Biology and Life Sciences

Abstract: The glymphatic system is a brain-wide perivascular network that facilitates cerebrospinal fluid-interstitial fluid exchange and the clearance of metabolic waste. Growing experimental and clinical evidence suggests that glymphatic dysfunction may represent a convergent upstream mechanism linking aging, neuroinflammation, and neurodegeneration. In this narrative review, we synthesize human imaging, clinical, and translational evidence implicating glymphatic dysfunction across major neurodegenerative diseases and integrate these findings with emerging data supporting its role in chronic low-grade inflammation associated with aging (inflammaging). We further discuss how alterations in the gut microenvironment may remotely influence glymphatic function and contribute to neurodegeneration through the gut–brain axis. Although supported by extensive preclinical evidence, studies in humans increasingly demonstrate impaired glymphatic function in several neurodegenerative disorders, most assessed using diffusion tensor imaging along the perivascular space (DTI-ALPS) index. Glymphatic dysfunction is associated with cognitive decline, motor impairment, and disease progression. Aging-related alterations in astrocytic function, aquaporin-4 polarization, blood-brain barrier integrity, and perivascular fluid dynamics provide mechanistic links between inflammaging and glymphatic failure. Gut dysbiosis may further exacerbate these processes by promoting central nervous system inflammation and vascular dysfunction. Together, these findings identify the glymphatic system as a clinically relevant pathway in neurodegeneration that may be regulated by aging-associated neuroinflammatory mechanisms involving the gut-brain axis. Finally, we discuss lifestyle factors that influence glymphatic function and propose a unified framework positioning glymphatic dysfunction as a central integrator of impaired brain clearance, with potential implications for biomarker development, clinical assessment, and disease-modifying therapeutic strategies in neurodegenerative disorders.

Abstract: Objectives: Amplitude rise time (RT) is a critical acoustic cue for speech perception, playing an important role in auditory processing of both speech and non-speech sounds. This study examined neurophysiological processing of RT in children with autism spectrum disorder (ASD) compared to typically developing (TD) peers. Methods: EEG was recorded during passive presentation of pure tones with five RT values (15, 30, 60, 120, 240 ms) in 42 children (ASD: n = 21, TD: n = 21, aged 4–10 years). Linear mixed models were used to analyze latencies and amplitudes of P1 and N2 components of event-related potential. Results: Children with ASD and TD peers showed distinct patterns of neural modulation across RTs. TD children show general increase in latency and decrease in amplitude of ERP components with increase in RT. While this pattern holds for P1 latency also for children with ASD, P1 amplitude was reduced in ASD compared to TD peers specifically at shorter rise times (15–60 ms), indicating weaker encoding of rapid acoustic onsets. For N2 latency children with ASD showed an atypical drop at 60 ms compared to 30 ms RT. P1N2 amplitude reached its minimum at 60 ms RT in ASD contrasting systematic decrease from 15 to 240 ms RT in TD. Conclusions: Together, these findings suggest that children with ASD show a less systematic pattern of neural modulation across the rise time continuum, particularly in the range of rapid acoustic onsets (15–60 ms), while processing of more gradual onsets remains relatively intact.

Abstract: Chronic neurophysiology studies using Rhesus macaques (Macaca mulatta) often require implanting cranial hardware, including headposts, recording chambers, and screws. Unfortunately, a macaque’s instinct to scratch and groom around these cranial devices has the potential to result in retraction of skin from implant margins, chronic inflammation, and regional or even systemic infections that negatively impact animal well-being and can sometimes necessitate early removal from the study. Current literature on chronic cranial implant care primarily advocates topical treatments, which may exacerbate these scratching and grooming behaviors. To address these challenges, we tested the use of 3D printed caps designed to protect cranial implants. These caps aim to mitigate the adverse effects associated with these undesirable behaviors by providing a detachable physical barrier that does not interfere with research objectives. We designed and developed 3D printed head caps that securely attach to a headpost, covering cranial implants and surrounding tissue margins. With a carbon fiber 3D printer, we created more durable caps and connector pieces that are also autoclavable. Caps are secured to the headpost using two screws that are easily removed prior to each chaired recording session. These caps can prevent the animal from physically interacting with cranial implants, improving surgical healing in the short term, and preventing potential complications over extended periods.

