Supramedullary neurons (SMNs) are located on the dorsal surface of the hindbrain and spinal cord in many adults of teleost fishes. Comparative morphological studies have revealed differences in SMN size, number and distribution among fishes. However, little information exists on the projection patterns of SMN neurites within the central nervous system. We focus on a single species of adult teleost fish, the cunner, Tautogolabrus adspersus, a fish that has 25-46 SMN somata aligned dorsally along the midline in the hindbrain and rostral third of the spinal cord. Light and transmission electron microscopic techniques provide new information on the general morphology of SMNs and Lucifer yellow filled SMNs reveal that these neurons are not morphologically homogeneous. Rather, four different morphotypes can be identified based on projection patterns of major neurites in the hindbrain and spinal cord wholemounts. The morphological variations suggest that some SMNs exit the brain exclusively through the first dorsal root while others exit the central nervous system through a dorsal root and the trigeminal nerve. Despite the remarkable size and accessibility of SMNs, their function(s) remains unknown. One proposed role of these cells is eliciting mucous secretion in response to skin abrasion from predation. Variation in projection patterns in the cunner provides a morphological framework from which to design electrophysiological studies to help reveal SMN function.

Glioblastoma (GBM), the most common and lethal primary brain cancer, has a median survival of 15 months. Despite repeated efforts over 20 years to introduce life-extending therapies, little has changed in the standard of care. Recent studies have revealed that GBM cells express daily rhythms in gene expression and sensitivity to chemotherapy. In this review, we highlight the role of circadian biology in GBM growth, and its potential applications to GBM diagnosis and treatment. The hallmarks of cancer often show daily variation. We emphasize opportunities to advance our understanding of glioblastoma pathophysiology by considering how brain tumors integrate into the host circadian system and respond to daily rhythms in neuronal, paracrine, or hormonal signals to promote growth. Circadian treatment strategies include disrupting daily rhythms in GBM cells, blocking their synchronization to the host, or finding best times of day for biopsy, surgery, radiation, or chemotherapy. We discuss an ongoing temozolomide chronotherapy trial in the context of recent evidence against chronotherapy and suggest ways to critically assess time-of-day effects in GBM. With over 500 active clinical trials for GBM, it is time to evaluate, and control for, circadian rhythms in care for brain cancer patients.

Gene therapy can target specific brain regions and may be an effective therapeutic tool for drug-resistant epilepsy. Neuroligin 2 (NL2) is a postsynaptic cell-adhesion protein involved in the formation of inhibitory synapses. Since epileptic seizures are attributed to excessive brain neuronal activity, we hypothesized that NL2-mediated inhibitory signaling suppresses seizures. Male C57BL/6J mice were bilaterally injected into the hippocampus (HPC) with an adeno-associated virus (AAV) vector expressing NL2 under the control of synapsin I promoter (AAV-NL2). Mice treated with AAV-NL2 were intraperitoneally administered with 35 mg/kg pentylenetetrazol (PTZ) every other day. Ordinal logistic regression analysis revealed that NL2 expression exerted a protective effect against seizure progression induced by repeated PTZ administration. In addition, ventral HPC c-Fos protein levels were significantly suppressed with AAV-NL2 injection. NL2 expression induced by intra-HPC AAV-NL2 injection attenuates the progression of PTZ-induced seizures and may represent a potential target for seizure control.

The neuronal endoplasmic reticulum (ER) forms a continuous membrane network that extends throughout the soma, dendrites, axons, and synaptic compartments. Although traditionally viewed as a structurally continuous intracellular organelle, recent advances in volume electron microscopy, super-resolution imaging, and live-cell functional analyses have revealed that the ER is highly compartmentalized into specialized structural and molecular domains. These domains organize local Ca2+ release, store refilling, luminal Ca2+ redistribution, and inter-organelle communication through membrane contact sites, thereby enabling the diverse physiological functions of the ER. Emerging evidence further indicates that ER topology is a fundamental determinant of diverse ER functions and that disruption of ER architecture is increasingly implicated in the pathogenesis of neurological disorders. In this review, I first summarize the ultrastructural organization of the neuronal ER based on representative electron microscopy observations and then discuss how spatial compartmentalization provides an organizational principle linking ER structure to intracellular signaling, neuronal homeostasis, and neurological disorders.

