Background/Objectives: Mild traumatic brain injury (mTBI) is common and may result in persistent cognitive and affective disturbances driven, at least in part, by delayed secondary injury mechanisms, including oxidative stress, neuroinflammation, apoptosis-related signaling, and impaired neuroplasticity. Pharmacological strategies targeting these interconnected processes remain limited. The present study investigated leucovorin, also known as folinic acid, a clinically approved reduced folate, as a potential repurposing candidate in an experimental model of mTBI. Methods: Male Wistar rats were subjected to mild diffuse brain injury using a modified weight-drop model and received a single intraperitoneal dose of leucovorin (20 mg/kg). Behavioral performance was evaluated using the open field, elevated plus maze, forced swim, and novel object recognition tests. Oxidative stress markers, including total antioxidant status (TAS), total oxidant status (TOS), and oxidative stress index (OSI), as well as inflammatory mediators tumor necrosis factor-α (TNF-α) and cyclooxygenase-2 (COX-2), caspase-3, brain-derived neurotrophic factor (BDNF), and acetylcholinesterase (AChE), were measured in hippocampal tissue and plasma. Histopathological and immunohistochemical evaluations were also performed in cortical and hippocampal regions. Results: Experimental mTBI was associated with anxiety-like and depressive-like behaviors and impaired recognition memory, whereas basal locomotor activity was not significantly altered. Trauma was also associated with increased oxidative stress, elevated inflammatory and apoptosis-related markers, reduced BDNF levels, altered AChE activity, and histopathological abnormalities. Compared with untreated mTBI animals, leucovorin-treated animals showed attenuation of biochemical and tissue alterations, accompanied by improved behavioral outcomes. Immunohistochemical findings were consistent with reduced inflammatory labeling and relative preservation of tissue architecture following leucovorin treatment. Conclusions: Leucovorin attenuated behavioral, biochemical, histopathological, and immunohistochemical alterations associated with experimental mTBI. These findings suggest that leucovorin may have neuroprotective potential in this setting; however, further studies are needed to clarify the underlying mechanisms, optimal treatment paradigms, and translational relevance.
Long-COVID, also referred to as post-acute sequelae of COVID-19 (PASC), is a heterogeneous disorder encompassing more than 200 reported symptoms that commonly affect the respiratory and nervous systems. Emerging clinical evidence indicates that unresolved lung inflammation, vascular injury, and immune dysregulation drive sustained neuroinflammation and impaired neurocognitive function in Long-COVID patients. Given the ethical and logistical constraints of human studies, biologically relevant animal models are essential for understanding the mechanisms and for evaluating therapeutic strategies against Long-COVID. In this review, we synthesize current evidence from preclinical animal models of Long-COVID, with a particular emphasis on the Golden Syrian Hamsters. Golden Syrian Hamsters are naturally susceptible to SARS-CoV-2 infection without the need for genetic modification and recapitulate key features of human disease, including robust viral replication, pulmonary pathology, and inflammatory response during acute infection. Importantly, accumulating evidence demonstrates that Golden Syrian Hamsters develop persistent post-acute abnormalities along the lung-brain-immune axis, including impaired alveolar repair, fibrotic lung remodeling, neuroinflammation, viral or antigen persistence, and behavioral alterations that parallel core features of Long-COVID. We compare the strengths and limitations of Golden Syrian Hamsters with other commonly used pre-clinical animal models including mice, and non-human primates, highlighting differences in translational relevance, feasibility, and ability to model chronic lung-brain-immune axis dysfunction. While there are limitations, particularly regarding limited availability of immunological reagents and validated cognitive and behavioral assays, the Golden Syrian Hamsters offers a balanced and accessible platform for mechanistic studies of PASC. Overall, this review positions Golden Syrian Hamster as a robust translational model for investigating lung-brain-immune axis pathology in Long-COVID and for advancing the development of targeted therapeutic interventions.