Abstract: Background: Many neurological and cognitive disorders have early oculomotor hallmarks. The Oculo-Cognitive Addition Test (OCAT) is a quick, objective screening tool that measures eye movement and time-based biomarkers of cognitive processing during simple mental addition tasks in under two minutes. Normative values for age, sex, education level, and genetic predisposition to Alzheimer’s disease must be established so cognitively normal populations are not misdiagnosed. Methods: 382 patients completed OCAT, and raw gaze data were processed to derive fixations, saccades, blinks, pupillary dynamics, and time-based features. Separate multiple linear regression models were fitted for each feature with age, sex, education, and apolipoprotein E Type 4 (APOE ε4) carrier status as predictors to establish demographic-adjusted normative equations. Results: Processing time, fixation time, fixation size and fixation area and their variability increased progressively from the first to the third number within each addition sequence, consistent with increasing cognitive workload. Demographic-adjusted multiple linear regression models generated normative equations for individual OCAT feature based on age, sex, education, and APOE ε4 carrier status. These models were used to derive individualized expected values, 95% reference intervals, and z-scores. Conclusions: These demographic-adjusted normative equations enable individualized interpretation of OCAT performance and are necessary steps towards clinical implementation.

Abstract: The retinal neurovascular unit (NVU) is not assembled by endothelial cells alone. It emerges through overlapping developmental interactions among neurons, astrocytes, Müller glia, microglia, endothelial cells, pericytes, extracellular matrix and blood flow. These interactions are often inferred from the postnatal mouse retina, yet human retinal vascularization follows a different developmental logic: the early central circulation has substantial histological and immunophenotypic evidence for vasculogenesis from resident vascular precursors, whereas later peripheral and intraretinal expansion proceeds mainly by angiogenesis. Laminar order also differs: the mouse develops superficial, deep and then intermediate plexuses, whereas comparative primate histology supports a superficial, intermediate and then deep sequence, with the clearest fetal timing resolved in macaque and human maturation extending after birth. Here, we integrate species-resolved anatomy with causal developmental studies to explain how vascular growth, perfusion, pruning and inner blood–retinal barrier (iBRB) maturation are coordinated but separable. Retinal ganglion cell axons and astrocytes organize the superficial interface; extracellular matrix, VEGF, Dll4–Notch, endothelial metabolism and haemodynamic forces regulate sprouting and remodelling; microglia refine astrocytic and neuronal populations and influence vascular topology; neural activity and Müller-cell relays direct laminar angiogenesis; and Norrin–FZD4–β-catenin signalling, suppression of caveolar transcytosis, pericyte recruitment and endothelial zonation establish barrier competence. We distinguish causal perturbation from depletion-associated effects, pharmacology, spatial association and hypothesis. We then benchmark fetal tissue, animal models, organoids and stem-cell-derived vascular systems against the functions they claim to reproduce. This framework focuses disease translation on retinopathy of prematurity and inherited Norrin-pathway vasculopathies, in which developmental timing and barrier specialization are central. The resulting synthesis defines five principles: species and compartment specify mechanism; multicellular relays matter; growth, perfusion and barrier acquisition are distinct outputs; refinement is active; and reciprocal stabilization is limited by developmental state and time.

