Metabolic derangement is considered as a key underlying cause and contributor of metabolic encephalopathy, which is featured by cognitive decline, psychiatric symptoms, and severe coma. Clinical and preclinical studies have demonstrated that malnutrition, electrolyte derangements, toxic agents, and organ failure lead to metabolic disturbances including hyper/hypoglycaemia, hyperammonaemia, vitamin deficiency, hyper/hypokalaemia, hyper/hyponatraemia, and hyper/hypoferraemia. These metabolic stressors result in cognitive impairment and changed mental health. Because metabolic imbalance is often attributed to abnormalities in multiple factors rather than one factor, its distinction and management are critical. In cases of severe metabolic imbalances, it is recommended to identify such abnormalities using multiple strategies. Given that impaired brain function is difficult to recover, long-term dietary regulation and proper management are required by considering underlying diseases or conditions. Hence, by exploring the connections between metabolic imbalances (e.g., glucose, ammonia, indoxyl sulfate, electrolyte ions, and vitamins), and cognitive and mental health, this review provides evidence that emphasises the critical importance of management of metabolic health. Comprehending psychoneurological impairment caused by metabolic disturbances highlights the potential overlap with cognitive/mental symptoms of underlying conditions. Therefore, identifying the key pathological mechanisms of metabolic stress-induced psychoneurological impairment provides valuable insignts into the development of effective management and therapeutic approaches.
While sleep disturbances are recognized as early markers of Alzheimer's disease (AD), the practical application of gold-standard polysomnography (PSG) for long-term monitoring is limited. This study aims to establish a novel methodological framework for the time-series analysis of sleep data collected via consumer-grade wearables and to explore whether this approach can detect differentiated signals across various stages of cognitive impairment. Daily sleep patterns of thirteen participants (5 healthy controls, 4 with aMCI, and 4 with mild AD) were monitored over three months using the Fitbit Charge 2. Rather than relying on aggregate nightly averages, we implemented a time-resolved analysis across 10-minute intervals to examine the temporal dynamics of sleep architecture. The proposed analysis revealed distinct, group-dependent temporal signatures. Specifically, the aMCI and AD groups exhibited shorter deep sleep during the early phase of the night, reduced REM sleep approximately three hours after sleep onset, and consistently elevated levels of light sleep and wake after sleep onset (WASO). These findings demonstrate that time-series analysis of wearable sleep data presents the potential to identify candidate digital phenotypes associated with cognitive decline. This study supports the feasibility of using longitudinal, dynamic sleep monitoring as an exploratory analytical framework warranting further validation for the detection of pathophysiological changes in older adults, shifting the focus from simple detection to the identification of candidate temporal sleep features. All reported findings are exploratory in nature and require replication in larger, independent cohorts.
Selenium-binding protein 1 (SELENBP1), previously implicated in several neurological and psychiatric disorders, was recently reported to be altered in the brains of individuals with Alzheimer's disease (AD). However, the cellular specificity of SELENBP1 in AD pathogenesis, including its role in amyloid-beta, remains unclear. Given the prominent role of microglia in amyloid-driven neuroinflammation and the hippocampal regional vulnerability in early AD, clarifying how SELENBP1 is regulated at both regional and cell-type-specific levels is essential. In this study, we examined age- and genotype-dependent changes in Selenbp1 expression in the hippocampus and prefrontal cortex of non-transgenic and 5XFAD mice at 1.5, 3, and 6 months of age by using western blot and immunofluorescence analyses. Western blot analyses revealed robust age-dependent increases in Selenbp1 expression in both regions, with no statistically significant genotype-dependent differences. However, immunofluorescence analyses showed that Selenbp1 levels were selectively increased in amyloid-vulnerable hippocampal subregions, including the dentate gyrus, dorsal subiculum, and retrosplenial cortex. Selenbp1 expression was expressed in microglia and was largely absent from neurons or astrocytes. These findings indicate that Selenbp1 elevation under AD-like conditions is region- and cell-type-specific, reflecting microglial responses detectable only through spatially resolved analysis. Therefore, Selenbp1 may represent a microglial molecular signature associated with early amyloid pathology.