Schwann cells (SCs), the predominant glial cell population in the peripheral nervous system (PNS), have undergone a paradigm shift from historically passive structural components of myelinated axons to active, multifunctional regulators of neural development, regeneration, and neuropathology. This review briefly outlines Schwann cell developmental origin as a biological backdrop, while centering on their inherent phenotypic plasticity and translational applications. Following peripheral nerve injury, SCs rapidly undergo context-dependent dedifferentiation and transcriptional reprogramming, acquiring a regenerative phenotype characterized by phagocytic activity, secretion of neurotrophic factors, and structural reorganization into Büngner bands. Notably, both endogenous and exogenously delivered SCs demonstrate capacity to migrate into lesioned central nervous system (CNS), including spinal cord injury sites, where they contribute to remyelination, modulation of glial scar formation, and partial restoration of electrophysiological connectivity and behavioral function. These attributes collectively establish SCs as phenotypically adaptable cellular mediators capable of facilitating neural repair across anatomically and functionally distinct compartments. To inform translational efforts, this review critically evaluates emerging strategies, including autologous cell transplantation and SC-derived exosomes, by appraising their mechanisms, limitations, and future perspectives. This review aims to deepen the mechanistic understanding of Schwann cell biology and provide a theoretical basis for the development of regenerative treatments for peripheral nerve injury and spinal cord injury.
Post-traumatic stress disorder (PTSD) is a complex mental disorder triggered by severe traumatic events. Its pathophysiology involves not only abnormalities in fear memory circuits and neuroendocrine imbalances but also immune dysregulation and alterations in gut homeostasis. In recent years, the gut microbiota, as a crucial regulatory factor connecting the periphery and the central nervous system, has garnered widespread attention for its potential role in the development and progression of PTSD, offering a new integrative perspective for understanding this disorder. This article focuses on the "gut microbiota-immune-brain axis" framework, reviewing evidence related to changes in the composition and function of the gut microbiota in PTSD. It summarizes how these changes may influence neuroplasticity abnormalities and PTSD-related behavioral phenotypes through mechanisms involving microbial metabolite production, modulation of intestinal barrier integrity, immuno-inflammatory responses, regulation of neuroendocrine homeostasis, and blood-brain barrier dysfunction. However, these mechanistic pathways remain incompletely validated in human studies. Existing research suggests that this axis holds significant value in explaining the multisystem pathological features of PTSD. Nevertheless, challenges persist, including ambiguous causal relationships in microbiota-host interactions, limited direct clinical evidence, and insufficient translational research. Current evidence primarily stems from observational studies, preclinical models, and preliminary intervention studies. The explanatory power varies across these evidence levels: population studies primarily establish correlations, animal models facilitate mechanistic validation, metagenomic and metabolic analyses yield functional insights, while clinical intervention data remain exploratory. This article aims to elucidate the key molecular and systemic mechanisms underlying this axis in PTSD and to evaluate the potential translational value and practical limitations of microbial intervention and immune modulation strategies.
Disruption of circadian rhythms is a key feature of neurodegenerative diseases and a non-motor feature of Parkinson's disease, which significantly impairs health-related quality of life; yet, the underlying mechanisms are only partially understood. Preclinical animal models with neuropathological and symptomatic significance might contribute to a better understanding of circadian dysfunction. Here, we investigated light-dark phase-dependent modulation of motor and non-motor behavior as well as suprachiasmatic nucleus integrity in α-synuclein-overexpressing rats and wild-type controls. Behavioral testing in 3-month-old animals revealed robust phase-dependent modulation of exploratory activity, locomotion, sucrose preference, and olfaction-guided feeding in wild-type rats, which was absent in their transgenic littermates. Histological analyses demonstrated reduced overall cell density and pronounced α-synuclein accumulation in the suprachiasmatic nucleus of α-synuclein rats, accompanied by altered cellular composition, including altered neuronal, orexinergic, and microglial markers. α-synuclein load was positively correlated with Orexin A+ fibers and Iba1+ cell counts, suggesting a link between protein aggregation, neuroinflammation, and altered light-dark phase-dependent behavior. These findings indicate that α-synuclein rats lack phase-dependent behavioral alternations and exhibit suprachiasmatic nucleus pathology already at an early disease stage with very mild motor impairment, providing a translational model to study different aspects of non-motor symptoms in Parkinson's disease.