Abstract: Tryptophan (Trp) metabolism plays a central role in neuroimmune communication, integrating immune, metabolic, endocrine, and neural responses. In addition to serving as a precursor for serotonin and melatonin biosynthesis, Trp is metabolized by both host cells and the gut microbiota, generating bioactive metabolites that influence gut homeostasis, immune regulation, and brain function. Approximately 95% of free Trp is metabolized via the kynurenine pathway through indoleamine 2,3-dioxygenase-1 (IDO-1) and tryptophan 2,3-dioxygenase (TDO), a pathway considered inflammatory, producing neuroactive metabolites such as kynurenine (KYN), quinolinic acid (QUIN), kynurenic acid (KYNA), and 3-hydroxykynurenine (3-HK). In parallel, a portion of intestinal tryptophan is converted by the gut microbiota into indole and indole-derived metabolites, including indole-3-acetic acid (IAA), indole-3-propionic acid (IPA), and indole-3-aldehyde (IAld). These microbial metabolites contribute to intestinal barrier integrity, immune homeostasis, and gut-brain axis signaling, primarily through activation of the aryl hydrocarbon receptor (AhR). Growing evidence indicates that inflammatory signals mediated by Toll-like receptors (TLRs), interferon-gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), and interleukin-1 beta (IL-1β) induce IDO-1 activity, redirecting tryptophan metabolism to the kynurenine pathway and promoting the accumulation of neurotoxic metabolites at the expense of neuroprotective indole-derived compounds. Furthermore, environmental factors such as heavy metals, pesticides, air pollutants, and microplastics can trigger gut dysbiosis and neuroinflammation, thus disrupting tryptophan metabolism and gut-brain communication. This review discusses the mechanisms by which TLR activation, environmental toxins, gut dysbiosis, and dysregulation of the kynurenine and indole pathways contribute to neuroinflammation and neurodegeneration. Additionally, we highlight emerging therapeutic targets, including IDO-1 inhibitors and modulation of kynurenine monooxygenase (KMO), sensitization of AhR, GPR35, and microbiota-derived metabolites, as promising strategies for the prevention and treatment of neurodegenerative disorders.

Abstract: Microglia encounter combinations of soluble, membrane-bound and mechanical signals whose meaning changes with anatomical niche, developmental or disease stage, receptor state, metabolism, sex and prior experience. Yet most mechanistic studies isolate one ligand–receptor pair, and the term signal integration is often applied to evidence that demonstrates only co-expression or context dependence. Here, we define direct integration as a functional interaction between two or more experimentally manipulated inputs and distinguish it from sequential or multicellular relays, context dependence, coexistence and hypothesis. We then organize the literature around microglial decisions: where to position a process or cell; whether a contacted structure is a target; whether to internalize and degrade it; and how an executed function changes later state and output. The clearest direct example is noradrenergic antagonism of ATP–P2Y12-directed movement. In adolescent mesofrontal plasticity, dopamine-receptor signalling and P2Y12 are both required for enhanced microglial surveillance and bouton formation, although their direct interaction remains unresolved. Strong directional and reciprocal relays include astrocyte-derived IL-33 control of developmental engulfment, activity-gated microglia–astrocyte Wnt signalling, an injury-calibration circuit in which astrocytic ATP recruits tunable microglial IL-1β feedback, perivascular SPP1 control of a complement-linked phagocytic state, and MerTK-triggered TGF-β1 autocrine feedback. By contrast, dose-dependent IL-34 effects, sex-dependent TREM2 phenotypes and circuit-restricted complement requirements establish context dependence rather than cue–cue integration. We also identify major blind spots: two-signal inflammasome logic, GABA-receptive microglia, mechanical sensing, human-state validation and the frequent inability of static microscopy to distinguish engulfment from trogocytosis or scavenging. An evidence-graded framework exposes how few microglial cue combinations have been tested factorially and provides standards for converting spatial or single-cell predictions into causal, functionally interpretable mechanisms.

Abstract: Traditional calcium (Ca²⁺) imaging analysis often overlooks the non-stationary temporal complexity inherent in retinal circuits, reducing dynamic signals to static descriptors. In this study, we implement a transformative framework integrating continuous wavelet analysis with unsupervised machine learning to decode the rhythmic functional signatures of retinal neurons and Müller glial cells (MGCs) across avian and human models. We identify distinct operational subpopulations for neuronal and glial clusters that serve as the fundamental building blocks for retinal light processing in terms of Ca²⁺ mobilization under physiological conditions after blue light stimulation.Our results reveal a stark operational dichotomy dictated by cluster-specific kinetic regimes. Retinal neurons function as high-fidelity "digital" processors, exhibiting immediate phase-resetting and transitioning from a stochastic basal state into a centralized pacemaker hierarchy led by a stable homeostatic core. In contrast, Müller glial cells emerge as "analog" metabolic integrators, maintaining a decentralized autonomous mosaic. This glial network utilizes its kinetic heterogeneity to process the light stimulus across staggered temporal windows. We propose that this glial response is driven by a regulatory mechanism involving intrinsic opsin-dependent cascades (Opn3/Opn5). Notably, the first-time characterization of human-specific ultra-slow rhythms (>100 s) in the human MIO-M1 cell line highlights an increased kinetic complexity in the human model. These findings establish that retinal identity is fundamentally rhythmic and cluster-dependent, providing a novel benchmark for understanding how the healthy retina maintains functional integrity through calibrated network strategies.