With the acceleration of global population aging, early diagnosis and intervention of Alzheimer's disease (AD) and other neurodegenerative disorders have become major public health challenges. Olfactory dysfunction (OD) is increasingly recognized as one of the earliest clinical manifestations of AD, highlighting the importance of understanding the relationship between AD and olfactory impairment. This study integrates bibliometric analysis and genomic approaches to systematically characterize global research trends and explore potential molecular mechanisms underlying AD and OD from 2006 to 2025. Publications related to AD and OD were retrieved from the Web of Science Core Collection, and bibliometric analyses were performed using CiteSpace and VOSviewer, with results further validated through the Scopus database. A total of 1412 publications were identified, demonstrating sustained growth over the past two decades and a rapid expansion phase after 2019. The United States and China were the leading contributors in publication output and international collaboration, although research development remained geographically uneven. Keyword analysis revealed a gradual transition from behavioral and pathological investigations toward early diagnosis, biomarker discovery, therapeutic exploration, and advanced technologies. Genomic analysis identified 1838 shared genes between AD and OD, with key hub genes including AKT1, INS, and ALB involved in common biological pathways associated with neuronal function, cognitive regulation, and olfactory system homeostasis. This study provides a comprehensive overview of the evolving research landscape of AD and OD, identifies emerging trends and potential molecular targets, and offers valuable insights for early screening, mechanistic investigation, and translational research in neurodegenerative diseases.

The vomeronasal system (VNS) has been extensively associated with the regulation of sexual and social behaviors in mammals. In rodents, this system comprises two types of vomeronasal neurons sending parallel projections from the vomeronasal organ (VNO) to the anterior and posterior portions of the accessory olfactory bulb (aAOB and pAOB, respectively). Caviomorph rodents develop either a larger aAOB bias or a larger pAOB bias, which has been associated with ecological traits related to the pheromonal communication displayed by these species. However, it is still unknown how and when such AOB asymmetries emerge and whether experience may influence their establishment. To explore these factors, we studied the development of the VNS in Octodon degus, a caviomorph that exhibits an asymmetric AOB, in which the aAOB is larger and has more glomeruli than the pAOB. We found that both the VNO and the AOB are present at birth, but exhibit substantial immature traits. Both VNS structures develop postnatally, showing mature patterns by the end of the first postnatal month. By the second postnatal week, the aAOB becomes larger in size than the pAOB; however, in the glomerular layer, such a bias appears later, by the end of the first postnatal month. The AOB asymmetry increases in extent until adulthood, as in this period the pAOB shows a slower growth rate than the aAOB. Additionally, we found that animals raised in restricted social contexts displayed a reduced AOB asymmetry in comparison to wild degus. Overall, we suggest that social experiences contribute to the development of the AOB asymmetry in degus.

Alzheimer's disease (AD) is characterized by a progressive cognitive decline and pathological cascade involving amyloid-β (Aβ) plaque, hyperphosphorylated tau (pTau), neuroinflammation, and neurodegeneration. Although anti-amyloid antibody therapies have recently been approved, their clinical benefits remain limited and often accompanied with significant adverse effects. Physical activity has emerged as a promising non-pharmacological intervention for AD, with both aerobic and resistance physical activity showing beneficial effects in preclinical studies. However, the effects of different types of physical activity remain insufficiently understood. In this study, we investigated the effects of a forced treadmill running and ladder climbing physical activity procedure on cognitive behaviors, gliosis, and protein aggregate pathology in aged 3xTg-AD mice. Thirteen to fourteen months old 3xTg-AD mice were subjected to a six-week forced treadmill running and ladder climbing physical activity protocol. Cognitive functions were evaluated using the novel object recognition, Y-maze, and social behavior tests. Hippocampal and cortical tissues were analyzed by immunostaining for Aβ, pTau, Glial Fibrillary Acidic Protein (GFAP), Ionized Calcium-Binding Adapter Molecule 1 (IBA1), and inhibitory neuron markers. Our study demonstrated that the six-week forced treadmill running and ladder climbing physical activity procedure reduced age-associated cognitive declines in spatial working memory, object recognition memory, and sociability in aged 3xTg-AD mice. Such physical activity procedure also reduced Thioflavin S (Thio S) labeled misfolded protein aggregates and reactive gliosis in the cortex and/or hippocampus. Notably, forced treadmill running and ladder climbing physical activity procedure decreased Thio S positive neuropathology within somatostatin-positive interneurons of the hippocampus and cortex, indicating a cell-specific neuroprotective effect. Our results demonstrated that forced treadmill running and ladder climbing physical activity procedure produced significant behavioral and neuropathological benefits in aged 3xTg-AD mice, supporting physical activity as a promising non-pharmacological intervention for modulating gliosis and protein aggregate pathology in aging and AD.

The study by Wang and colleagues proposes that three connected brain areas link facial nerve injury to pain and depression-like behavior in mice. The experiments are ambitious and potentially important. However, the nerve-injury model differs from the defining pattern of human trigeminal neuralgia, several behavioral and drug controls leave alternative explanations open, and measurements from many cells were not clearly separated from the animals that supplied them. Clarifying these issues, and distinguishing results from whole tissue from results specific to neurons, would make the causal and clinical implications more secure.