The prevalence of methamphetamine use disorder (MUD) remains discouragingly high. Relatively few clinical trials have focused on identifying new pharmacotherapies for MUD, and no medications have received US Food and Drug Administration approval. The lack of available pharmacotherapies may be due to failure to follow a rational, translational medications development pipeline progressing from preclinical work to the human laboratory to clinical trials. Our review thus has 2 primary goals: to (1) assess the scope of the literature evaluating candidate medications for MUD and (2) identify drugs screened to treat MUD across research domains, analyzing concordance across contexts. We identified 36 randomized, double-blind, placebo-controlled clinical trials that evaluated 25 candidate medications for MUD. Only 5 of these putative treatments (aripiprazole, bupropion, d-amphetamine, modafinil, and naltrexone) had also been evaluated in human laboratory and preclinical laboratory contexts. Overall, most studies showed no change in methamphetamine use (ie, no effects of treatment) across contexts. Although literature from these contexts imply a high degree of negative predictive validity, we encountered limitations at each level of analysis that prevented us from fully confirming concordance (eg, lack of positive predictive validity). These trends and limitations highlight the extent to which methamphetamine treatments are under-researched relative to other substance use disorders, such as cocaine use disorder. To address this gap in the literature, we advocate for future work that identifies therapeutic targets and, by consequence, classes of medications (repurposed or novel) to treat MUD. We conclude this review with additional comments about future research directions and treatment considerations. SIGNIFICANCE STATEMENT: Investment in methamphetamine use disorder (MUD) medications development remains poor. To date, no pharmacotherapies have received US Food and Drug Administration (FDA) approval to treat MUD, and few candidate medications have been systematically evaluated using a translational medications development pipeline (eg, beginning with preclinical research and progressing to human laboratory research and clinical trials). Adhering to the translational pipeline while incorporating new FDA guidance, such as evaluating nonabstinence outcomes, may be useful in facilitating MUD medications development.
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the progressive loss of upper motor neurons (UMNs) and lower motor neurons (LMNs). Despite significant advances in molecular and neuroimaging biomarkers, the initial site of pathology and the causal contribution of UMN dysfunction to disease progression remain undetermined. Accumulating neurophysiological evidence points to cortical hyperexcitability as an early and potentially upstream mechanism, raising the possibility that UMN pathology drives LMN degeneration through an anterograde dying-forward process. In this review, we synthesize findings from noninvasive brain stimulation (NIBS) studies, with particular emphasis on transcranial magnetic stimulation (TMS)-based neurophysiological markers of UMN dysfunction. We review evidence from TMS-electromyography (TMS-EMG) and TMS-electroencephalography (TMS-EEG) paradigms demonstrating cortical disinhibition and excitatory-inhibitory imbalance in ALS, consistent with impaired GABAergic interneuronal dysfunction and supportive of a cortical onset hypothesis. Finally, we propose integrating transcranial focused ultrasound (tFUS) with TMS as a novel experimental and translational framework to directly examine and modulate cortical hyperexcitability and test the causal role of UMN dysfunction in ALS. The combination of targeted neuromodulation with sensitive neurophysiological readouts in controlled experimental designs offers a promising avenue to advance mechanistic insight, refine biomarkers, and inform mechanism-based therapeutic strategies. Together, these approaches position noninvasive neurophysiology as a powerful tool for elucidating UMN dysfunction in ALS.