Understanding the brain requires mapping not only neuronal circuits but the full landscape of intercellular communication. Here we introduce "signaling connectomics", a systems framework for interpreting divergent signaling context. It charts brain-wide signaling across synaptic, neuromodulatory, immune, glial, and vascular pathways. By integrating targeted perturbations with multiplexed molecular and imaging readouts, this approach infers causal signaling networks that operate beyond conventional synapses. It challenges circuit-centric models by emphasizing how dynamic receptor landscapes, extracellular cues, and non-synaptic interactions collectively shape neural function and dysfunction. Combining cell-type-specific optogenetics, biosensors, and spatial transcriptomics, signaling connectomics enables systematic mapping of intercellular signaling dynamics and cross-talk in vivo, providing a multidimensional view of how the brain coordinates activity across diverse cell types. Ultimately, this framework provides conceptual and methodological foundations for linking multicellular signaling to circuit-level plasticity and behavior via explicit causal chains.
Environmental pollution from synthetic drugs undermines Sustainable Development Goals while exhibiting limited efficacy and adverse effects in mood disorder treatments. Tenebrio molitor larvae (TM) demonstrate significant health benefits including anti-inflammatory, antioxidant, and cognitive enhancing effects. Enzymatic hydrolysis enhances protein bioactivity by improving digestibility and releasing bioactive peptides. This study evaluated neuroprotective effects of TM hydrolysates (TMH) against lipopolysaccharide (LPS)-induced neuroinflammation. Cell viability was measured by WST assay and cytotoxicity was measured by LDH release assay. Inflammatory cytokine mRNA levels were quantified by qRT-PCR, and NF-κB-, MAPKs-, and apoptosis-related biomarkers protein expressions were assessed by western blot. The TMH was administered intracerebroventricularly and LPS was injected intraperitoneally into ICR mice. Behavioral assessments were performed 24 h after LPS injection for sickness-like phenotypes and 28 h after for depressive-like behavior. Mice were sacrificed immediately after the behavior test to collect hippocampal tissue for cytokine mRNA analyses. TMH prevented LPS-induced sickness-like phenotypes and depressive-like behavior increases. Hippocampal IL-1β mRNA levels decreased significantly while IL-6, TNF-α, and IL-10 expression showed downward trends. Cell viability was preserved with reduced LDH release and attenuated upregulation of IL-1β, NF-κB, JNK, ERK, and Caspase-3 in PC-12 cells. TMH demonstrated robust protection against LPS-induced neuroinflammatory and behavioral alterations, indicating therapeutic potential for mood disorder interventions through sustainable, bioactive compound utilization. TMH mitigates both neurotoxic and depressive-like effects of systemic LPS in complementary cell and animal models, supporting its potential development as an eco-friendly, non-synthetic therapeutic agent for neuroinflammatory mood disorders.
Alzheimer's disease (AD) imposes a growing burden on global healthcare systems. Current therapeutic interventions primarily alleviate cognitive and functional symptoms but have limited impact on the underlying neurodegenerative processes driving disease progression. This underscores the urgent need for treatments that target the pathogenic mechanisms of the disease. Advances in monoclonal antibody therapies against amyloid-β (Aβ) provide encouraging evidence for disease modification, though challenges related to dosing, cost, and safety constrain their broader application. Small molecule therapeutics represent a compelling alternative owing to advantageous properties such as enhanced brain penetration, oral bioavailability, and suitability for long-term administration in elderly patients. Building on these attributes, this review evaluates small molecule therapeutics as promising candidates for AD treatment. It summarizes small molecule compounds targeting Aβ across mechanisms that include modulating production, inhibiting aggregation, disassembling aggregates, enhancing clearance, and mitigating neurotoxicity. A comprehensive assessment of current data emphasizes the importance of continued research to overcome ongoing challenges and fully leverage the potential of small molecules. The limited number of candidates in late-stage clinical trials indicates that substantial efforts are still required to identify and refine effective agents. Continued investigation into their mechanisms and optimization of compound profiles will advance the development of small molecule-based therapies for AD.