Children and adolescents globally experience inadequate sleep, which harms their cognitive functions and emotional regulation. The role of circadian clock genes in influencing the antioxidant and anti-inflammatory capabilities has been well-established. Previous studies reported that the impairment of neural activity within the suprachiasmatic nucleus (SCN) can lead to anxiety-like behaviors in mice. Our study was designed to explore the role of BMAL1 expression in SCN, which could be responsible for anxiety-like behaviors induced by chronic sleep restriction (SR) in young mice. Here, 5-week-old male mice were divided into four groups (CONGFP, CONAAV, SRGFP, SRAAV), with chronic sleep restriction applied to the SRGFP group for 4 weeks using an automatic sleep restriction system. Meanwhile, the SRAAV group received AAV injections overexpressing BMAL1 in the SCN before sleep restriction. Anxiety-like behaviors were assessed through the elevated cross-maze and three-box social experiments. In the SRGFP group, there was a significant reduction in the number and duration of mice entering the open arm and the S2 chamber, which was further reduced by BMAL1 overexpression. Mechanistically, BMAL1 compensated for synaptic plasticity damage in the medial prefrontal cortex (mPFC) by upregulating the MAPK-induced inflammatory response, increasing the SOD level, and reducing the MDA level, ultimately restoring BDNF signaling. The study concludes that sleep restriction induces anxiety-like behaviors and impairs synaptic plasticity in the mPFC due to inflammation. Strengthening the molecular clock by BMAL1 overexpression in the SCN alleviated these effects during chronic sleep restriction.

Developmental dynamics involve the specification of diverse cell types and their spatial organization into multicellular niches1. Here we combine single-cell and spatial multiomics to define 21 distinct tissue niches in the developing heart, which we use to develop a context-aware, resolution-agnostic niche classification tool (TissueTypist). Applying high-resolution spatial profiling to the developing sinoatrial node, we resolve three pacemaker cell subtypes arrayed along a linear axis. First trimester subpopulations, such as pacemaker cells in the sinus horn and sinoatrial node head region, display neuroattractant programs and interact with parasympathetic neurons via interactions that include Eph-ephrin and semaphorin-plexin signalling. Temporal trajectories map the maturation of atrial and ventricular cardiomyocytes and uncover a lipid-metabolic switch and potential key regulators of cell-type identity. In the ventricle, we identify cellular and transcriptional gradients along both pseudotime and transmural axes, which provide molecular insights into myocardial compaction and maturation. Comparative profiling revealed that hearts with trisomy 21 are depleted in compact cardiomyocytes and exhibit increased apoptosis relative to euploid hearts. This finding was validated in isogenic-matched trisomy 21 and euploid cardiomyocytes derived from induced pluripotent stem cells. These early developmental perturbations may contribute to the increased risk of congenital heart disease associated with Down's syndrome. In summary, we present a spatially resolved framework of human cardiac development to enable systematic explorations of developmental niches in health and disease.

Recurrent attractor networks are widely thought to form the basis of working memory1-3, but how they can be rapidly switched on and off is unclear4-7. Here we investigate stability and switching in a recurrent circuit of the fly navigation centre8. h∆K and PFG neurons are recurrently connected in a ring structure and exhibit shared persistent bump activity that turns on with odour and terminates at the end of a goal-directed run. Using whole-cell recordings, we show that persistence in h∆K depends on recurrence, and that h∆K receives slow recurrent excitation and fast inhibition from its synaptic partners. Computational modelling reveals that these synaptic dynamics yield persistent attractor dynamics over a range of synaptic strengths. Next we examine the mechanisms of rapid switching. We find that whereas both populations show similar activity during runs, they become decoupled during turns and rest. We can reproduce these differential dynamics in our model by using inhibition to dynamically uncouple activity in h∆K from PFG. When h∆K is inhibited, PFG neurons follow their inputs from the compass system; when h∆K is disinhibited, recurrent interactions lock this input into place, forming a heading memory. Consistent with this model, we find that inhibitory inputs onto h∆K increase during turns and are suppressed during odour and goal-directed runs. Our work reveals how disinhibition can serve as a gate to rapidly write an ongoing measurement to a recurrent circuit.

Disrupted axonal transport and astrocyte dysfunction are implicated in amyotrophic lateral sclerosis (ALS). Here we show these processes are linked-human-induced pluripotent stem-cell-derived astrocytes carrying the C9ORF72 mutation disrupt mitochondrial axonal transport and mitochondrial function in cocultured motor neurons (MNs). Conversely, isogenic gene-corrected astrocytes or boosting astrocytic mitochondrial bioenergetics rescue axonal mitochondrial transport deficits in C9ORF72 MNs. Our results delineate a non-cell-autonomous role for astrocytes in regulating mitochondrial transport along axons in ALS models.