Background/Objectives: Trace elements may influence autism spectrum disorder (ASD) severity through interactions with the gut microbiota and microbial metabolic functions, but calcium-related evidence remains limited. This cross-sectional study examined associations among hair calcium, gut microbial taxa, metabolic pathways, and behavioral phenotypes in children with ASD. Methods: We analyzed 183 children with ASD who had behavioral assessments, hair calcium measurements, and fecal shotgun metagenomic sequencing data. Participants in the lowest and highest calcium quartiles were first compared to characterize group-level microbiome differences. Full-sample analyses then tested associations among continuous hair calcium, microbial taxa, metabolic pathways, and behavioral measures after covariate adjustment. Benjamini-Hochberg false discovery rate correction was applied for multiple testing. Results: Hair calcium was positively associated with CARS, ATEC-Total, ATEC-1, and ATEC-3 scores, with the strongest associations involving ATEC-1 and ATEC-3. Alpha and beta diversity did not differ significantly between calcium quartile groups, but group-based microbiome analyses identified 63 differential species and 22 differential MetaCyc pathways. Full-sample integrated analyses connected calcium-associated microbial taxa, metabolic pathways, and ASD behavioral measures. Conclusions: Hair calcium was associated with ASD behavioral severity, selected gut microbial species, and microbial metabolic pathways. These findings support an association framework connecting longer-term calcium-related mineral profiles, gut microbial functional potential, and behavioral phenotypes, providing a basis for future longitudinal and multi-omics studies.
Preterm infants often receive central venous catheters (CVCs) for parenteral nutrition during initial enteral feeding advancement. Whether the use of CVCs promotes growth and neurodevelopmental outcomes is currently unknown. Using German Neonatal Network data, this retrospective population-based cohort study evaluated long-term outcomes in very low birth weight infants (VLBWI) born < 29 weeks of gestation. Multivariate regression analyses and propensity score matching were applied to assess associations between CVC use, somatic growth, and cognitive outcomes (Wechsler Preschool and Primary Scale III intelligence quotient (IQ), Strengths and Difficulties Questionnaire (SDQ)) at 5-7 years of age. In the follow-up cohort of 2072 infants, 74% had a history of neonatal CVC use. VLBWI with CVCs had a significantly lower mean gestational age (25.97 vs. 26.97 weeks, p < 0.001) and lower somatic parameters at birth (mean weight: 829 vs. 986 g, length: 33.7 vs. 35.7 cm, head circumference: 23.8 vs. 25.1 cm, all: p < 0.001) than those without CVCs. Before risk adjustment, mean weight, head circumference, and body mass index at preschool age were significantly lower in children with prior CVC use. These children additionally exhibited lower IQ and higher SDQ scores. Adjusting for potential confounders, linear regression analyses and propensity score matching indicated that CVC use itself was not associated with differences in weight, length, head circumference, or cognitive outcomes at preschool age. Notably, In infants with CVCs, full enteral feeding was achieved approximately 8 days later than in those without CVCs (21.5 vs. 13.2 d, p < 0.001). Prolonged attainment of full enteral feeding was associated with reduced preschool IQs (β: -0.069, CI: -0.116 to -0.022, p < 0.001). In this study, CVC use was not associated with improved somatic growth or psychomotor outcomes at preschool age. Furthermore, our data suggest that earlier attainment of full enteral feeding is associated with more favorable long-term psychomotor outcomes. Within the limits of an association study, these findings support prioritizing strategies that facilitate early enteral feeding advancement in VLBWI, while avoiding routine CVC insertion whenever clinically appropriate.
Cordycepin, a major bioactive constituent of Cordyceps militaris, exhibits diverse pharmacological properties including anti-inflammatory and antioxidant activities. However, its neuroprotective effects against aluminum-induced neurotoxicity in aquatic organism models remain largely unexplored. In this study, we investigated the neuroprotective effects and intrinsic regulatory pathways by which cordycepin alleviates aluminium chloride (AlCl3)-induced neurotoxicity in zebrafish (Danio rerio) embryos using behavioral, molecular, and transcriptomic approaches. Exposure to low-dose AlCl3 significantly induced developmental neurotoxicity, as manifested by reduced body length and reduced heart rate. AlCl3-treated larvae displayed locomotor deficits and cognitive dysfunction. Notably, cordycepin treatment markedly attenuated these AlCl3-induced neurodevelopmental abnormalities and aluminum chloride (AlCl3)-induced locomotor and anxiety-related behavioral impairments.RNA-Seq analysis revealed 605 upregulated and 241 downregulated genes following co-exposure to cordycepin and AlCl3. Functional enrichment analyses based on Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) screened out defense reaction and inflammatory signaling cascades as the remarkably enriched functional pathways, which implied these biological processes exert key functions in the nerve protection produced by cordycepin. Furthermore, pharmacological inhibition targeting the Wnt cascade via IWR-1-endo (IWR-1) markedly counteracted cordycepin's protective capacity to reverse AlCl3-triggered behavioral impairments, indicating that Wnt signaling is essential for its neuroprotective action. Collectively, these findings demonstrate that cordycepin effectively mitigates AlCl3-induced neurotoxicity and AlCl3-induced locomotor and anxiety-related behavioral impairments in zebrafish by regulating inflammatory reactions and the Wnt signal cascade, highlighting its promising value for the clinical intervention of AD.