Eye movement desensitization and reprocessing (EMDR) is a popular psychotherapy used to alleviate mental distress associated with anxiety and trauma-related disorders. Although working memory taxation has been proposed as an underlying mechanism of the therapy, such claim yet remains controversial due to lack of neurobiological foundations and conflicting findings among studies. In this study, we distracted rats with flickering lights during their training of fear memory extinction. Temporal overlap of twenty-second visual stimulations with the anticipatory shock timing of trace fear conditioning effectively facilitated fear extinction in a subset of animals that showed relatively low freezing during the conditioning day, while random intermittent visual stimulations did not. Moreover, fear extinction in delay fear conditioned animals was not affected either by the same visual stimulations or the stimulations that overlapped with shock timing. These results show that attentional distraction facilitates trace fear extinction, and proper timing is a necessary condition for a sensory stimulation to effectively facilitate trace fear extinction. Implications of our findings in EMDR and potential neurobiological mechanisms are discussed.
Postoperative cognitive dysfunction (POCD) is a clinically significant complication in elderly patients, largely driven by surgery-induced neuroinflammation. The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, a crucial regulator of innate immunity, has been implicated in neuroinflammatory activation. This study investigated whether electroacupuncture (EA) improves POCD by modulating this pathway in aged rats. Aged male Sprague-Dawley rats were subjected to sevoflurane anesthesia and splenectomy to establish a POCD model. Animals were divided into sham, POCD, POCD+EA, and POCD+EA+cGAS inhibitor groups. The EA groups received stimulation at Baihui (Governor Vessel 20 (GV20)), Neiguan (Pericardium 6 (PC6)), and Zusanli (Stomach 36 (ST36)) acupoints. Cognitive function was evaluated using the Morris water maze, while hippocampal expression of cGAS-STING pathway components and downstream effectors-interferon regulatory factor 3 (IRF3), nuclear factor kappa B (NF-κB), and interleukin-1 beta (IL-1β)-was assessed by Western blot. Cellular localization was determined by immunofluorescence staining. Compared with the Sham group, rats in the POCD group showed significant impairments in spatial memory, accompanied by upregulated protein expression of cGAS, STING, NF-κB, IRF3, and IL-1β in the hippocampus. Upon pathway activation, cGAS and STING proteins were predominantly co-localized with neurons, and their fluorescence intensity in the hippocampus was markedly increased. These behavioral deficits and molecular alterations were partially reversed in both the POCD+EA and POCD+EA+inhibitor groups. Electroacupuncture alleviates POCD in aged rats by inhibiting hippocampal cGAS-STING pathway activation and reducing neuroinflammation, suggesting a promising non-pharmacological strategy for POCD management.
In Alzheimer's disease (AD), persistent microglial neuroinflammation and the poor brain exposure and durability of current therapies underscore the need for new, long-acting treatments. We developed a non-viral gene therapy that suppresses microglial Toll-like receptor 2 (TLR2) signaling using poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) loaded with a plasmid encoding the anti-TLR2 single-chain variable fragment (scFv33). Following intra-cisterna magna delivery, PLGA NPs exhibited microglia-biased uptake and enabled brain-wide transgene expression in mice. In 5xFAD mice, a single administration of scFv33 NPs improved recognition memory in the novel object recognition (NOR) assay, outperforming 8 weeks of weekly recombinant scFv33-Fc dosing. Histology showed selective reduction of small hippocampal Aβ plaques and a shift toward a ramified microglial morphology, indicative of reduced activation. In primary neuron-microglia co-culture, scFv33 reduced microglial hypertrophy, restored process complexity, and enhanced Aβ phagocytosis. Together, these data indicate that sustained, local expression of an anti-TLR2 scFv via a clinically translatable PLGA platform recalibrates microglial state and preferentially limits early-stage plaque accumulation, yielding cognitive benefit after a single dose.