Abstract: Spongiform degeneration, or status spongiosis, is characterized by vacuoles within the central nervous system. It appears in numerous neurological diseases, including trans-missible spongiform encephalopathies, mitochondrial disorders, and lysosomal storage diseases. Traditionally considered secondary to neurodegeneration, vacuolar changes frequently involve white matter and form within the myelin sheath. This review ex-amines the evidence from various diseases and genetic models that exhibit this pathology to support the hypothesis that white matter vacuolation represents a myelin defect, and explores potential causative mechanisms. Our findings suggest that spongiform change in white matter represents a common endpoint of pathway disruptions that lead to metabolic or ionic dyshomeostasis, causing an osmotic imbalance and vacuole formation within myelin. We advocate for further research into myelin-preserving pathways as potential therapeutic avenues to treat conditions exhibiting this pathology.

Abstract: Heart-rate variability (HRV) tracks sleep stages in real time, with parasympathetic dominance concentrated in slow-wave sleep (SWS) and attenuated during REM sleep. Evidence indicates that this coupling is causally, not merely correlationally, linked to post-exercise cardiac autonomic recovery: enhancing slow-wave activity increases parasympathetic HRV, sleep restriction disrupts nocturnal autonomic state directly, and post-exercise vagal reactivation is depressed on nights following intense exercise, localized to the SWS stage. This review synthesizes the literature into a framework in which SWS functions as a physiological gate for post-exercise autonomic recovery, integrating brainstem circuitry and neurotransmitter systems, causal manipulations (acoustic, pharmacological, deprivation-based), exercise dose-response, and boundary conditions (age, sex, training status, sleep, and cardiovascular disorders) under which the coupling is preserved, attenuated, or absent. The gating effect is graded and window-specific rather than uniform: robust in the early post-exercise reactivation phase and during nocturnal SWS, but not established across the full multi-hour recovery curve. The framework is translated into falsifiable predictions and candidate study designs, including a critical appraisal of the validity of wearable and nearable sleep-tracking. Two evidentiary gaps are transparently addressed: the human circuit-level mechanism remains largely inferred from rodent work, and independent citation-network verification is not feasible for all foundational sources.

Abstract: Introduction: Cognitive dysfunction ("brain fog") is a common manifestation of post-acute COVID-19 syndrome (PACS) and may persist long after the acute infection. While cross-sectional studies have described cognitive deficits, longitudinal evidence on recov-ery trajectories remains limited. Methods: We conducted a longitudinal observational study of neurocognitive performance and neuropsychiatric symptoms in patients with PACS. Participants underwent assessment with 20 standardized tests covering five cogni-tive domains (memory, attention, language, executive functions, psychomotor processing speed); anxiety, depression, and sleep quality were assessed at three time points. Changes were analysed using the Friedman test. Results: Forty-two patients were included (median age 57 years; 35.7% female) from a predominantly hospitalized cohort (81% hospitalised; 66.7% requiring respiratory support). Comparison with non-completers (n=544) showed that completers were more severely ill during the acute phase rather than healthier or more motivated. Significant improvements over time were observed in verbal short-term learning, visuospatial memory, working memory, constructional praxis, phonological verbal fluency, and psychomotor processing speed (all p≤0.05). Sleep quality also im-proved (p< 0.0001). Conclusion: Patients with PACS may show gradual, heterogeneous and domain-specific cognitive improvement, with persistent deficits in a proportion of in-dividuals. These findings highlight the importance of long-term neuropsychological mon-itoring and integrated cognitive-psychiatric evaluation in post-COVID care. Given the small, predominantly hospitalized sample, improvements should be interpreted cau-tiously and confirmed in larger controlled studies, although alternate test forms make practice effects unlikely.

Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β plaques, neurofibrillary tau tangles, neuroinflammation, and progressive cognitive decline. Beyond these classical pathological features, emerging evidence implicates microbial dysbiosis as a contributing factor, with the gut and oral microbiomes currently providing the strongest evidence for microbiome AD associations. In contrast, the ocular microbiome represents a biologically plausible but largely unexplored candidate whose potential contribution to AD pathogenesis remains hypothetical and requires rigorous investigation. The ocular surface shares embryological, anatomical, and functional connections with the central nervous system, and the retina has emerged as a non-invasive window into neurodegenerative brain changes. Bacterial taxa detected in ocular specimens, including Cutibacterium acnes and Acinetobacter johnsonii, overlap with those reported in some studies of AD brain tissue, prompting speculation about an ocular–brain microbial interface. However, this overlap does not establish microbial trafficking, and no direct evidence currently supports the proposition that ocular microorganisms translocate to, colonize, or contribute causally to AD brain pathology. This review critically appraises the existing evidence, graded by methodological rigor and evidence strength, across gut, oral, nasal, ear, and ocular microbiome compartments. We address the substantial methodological challenges inherent in low-biomass microbiome research, emphasize the importance of distinguishing contamination artifacts from biological signals, and delineate the evidence gaps that separate association from causation. We conclude by proposing a research framework that places the ocular microbiome as an emerging hypothesis warranting experimental validation, rather than an established contributor to AD.

Abstract: Autism’s social signs vary widely: absence of declarative pointing, palm-reversed waving, reduced joint attention, and difficulty locating oneself relative to others. These are usually studied as separate deficits. I propose they share one upstream source.The entorhinal–hippocampal system encodes space through a hexagonal grid-cell code. Recent work shows this code also represents non-spatial and social information. I hypothesize that a distorted grid code in the entorhinal–hippocampal system is an upstream source of a coherent cluster of autism’s social features, supplying incorrect coordinates to downstream regions that depend on it, including the temporoparietal junction (TPJ), a central node in self–other distinction and perspective transformation. If the coordinate input is faulty, the TPJ cannot reliably compute this distinction. On this account, autism’s social signs are downstream effects of a single disrupted coordinate system rather than independent failures.I review the evidence linking grid codes to social and conceptual representation, connect it to reported TPJ differences in autism, and derive falsifiable predictions. Because this circuit is metabolically costly, I link the proposal to the energy-deficit framework of autism: a high-demand system is one that an energy shortage would compromise early. Identifying what disrupts the grid code is a key entry point to autism’s root etiology.

Abstract: Perfusion impairment is one of the major barriers to using machine perfusion to prepare brain tissue for research and clinical applications. As ischemia progresses, multiple mechanisms, including intravascular obstructions, perivascular cellular edema, mural cell contraction, and vessel wall breakdown, progressively limit the uniform delivery of preservative solutions. This problem is particularly important for connectomics, wherein successful preservation requires both widespread distribution of preservative chemicals and the maintenance of the cellular ultrastructure needed for circuit reconstruction. We conducted a narrative review of interventions used to ameliorate perfusion impairment across multiple fields, including organ transplantation, resuscitation medicine, forensic pathology, embalming, and neuroscience. We evaluated the evidence for these approaches in their original contexts and considered their potential application for brain banking aimed at preserving tissue for connectome reconstruction. We classify interventions into several categories, including anticoagulants, fibrinolytics, vasodilators, washout solutions, surfactants, osmotic agents, colloids, hypothermia, and perfusion pressure optimization. Many of these interventions have the potential to improve perfusion, but each also carries tradeoffs that may adversely affect tissue preservation. As connectomics advances toward profiling larger volumes of human brain tissue, overcoming perfusion impairment is likely to become an increasingly important challenge. This review provides a mechanistic framework for evaluating existing interventions and guiding the development of future perfusion protocols.