Neuropathic pain is a debilitating condition lacking objective and quantitative assessment tools, as current evaluations rely largely on subjective reports. Hyperspectral imaging (HSI) is a non-invasive technology that quantifies spatial and spectral tissue characteristics and has been applied in rheumatologic and metabolic disorders. This study investigated whether HSI-detected paw skin alterations correlate with graded nerve injury severity in a chronic constriction injury (CCI) model. Sprague-Dawley rats were assigned to sham or CCI groups with one to four sciatic nerve ligatures. Behavioral assessments (CatWalk XT gait analysis, thermal hyperalgesia, and mechanical allodynia) and paw HSI measurements were performed longitudinally. Histological and molecular analyses were conducted from paw skin to dorsal spinal cord tissues. At 1100 nm, HSI demonstrated progressive and significant spectral deviations proportional to injury severity across all CCI groups, whereas 1300 nm changes were only detected in severe injuries. Histology revealed increased fibrosis, NGF, TNF-α, synaptophysin, and microglial activation with greater injury severity, alongside reduced PGP9.5, neurofilament, AChR, Desmin, GAP-43, Pax3, and BDNF expression. These molecular findings were supported by electrophysiological and behavioral impairments, which correlated with injury grade by HSI. In conclusion, HSI at 1100 nm provides a sensitive and objective indicator of neuropathic pain severity and holds promise as a quantitative translational tool.
The medial prefrontal cortex (mPFC) plays a pivotal role in attention by exerting top-down control to allocate cognitive resources toward behaviorally relevant stimuli based on learned context and expectations. mPFC neurons project to multiple cortical and subcortical regions, including the locus coeruleus (LC)-the brain's primary source of norepinephrine (NE). The mPFC also receives inputs from the LC, which release NE to modulate mPFC neuronal activity and downstream cellular signaling. While enhanced functional connectivity between the mPFC and LC in mice during sustained attention tasks suggest an important role for the mPFC-LC circuit, and in particular for mPFC neurons projecting to the LC (mPFC-LC projectors), functional evidence directly implicating this population in attention is lacking. Here, we investigated the role of the mPFC-LC projectors in attention by comparing selective chemogenetic manipulation of these neurons to broad chemogenetic manipulation of mPFC neurons. Selective activation of mPFC-LC projectors in mice performing the rodent continuous performance test (rCPT), a translational sustained attention task, robustly improves attentional performance by enhancing discrimination while non-selective activation of mPFC neurons increases attentional performance by increasing responsiveness. Behavioral effects of mPFC-LC projector activation were mediated by recruitment of a microcircuit involving LC-NE neurons and glutamate and GABA peri-LC neurons that resulted in an increase in NE tone within the mPFC. while effects of non-selective activation of mPFC neurons were mediated by engaging downstream targets such as the nucleus accumbens (NAc) as well as the LC/peri-LC region. These findings demonstrate that subpopulations of mPFC neurons engaging distinct downstream targets control different domains of attentional performance, providing a circuit-level framework for understanding the mechanisms of sustained attention and for developing targeted therapies for attentional deficits across neuropsychiatric disorders.