Chrysanthemum zawadskii flower ethanol extract (CZ-F) was evaluated for its neuroprotective potential against inflammation-associated cognitive impairment. To assess its anti-inflammatory properties, we first conducted in vitro studies using LPS-stimulated BV2 microglial cells. CZ-F demonstrated strong antioxidant activity with IC50 values of 186.04 μg/ml (DPPH) and 94.56 μg/ml (ABTS), suppressed the production of reactive oxygen species and nitric oxide, and downregulated the expression of iNOS and IL-1β, likely via inhibiting the NF-κB signaling pathway. CZ-F also decreased inflammation-induced acetylcholinesterase (AChE) expression and directly inhibited AChE activity. Among the constituents of CZ-F, quercetin and luteolin exhibited the strongest anti-inflammatory and antioxidant effects, while linarin most potently inhibited AChE activity. In an in vivo zebrafish model, CZ-F treatment ameliorated learning and memory impairments induced by sleep deprivation. These findings suggest that CZ-F can attenuate neuroinflammation and modulate cholinergic dysfunction, providing a potential therapeutic approach for inflammation-related cognitive deficits.
Listening to rhythmic patterns leads to neural entrainment to beat and meter periodicities. The debate over whether entrainment is a mere reflection of external stimuli, or an inherent intrinsic response persists. The objective of this study was to ascertain whether there are cerebral cortices, which satisfy 3 distinct features of intrinsic entrainment; first, the ability to sustain neural oscillations even in random beat omission; second, a requisite latency period for the build-up before initiating a response to rhythmic stimuli; and third, the persistence of these neural oscillations gradually recedes following the cessation of the stimulus. In 27 patients with medically intractable epilepsy, electrocorticography data were obtained with 2- or 3-beat sound stimulations with random omissions. We found that there are cortices which satisfy all three requirements of intrinsic entrainment. The cortices synchronized with beat were in Brodmann areas (BA) 21, and 22, whereas the cortices synchronized with meter corresponded to BA3, 6, 9, 22, 40, and 44. We showed that entrainment is an intrinsic response, with distinct neural processing for beat and meter. These insights advance our understanding of neural entrainment to beat and meter periodicities.
Mitochondrial bioenergetics plays a fundamental role in neuronal development and function. Prenatal exposure to corticosterone in rats (Corti. Pup) has previously been shown to cause delayed neurodevelopment and synaptic plasticity deficits, showing attention deficit hyperactivity disorder (ADHD) - like behaviors. However, the underlying mitochondrial metabolic adaptations remain unclear. This study investigated mitochondrial function and metabolic remodeling in prefrontal cortex neurons of Corti.Pups, focusing on oxidative phosphorylation, calcium handling, and redox balance. We assessed neuronal viability, reactive oxygen species (ROS) production, and oxygen consumption rate (OCR) through experiments conducted in both neuron-glia co-culture and neuron-only conditions. Furthermore, we evaluated electron transport chain (ETC) activity, mitochondrial membrane potential (MMP), and mitochondrial Ca2+ uptake in purified isolated mitochondria. In results, Corti.Pup neurons exhibited increased vulnerability to glutamate-induced excitotoxicity in the absence of glial support. Despite reduced ROS production, these neurons showed elevated mitochondrial OCR and proton leak, coupled with decreased non-mitochondrial OCR and ETC complex activity. Surprisingly, MMP remained elevated despite ETC dysfunction, and mitochondrial Ca2+ uptake was suppressed. These features indicate mitochondrial metabolic reprogramming, prioritizing MMP maintenance over ATP synthesis. The observed mitochondrial inefficiency and compensatory adaptations may impair energy production, contributing to delayed neuronal development in Corti.Pups. These findings suggest that mitochondrial dysfunction and metabolic remodeling play central roles in the pathogenesis of neurodevelopmental disorders such as ADHD.