Abstract: Human vision is profoundly non-uniform. Spatial resolution, contrast sensitivity, colour discrimination decrease, and the appearance of visual features become increasingly distorted with retinal eccentricity, yet visual experience appears remarkably rich and stable across the entire visual field. This apparent paradox has been a central challenge in vision science: how can a perceptually rich world emerge from a sensory system that samples only a small fraction of the environment with high precision? We argue that the apparent richness of peripheral vision cannot be explained solely by cognitive biases. Instead, it reflects genuine perceptual processes. Information sampled in central vision can be extrapolated to peripheral appearance, while prior knowledge and learned regular-ities allow the visual system to infer missing or distorted peripheral information. These processes operate within the constraints of active vision, where eye movements selectively sample task-relevant information rather than building a complete detailed representation of the scene. We propose that rich peripheral experience emerges from the interaction between centre to periphery extrapolation, and learned predictions, allowing the visual system to maintain a coherent and useful representation of the world.

Abstract: Methamphetamine (METH) is a known proinflammatory agent; however, the impact of inflammasomes on its neurotoxic effects is not fully understood. In the present study, we assessed the impact of a prolonged METH administration on the hippocampal inflammasome profile in male and female mice and determined alterations of inflammasome profile in response to METH. In addition to inflammasome activation, METH induced both systemic and hippocampal-specific inflammatory responses, leading to cognitive impairments, reduced hippocampal cell proliferation, and altered proteomic profiles. Importantly, the responses to METH exposure exhibited important sexual dimorphism. Treatment with inflammasome inhibitor MCC950 attenuated METH-induced inflammatory events; however, we also observed several off-target effects of this inhibitor affecting mouse anxiety-like behavior and cognitive functions. Overall, our results indicate the preventive potential of MCC950 in METH-related neurotoxicity, while underscoring its limitations due to distinct sex-dependent differences in response to both METH and MCC950 and highlighting significant sexual dimorphism.

Abstract: DNA methylation is a key regulator of epileptogenesis. Sarcosine, a glycine transporter 1 (GlyT1) inhibitor and methyl donor, suppresses kindling-induced epileptogenesis and alters hippocampal DNA methylation, but its locus-specific epigenetic effects remain poorly understood. Here, reduced representation bisulfite sequencing (RRBS) was combined with targeted gene expression analysis in the hippocampus of sarcosine-treated kindled rats. RRBS identified 563, 533, and 390 differentially methylated regions (DMRs), corresponding to 521, 499, and 374 DMR-associated genes, in vehicle-kindled versus sham (vKD vs vSH), sarcosine-kindled versus sham (sKD vs vSH), and sarcosine-kindled versus vehicle-kindled (sKD vs vKD) comparisons, respectively. Pathway enrichment analysis identified 217 significantly affected pathways, including glutamatergic signaling, extracellular matrix (ECM) organization, chromatin regulation, axon guidance, and apoptotic processes. Eleven candidate genes involved in epigenetic regulation, excitatory neurotransmission, and ECM remodeling were selected for transcriptional validation. All 11 genes were significantly upregulated in kindled hippocampi, whereas sarcosine normalized expression of eight genes (Hdac9, Fos, Smad7, Unc5a, Grik2, Gpr37l1, Cacna2d2, and Yy1) toward control levels. Collectively, these findings indicate that sarcosine remodels DNA methylation-associated transcriptional networks during epileptogenesis and support GlyT1 inhibition as a potential disease-modifying strategy for epilepsy.