Explainable Artificial Intelligence (XAI) is gaining popularity in early diagnosis and monitoring of dementia. Herein, we recommend the incorporation of the National Institute of Mental Health's Research Domain Criteria (NIMH-RDoC) framework with XAI-informed diagnostic protocols to help establish diagnosis at early stages of Alzheimer's disease (AD). RDoC has a dimensional structure that extends across units of analysis from genes and molecules to circuits, physiology, behavior, and introspection. By restructuring diverse features as inputs including apolipoprotein E (APOE) genotype, amyloid and tau biomarkers, computational neuroimaging-informed cortical atrophy, Positron Emission Tomography (PET) hypometabolism, quantitative electroencephalography (qEEG) rhythms, cognitive tests, and digital behavioral markers), onto RDoC units provides more insightful and inclusive models. In this context, data-driven approaches such as XAI can achieve not only increased interpretability but also enhance their mechanistic validity. Such an innovative approach places data-driven model outputs within neurobiologically based domains such as Cognitive Systems, Negative Valence, and Arousal/Regulatory Systems. Our synthesis suggests that a 'converging RDoC and XAI' approach may help bolster the coherence of AD biomarkers, promote model exploration in clinical decision-making. This approach is also expected to provide a strategic roadmap for translational neuroscience and personalized medicine. Another major aim of this study is to critically analyze current XAI approaches used in dementia research, particularly the diagnostic and prognostic aspects. By explicitly grounding explanations in RDoC cognitive domains and paradigms, the framework also aims to make model outputs meaningful in terms of specific mental functions (e.g., episodic memory, cognitive control), thereby supporting neuropsychologically-informed diagnosis, categorization, and communication with patients and caregivers.
Social stress, beneficial for evaluating threats and resource opportunities, influences the development of anxious and depressive disorders. Stress responses are initiated via a pro-stress circuit in the anterior region of the basolateral amygdala (aBLA). This circuit contains pyramidal glutamatergic neurons that express genetic markers Camk2α, Rspo2, and Hcrtr1, which enhance stress-vulnerable behaviors via Orx1R activity, and are inhibited directly by Orx2R activation on Gad1, Hcrtr2, Cck GABAergic neurons. Our results have suggested stress circuitry in BLA is modulated by Orx1R and Orx2R activity, which counterbalance stress responsivity via Rspo2-positive glutamatergic neurons in aBLA, but whether these effects are consistent with systemic delivery is unknown. These receptor-dependent biases contribute to behavioral, physiological and molecular outcomes associated with psychiatric disorders, such as anxiety, depression, and post-traumatic stress disorder. Administration of a selective orexin receptor cross-over (SORCO; Orx1R antagonist and Orx2R agonist combination) treatment alleviates anxiogenic behavioral outputs in socially stressed mice, by decreasing escape latency in stress-vulnerable (Stay) mice (phenotypic reversal; vulnerable to resilient), and reducing the time spent freezing in response to the presence of a social aggressor (socially induced) in stress resilient (Escape) mice. Behavioral results coincided with a decrease in Rspo2 and an increase in Hcrtr2 gene expression in aBLA of SORCO-treated Stay mice, and an increase in Akt3 and Mtor transcription in Stay mice treated with an Orx2R agonist (YNT-185). Our findings indicate that a combination of OrxR drugs (SORCO) provides potentially therapeutic outcomes through modifications of stress neurocircuitry, triggered by increasing expression of genes associated with neuroplasticity.