Posttraumatic stress disorder (PTSD) has been associated with structural brain alterations, suggesting accelerated brain aging. Evidence from peripheral biological markers supports this hypothesis, although direct neuroimaging findings remain limited. Moreover, this phenomenon remains insufficiently examined in younger populations. To address this gap, this study investigated accelerated brain aging in young women with PTSD and its association with symptom severity. The study included 85 women younger than 40 years: 34 with PTSD and 51 age-matched, trauma-unexposed healthy controls (HCs). T1-weighted magnetic resonance imaging scans were analyzed using a population-specific deep learning model to estimate brain age. The brain age gap (BAG) was calculated as the difference between predicted brain age and chronological age. PTSD symptoms were assessed with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), providing total and domain-specific scores. Women with PTSD demonstrated significantly accelerated brain aging, with a mean BAG increase of approximately 2.1 years relative to HCs (p=0.022). The positive association between total CAPS-5 scores and BAG reached marginal significance (β=0.304, p=0.066). Notably, greater severity of negative alterations in cognition and mood (Criterion D) was significantly associated with a larger BAG (β=0.338, p=0.036). These findings suggest that PTSD may accelerate brain aging even when onset occurs in young adulthood. This effect appears particularly related to cognitive and mood symptom severity. The results underscore the impact of trauma on neural health and highlight the potential of the BAG as a biomarker for specific symptom dimensions in PTSD, with possible implications for targeted intervention strategies.
Artificial intelligence (AI) is an emerging tool for high-resolution behavioural analysis and conduction of human-free behavioural experiments. Here, we applied an AI-based system, AVATAR, which automatically virtualises 3D motions from the detection of 9 body parts. This allows quantification, classification and detection of specific action sequences in real-time and facilitates closed-loop manipulation, triggered by the onset of specific behaviours, in freely moving mice.
Early-life stress (ELS) is a major contributor to neurodevelopmental vulnerability, particularly within the dentate gyrus (DG), where oxidative burden and microglial activation disrupt adult neurogenesis. Here, we examined whether N-acetylcysteine (NAC), a cysteine prodrug and glutathione precursor, could counteract impaired neurogenesis induced by neonatal maternal separation (NMS). Adolescent NAC administration restored the number of Ki67+ proliferating progenitors and DCX+ immature neurons in the DG of NMS rats, accompanied by reduced reactive oxygen species, suppressed iNOS induction, and attenuated microglial activation. NAC also normalized EAAC1 expression, indicating enhanced neuronal antioxidant capacity. Notably, NAC rescued diminished neurogenesis in EAAC1 knockout mice, demonstrating its efficacy under both stress-induced and transporter-deficient redox imbalance. These findings identify NAC as a potent modulator of hippocampal neuroplasticity, acting through the restoration of redox and inflammatory homeostasis, and support its potential as an early therapeutic strategy to mitigate long-lasting neurodevelopmental consequences of ELS.
The ability to cope with changing environments is critical for healthy functioning, yet this flexibility is impaired in many neuropsychiatric disorders. However, neural mechanisms underlying flexible behavior remain elusive. Here, we report that oscillatory dynamics in the medial prefrontal cortex (mPFC) support learning to flexibly overcome established behavioral bias. Mice performed a delayed non-match-to-sample task that required trial-by-trial adjustment of arm choice strategy despite persistent arm bias. Decoding analysis of delay-period local field potentials (LFPs) and single-unit activities revealed evolving neural representations across trials as mice adapted to the task. Notably, mPFC neurons modulated by theta (4~12 Hz) bursts selectively encoded upcoming choice information after acquiring the new rule. In contrast, beta (12~30 Hz) bursts correlated with perseverative behavior and appeared to inhibit theta-modulated neuronal firing in mice showing adaptive behavior. These theta and beta bursts were temporally separated over the delay period, reflecting a dynamic gating mechanism. Thus, beta bursts shape neuronal ensembles that are modulated by theta bursts to facilitate flexible learning. This dynamic interaction provides a mechanistic basis for cognitive flexibility and provides insights into cognitive rigidity seen in neuropsychiatric disorders such as schizophrenia and autism.
