limited regenerative capacity of adult neurons and the lack of biomaterials that can effectively guide repair. While substrate stiffness is known to influence cell behavior, translating this knowledge into effective nerve guides requires both identifying an optimal mechanical range and understanding the underlying cellular mechanisms. This study addresses this dual challenge by first engineering a tunable chitosan-based hydrogel platform to discover a pro-regenerative stiffness. More importantly, we leverage this material system to uncover a previously unknown mechano-transduction pathway-the Man2b1-lysosome-adhesion axis-that is essential for translating optimal mechanical cues into neuronal growth and regeneration. This work therefore provides not only a promising material strategy for advanced nerve guides but also a fundamental mechanobiological principle that could inform the design of biomaterials for a wide range of regenerative applications.

Graphdiyne-Ivy fiber neural scaffold promotes stem cell directed differentiation and neuronal maturation.

Consistent with differences in behaviors between sexes, studies reveal sex differences in the organization of neural circuits, synaptic function, and neuronal excitability, as well as sex-dependent recruitment of specific neuronal subtypes during behavior. These studies demonstrate sex differences in cell numbers, brain region volumes, cellular composition of brain areas, and density and strength of synapses in many brain regions, innervation of neuronal subtypes, receptor-mediated transduction mechanisms, neurotransmitter and neuropeptide release, and the influence of neuronal growth factors. Beyond insights into the mechanisms of sex differences in behaviors, understanding sex-typical circuit, cellular, and synaptic processes is crucial for identifying the causes of sex-typical vulnerabilities to nervous system disorders, such as the high prevalence of autism spectrum disorders and attention deficit hyperactivity disorder in males, and the higher incidence of affective, anxiety, and trauma-related disorders in females. Because these disorders often emerge during various developmental stages, it is essential to understand how development interacts with genetic, epigenetic, metabolic, hormonal, and environmental factors to affect the nervous system across sexes. Consequently, future research that examines the interaction between the nervous system and these critical factors is expected to elucidate the mechanisms underlying nervous system disorders. Additionally, targeting sex-specific mechanisms involved in these disorders could open new opportunities for more effective treatments in both sexes.

Chondroitin sulfate (CS) is an essential sulfated glycan in the brain, but standard LC-MS/MS disaccharide analysis provides only limited quantitative accuracy for detecting CS structural changes under physiological and pathophysiological conditions. Here, we incorporated eight distinct 13C-labeled CS disaccharide calibrants into the analytical workflow. Using this enhanced approach, we identified structural alterations in both sulfation patterns and total CS abundance in pre-clinical and clinical Alzheimer's disease (AD) brain samples compared with controls. Analysis of cerebrospinal fluid (CSF) from AD patients further revealed elevated levels of the CS-E disaccharide and reduced levels of hyaluronic acid. Functionally, we found that synthetic CS-E 19-mer-but not other synthetic CS 19-mer subtypes-impaired neuronal growth, underscoring the need to pinpoint specific CS structures that contribute to neurodegeneration. Because CS abnormalities are detectable in the pre-clinical AD brain, our findings raise the possibility that CS glycans could serve as early biomarkers for AD.

Primary neuronal cultures from the brain are critical for investigating disease-specific cellular and molecular mechanisms in mouse models. Current methods for obtaining primary cultures require embryonic brains that are affected by embryonic lethality and genotypic characterization in severe disease models such as sickle cell disease (SCD). Furthermore, these neuronal cultures require about 14 days in vitro (DIVs) for neurite outgrowth to mature. We adapted and optimized a relatively simplified and reproducible method using brains from postnatal day 1 mouse pups for isolating and culturing hippocampal and cortical neurons. This approach produces viable neurons that attach, extend neurites, and express key synaptic markers by 7 DIV and also minimizes glial outgrowth. We successfully applied this approach to isolating and culturing hippocampal and cortical neurons from the brains of one-day-old (P1) pups of humanized transgenic homozygous BERK sickle cell and control mice. Morphological observations at 3, 7, and 14 DIVs demonstrated robust neuronal attachment, neurite outgrowth, and overall structural development in both male and female hippocampal and cortical neurons. Neurons in culture expressed key markers including neuronal nuclear protein (NeuN/Rbfox3), neurofilament 200 (NF200), microtubule-associated protein 2 (MAP2), vesicular glutamate transporter 1 (VGLUT1), postsynaptic density protein 95 (PSD 95), and glutamate N-methyl-D-aspartate receptor subunit 2B (GluN2B). Notably, male SCD hippocampal neurons evinced a higher density of PSD 95 puncta on dendritic spines compared to controls on 7 as well as 14 DIVs. Incubation of male hippocampal neurons in a sickle cell-like microenvironment with TNF-α and heme further increased the density of PSD 95 puncta and colocalization of GluN2B with PSD 95, supporting the utility of this culture system for examining disease-relevant structural and molecular responses. This optimized culture system provides a simplified and reproducible platform to investigate the mechanisms involving neuronal dysfunction in challenging mouse models of brain disorders.