Accelerated high-frequency repetitive transcranial magnetic stimulation (aHF-rTMS) is an emerging modality in both human and veterinary medicine. Although previous studies show brain changes and behavioral improvements in healthy and patient dogs, the effects of aHF-rTMS on neurotransmitter levels remain poorly understood. This study aimed to compare monoaminergic metabolite profiles in healthy and anxious dogs, and to evaluate short-term, long-term, and dose-dependent effects of aHF-rTMS on these metabolites. A total of 79 dogs were included, comprising 59 healthy controls and 20 anxious dogs. Cerebrospinal fluid samples were collected to measure dopaminergic (3,4-dihydroxyphenylacetic acid [DOPAC] and homovanillic acid [HVA]) and serotonergic (5-hydroxyindoleacetic acid [5-HIAA]) metabolites before and after various aHF-rTMS protocols with varying dosing and duration. Generalized linear mixed-effects models were used to assess baseline differences and stimulation-induced changes across protocols and timepoints. Patient dogs consistently showed lower baseline levels of all three metabolites (DOPAC, HVA, and 5-HIAA) than healthy controls, supporting a neurochemical basis for canine anxiety. Furthermore, neuromodulatory effects of aHF-rTMS were selective and dependent on protocol and timing. In healthy dogs, the short-term stimulation increased 5-HIAA whereas longer protocols reduced HVA. In patient dogs, long-term follow-up revealed significant fluctuations in DOPAC, whereas HVA and 5-HIAA remained stable. These findings indicate baseline monoaminergic deficits in anxious dogs and support a neurochemical basis for canine anxiety. Moreover, aHF-rTMS induces distinct, state- and duration-dependent neurochemical responses. Overall, this study provides novel insights into the neurobiology of anxious dogs and supports further investigation of aHF-rTMS as a neuromodulatory approach in dogs with translational relevance.
Sleep is essential for health and light is an important environmental signal influencing its timing, quality, and regulation. Retinal light exposure reflects the interplay between environmental illumination and behavioral choices, yet it remains unclear which habitual light exposure-related behaviors meaningfully impact sleep outcomes. In this preregistered secondary data analysis, we examined associations between these behaviors, sleep timing, and sleep complaints in a large, international community sample (N = 775, Mage = 32.6 ± 14.6 years). Participants completed the Light Exposure Behavior Assessment (LEBA), with four behavioral domains included in the analyses. Sleep timing, sleep disturbances and sleep-related daytime impairment were measured using established questionnaires. Bayesian analyses indicated that time spent outdoors and device use in bed were most strongly associated with sleep outcomes. Greater time outdoors was linked to earlier sleep timing and fewer sleep complaints, whereas more frequent device use in bed was associated with greater sleep disturbance and daytime impairment. Morning and daytime lighting practices and evening light control showed no conclusive evidence. Together, these findings highlight the relevance of everyday light exposure-related behaviors for sleep and support behavioral approaches to promoting healthy sleep in real-world contexts.
Early life stress (ELS) is a major risk factor for disorders of gut-brain interaction (DGBIs), particularly irritable bowel syndrome (IBS), through the induction of persistent visceral hypersensitivity. This review synthesizes evidence from epidemiological studies, clinical observations, and preclinical models to establish ELS-induced visceral hypersensitivity as a core pathophysiological axis. I delineate the multi-level mechanisms underlying this phenomenon, encompassing: (1) central neuroendocrine dysregulation (hypothalamic-pituitary-adrenal axis, corticotropin-releasing factor signaling) with epigenetic modifications (histone acetylation, non-coding RNAs) in limbic circuits; (2) spinal sensitization via brain-derived neurotrophic factor upregulation, glutamate transporter dysfunction, and potassium channel downregulation; (3) peripheral alterations including enterochromaffin cell hyperplasia, mast cell activation, enteric glial phenotypic switching, barrier disruption, and microbiota dysbiosis. I highlight critical modifiers including sexual dimorphism (estrogen-dependent mechanisms) and resilience factors (benevolent childhood experiences, environmental enrichment). Finally, I present a translational roadmap integrating pharmacological, nutritional, and behavioral interventions targeting ELS-programmed dysfunction along the brain-gut axis, emphasizing opportunities for prevention and precision medicine.