Spinocerebellar ataxia type 3 (SCA3) is an autosomal-dominant neurodegenerative disorder caused by an expanded polyglutamine repeat in the ataxin-3 gene. The resulting mutant ataxin-3 protein forms intraneuronal inclusions that lead to neurodegeneration in the cerebellum and other brain regions. This study aimed to develop a novel nonhuman primate model of SCA3 to address the limitations of existing knock-in and transgenic models using an adeno-associated virus (AAV) to deliver the mutant gene. AAV viral vectors carrying mutant ataxin-3 were stereotaxically injected into the cerebellum of monkeys. The animals were monitored over an 8-week period, during which behavioral and neuroimaging assessments were conducted. This was followed by a detailed pathological examination. The AAV vector successfully spread throughout the cerebellum, and the expression of mutant ataxin-3 was confirmed. Neuroimaging revealed a reduction in N-acetylaspartate (NAA) levels, whereas histological analysis showed significant damage to the Purkinje cell layer. Notably, the monkeys exhibited sleep disturbances, a prodromal symptom commonly observed in human patients with SCA3. AAV-mediated delivery of mutant ataxin-3 can effectively replicate the key pathological and clinical features of SCA3 in primates. This approach offers a promising new model for studying disease mechanisms and evaluating potential therapies.
Parkinson's disease (PD) is a neurodegenerative disorder associated with neuroinflammation and gut dysfunction. The G protein-coupled estrogen receptor (GPER) has showed therapeutic potential in inflammatory bowel diseases (IBD), yet its role and underlying mechanisms in PD remain unclear. Here, we aimed to investigate the role and mechanisms of GPER in protecting PD. Female mice underwent bilateral ovariectomies (OVX) and were treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to induce PD, followed by administration of GPER agonist G1. The expressions of tyrosine hydroxylase (TH) and α-synuclein (α-syn), as well as activations of inflammatory cells and NLRP3 inflammasome in the brain and ileum were evaluated. BV2 cells were pretreated with G1 and/or the antagonist G15, then treated with LPS and ATP to activate NLRP3 inflammasome. Activation of NLRP3 inflammasome in BV2 cells was assessed. Results demonstrated that G1 treatment increased TH expression, reduced α-syn expression, and suppressed inflammation and NLRP3 inflammasome in both the midbrain and ileum of MPTP-treated OVX mice. Pretreatment with G1 suppressed the activation of NLRP3 inflammasome in BV2 cells, while the effect was reversed by G15. These findings indicate that GPER activation exerts a protective effect in MPTP-induced OVX mice by modulating NLRP3 inflammasome in both brain and gut, which might provide novel insights into the pathogenesis and therapy of PD.
Dynamic facial expressions carry a wide range of signals, encompassing emotional but also more conversational content important for social interaction, for which the dynamic aspect is crucial. Likewise, we know from previous behavioral and neuroimaging studies that processing of emotional stimuli changes across aging - little, however, is known about how age may impact brain activity for dynamic facial expressions. To address this open issue, here we used two cohorts of older and younger adults (total N=77) within a whole-brain MVPA decoding paradigm in fMRI. We used a range of dynamic and conversational expressions as stimuli shown with a foil task in the scanner and had participants rate these post-scanning in terms of their affective content along 12 dimensions (including valence and arousal). The behavioral ratings were used to cluster the facial expressions and the resulting similarity matrix was used in a searchlight decoding paradigm to identify common areas. Using robust bootstrap analyses, we identified the insula as a common brain region able to decode the wide range of emotional and conversational dynamic facial expressions for both participants groups. We also discuss additional brain areas specific to the younger group. Our study adds to the growing literature on neural processing of dynamic expressions in the context of aging.
Neurotrophic factors (NTFs) are secreted proteins that are crucial in neuronal growth, survival, and function. Individuals with neurodegenerative diseases, characterized by neuronal loss and various functional disorders, have been reported to exhibit altered levels of NTFs. This suggests that modulating NTF levels may offer a promising therapeutic strategy to alter the progression of neurodegenerative diseases. Although numerous efforts have been made to deliver NTFs to target regions, their clinical application remains challenging due to their inability to cross the blood-brain barrier (BBB) and the adverse side effects observed in clinical trials. Consequently, various delivery methods have been explored to overcome these limitations. In this review, we discuss recent therapeutic approaches utilizing NTFs and their signaling pathways as interventions against neurodegenerative diseases.