Abstract: Neurotoxicity is generally thought to result from exogenous agents like environmental chemicals, drugs and biological toxins. However, increasing evidence suggests that many endogenous molecules that play a critical role in normal brain function can become neu-rotoxic when the regulatory mechanism involved in their production, metabolism, com-partmentalization and clearance are disrupted. This shift underlies the basis of endoge-nous neurotoxicity. This review discusses the major endogenous sources of neurotoxicity: metabolic neuro-toxins, dysfunctional neurotransmitters, protein aggregates and inflammatory mediators. These endogenous factors arise from different physiological pathways, but share common pathogenic mechanisms, all of which involve an underlying state of oxidative stress, mi-tochondrial dysfunction, impaired proteostasis, excitotoxic signalling, neurovascular dysfunction and maladaptive neuroglial responses. This is not a singular process but a network of interconnected processes, which work together to progressively diminish neu-ronal resilience and promote synaptic dysfunction and neurodegeneration. The review also underscores the critical role of astrocytes, microglia and other glial cells in the maintenance of neuronal homeostasis. By integrating diverse endogenous neurotoxic pathways within a unified homeosta-sis-centred framework, this review provides a broader perspective on the mechanisms linking metabolic disorders, aging and neurodegenerative diseases. This framework sug-gests that effective therapeutic strategies may require restoration of physiological regula-tory networks rather than targeting individual neurotoxic molecules in isolation. A sys-tems-level understanding of endogenous neurotoxicity may therefore facilitate the devel-opment of earlier biomarkers and more effective interventions aimed at preserving neu-ronal homeostasis and preventing progressive neurological dysfunction.

Abstract: The basal amygdala (BA) nuclei (basal nucleus and accessory basal nucleus) have been proposed as an emotional sensory gateway that evaluates the environmental significance of stimuli, processes both threats and rewards, is involved in translating those experiences into memories, guiding both emotional responses and goal-directed behaviors. BA circuits mature during adolescence, and alterations in this process during this critcal period have been proposed to be related to the emergence of stress-related psychiatric disorders. Understanding the molecular factors driving normal amygdala development may yield insight in the underlying pathological mechanisms of these disorders. So far however, there is no data on the cell type specific molecular changes occurring in BA during this developmental period in human or primates. To address this gap, we performed single nucleus RNA sequencing (snRNA-seq) of the BA from 68 pre- and periadolescent rhesus macaques. We identified 29 cell types including neuronal and glial cell types as well as cells mapping to the intercalated nuclei, confirming and extending previous analyses. The gene expression profiles of the BA showed limited but robust association with circulating cortisol levels, underlining the role of the BA in stress processing. Importantly, we observed 158 genes across 16 cell types to be significantly associated with developmental age, with pathway enrichment analyses supporting a broad downregulation of cell adhesion programs and associations with synaptic pruning pathways. Genes showing age-associated expression were significantly enriched for genetic risk loci underlying a hierarchical general psychopathology (“p”) factor derived from psychiatric GWAS, with a further, more lenient-threshold overlap emerging for an internalizing-specific factor. Because this developmental window coincides with the peak onset of several psychiatric disorders, these findings from a nonhuman primate model support a link between developmentally regulated amygdala gene expression and risk for stress-related psychopathology. The findings also highlight the relevance of primate models in understanding neurodevelopmental risk factors for psychiatric illnesses.

Abstract: Spinal cord injury (SCI) is a devastating neurological condition characterized by irreversible primary damage followed by a complex secondary injury cascade involving oxidative stress, neuroinflammation, iron dysregulation, and regulated cell death. Among these mechanisms, ferroptosis a distinct, iron-dependent form of regulated cell death driven by lipid peroxidation and redox imbalance is increasingly recognized as a critical mediator of neurodegeneration after SCI. The miRNAs play essential roles in neural injury responses by modulating inflammation, oxidative stress, and cell death pathways. Growing evidence indicates that miRNAs closely regulate ferroptosis-related signaling networks following SCI, influencing key molecular targets including iron metabolism, antioxidant defense systems, and lipid peroxidation pathways. Conversely, ferroptotic stress may alter miRNA expression profiles, suggesting a bidirectional regulatory relationship. In addition, ferritinophagy a selective autophagy pathway degrading ferritin via nuclear receptor coactivator 4 (NCOA4) has emerged as an important yet underexplored regulator of intracellular iron homeostasis and ferroptosis susceptibility in SCI. This review systematically summarizes current evidence on the molecular mechanisms linking miRNAs and ferroptosis in SCI, highlights how miRNA-mediated regulation of ferroptosis contributes to neuronal death, glial responses, and impaired regeneration, and discusses emerging therapeutic strategies targeting this axis to promote neuroprotection and functional recovery. By integrating recent experimental findings, we aim to provide mechanistic insight and identify translational opportunities for miRNA and ferroptosis-based interventions in SCI.