The Adult Chronic Pancreatitis (CP) Working Group, formed at inception of the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer (CPDPC), has developed a robust framework and infrastructure to conduct clinical, translational, and mechanistic studies of CP. At its core is PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translational StuDies (PROCEED), the first longitudinal cohort study of CP in US adults, launched in 2017. PROCEED has developed a well annotated clinical dataset of over 2,000 deeply-phenotyped participants, a biorepository and an imaging repository. Investigators have published promising data on blood- and imaging- based biomarkers of CP diagnosis and pain, which are awaiting validation. Clinical observations include classification of patients into mechanism-based pain phenotypes using responses to PROMIS questionnaires, prevalence and predictors of opioid use, prevalence of psychological comorbidity, and osteopathy in CP patients. Pilot clinical trials have evaluated the effect of oral indomethacin on pancreas fluid prostaglandin E2 levels, and Internet-based cognitive behavioral therapy (CBT) for chronic pain. Results of pilot trials have led to an ongoing definitive randomized clinical trial for CBT. The rich environment and resources have facilitated mentorship and academic development of many early-stage investigators. Investigators outside of the consortium have opportunities for collaboration. In the next 5 years, the Working Group plans to further strengthen the research platform, complete primary and key secondary analyses of PROCEED and ancillary studies, continue efforts to develop biomarkers for diagnosis and prognosis of CP, and complete ongoing clinical trials to address unanswered questions in the field.
This study evaluated the prophylactic neuroprotective effects of dapagliflozin (Dapa), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, in a non-diabetic rat model of cerebral ischemia/reperfusion (C/IR) injury. Forty male Sprague-Dawley rats were randomly assigned to four groups: Sham, C/IR, C/IR + Dapa 1 mg/kg, and C/IR + Dapa 10 mg/kg. The Sham and C/IR groups received vehicle, while the Dapa groups were administered 1 or 10 mg/kg orally for one week prior to surgery. Focal cerebral ischemia was induced for 60 min, followed by 24 h of reperfusion. Outcome assessments included neurological deficit scoring (NDS), behavioral testing, and infarct-area quantification by TTC staining, together with Western blot, ELISA, and oxidative stress analyses. Dapa treatment dose-dependently reduced NDS scores and adhesive-removal time and increased grip strength relative to the C/IR group, and significantly reduced infarct area. At the molecular level, Dapa was associated with increased BDNF, TrkB, p-PI3K, p-Akt, and Bcl-2 and decreased Bax and cleaved caspase-3. Serum levels of the systemic inflammatory mediators IL-1β, IL-6, TNF-α, and NLRP3 were reduced, while tissue antioxidant enzyme activities (SOD, CAT, GSH-Px) were increased and MDA levels decreased. Prophylactic Dapa conferred marked neuroprotection against acute C/IR injury in non-diabetic rats, reducing infarct size and neurological deficit while attenuating oxidative stress, systemic inflammation, and apoptosis. These effects were strongly associated with activation of the BDNF/TrkB/PI3K/Akt survival axis, which represents a promising target for further mechanistic and translational study.
The aging epigenome is shaped by three mechanistically distinct histone post-translational modifications-acetylation, lactylation, and glycation-each driven by a different metabolic flux: mitochondrial oxidative phosphorylation, glycolytic lactate production, and reactive carbonyl stress, respectively. Understanding their interplay is central to a molecular physiology of epigenetic aging. This mini review synthesizes current evidence on the mechanisms of histone acetylation, lactylation, and glycation in aging; their crosstalk and convergence on shared regulatory nodes; and their modulation by environmental, nutritional, and behavioral factors. Key controversies and research gaps are critically appraised. NAD + decline in aging disables the sirtuin deacetylase family, dysregulating the histone acetylation landscape and impairing autophagy, mitochondrial biogenesis, and DNA repair. Histone lactylation, written by p300 at H3K18 and related lysine residues, is context-dependent: physiological pulses during exercise and sleep are adaptive, while chronic accumulation in diabetic microglia drives neuroinflammation via TLR4/NF-κB, and excess in tumor cells enables senescence bypass. Histone glycation by methylglyoxal irreversibly displaces regulatory marks and inactivates sirtuin proteins; pharmacological induction of glyoxalase I and glycation-lowering interventions reduce this burden and extend healthspan. These three axes may converge on a unified metabolic-epigenetic collapse that we propose constitutes the cellular basis of an 'aging' metabolic memory. Lactylation erasers remain uncharacterized; the pro-versus anti-senescence duality of H3K18la is unresolved; and genome-wide histone glycation mapping in human tissues is absent. Combinatorial interventions targeting NAD + restoration, modulation of lactylation, and reduction of carbonyl stress offer the most evidence-based approach to slowing metabolic-epigenetic aging.