Journal of integrative neuroscience最新文献

Background: Spinal cord injury (SCI) is a severe medical condition resulting from trauma, disease or degeneration, leading to partial or complete loss of sensory and motor functions. Huntingtin-associated protein 1 (HAP1) is a classical neuronal protein that plays a crucial role in the nervous systems. Although numerous proteins and molecules have been extensively studied, the mechanisms underlying SCI pathogenesis remain incompletely understood. This study aimed to elucidate how HAP1 modulates functional recovery and tissue repair post-SCI through a multifaceted experimental approach.

Methods: Immunofluorescence staining was used to evaluate the spatial distribution and expression levels of HAP1 in spinal cord. An SCI model was established to assess behavioral functions using the Basso Mouse Scale, forced swim, inclined plate and hot plate tests. Luxol fast blue staining was used to assess morphological repair. The protein and mRNA expression levels of brain-derived neurotrophic factor (BDNF) were quantified post-SCI using enzyme-linked immunosorbent assay and quantitative real-time polymerase chain reaction, respectively. To elucidate the functional role of HAP1 in the SCI process, BDNF injections and behavioral tests were performed. Finally, RNA sequencing followed by bioinformatics analyses (Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathways and Gene Ontology (GO) term enrichment) were performed to identify differentially expressed genes and signaling pathways associated with HAP1 in the SCI process.

Results: HAP1 is abundantly expressed in spinal cord neurons and plays a crucial role in post-traumatic recovery. HAP1 deficiency significantly impairs both functional recovery and morphological repair following spinal cord injury. Comparative analysis revealed lower BDNF levels in HAP1 heterozygous (HET) mice than in wild-type (WT) controls post-injury. Exogenous BDNF administration partially rescued behavioral deficits in HET mice, indicating BDNF-dependent compensatory mechanisms. RNA-seq analysis identified 444 differentially expressed genes and potential pathways associated with HAP1 in the SCI process.

Conclusions: HAP1 significantly enhances functional recovery and morphological repair post-SCI through potentiation of BDNF signaling pathways. These findings position HAP1 as a novel therapeutic target for SCI treatment.

Background: Spinocerebellar ataxia (SCA) is an autosomal dominant neurodegenerative disorder marked by progressive loss of cerebellar function. Over 40 genetically defined SCA subtypes have been identified, arising from mechanisms such as cytosine-adenine-guanine (CAG) trinucleotide repeat expansions, point mutations, and gene deletions. Spinocerebellar ataxia type 14 (SCA14) stems from mutations to the protein kinase C gamma (PRKCG) gene, which codes for protein kinase C gamma (PKCγ), a signaling protein predominantly expressed in cerebellar Purkinje cells. Although the genetic basis of SCA14 is well established, the mechanisms driving Purkinje cell dysfunction remain poorly understood. Notably, transgenic mice expressing the common PKCγ-Gly118Asp (G118D) mutation, located in the protein's regulatory domain, do not exhibit an overt disease phenotype, raising questions about potential compensatory changes at the molecular level.

Methods: We examined the expression of regulator of G protein signaling 8 (Rgs8), a molecule implicated in SCA-related pathways. Organotypic slice cultures and primary cerebellar cell cultures were generated in vitro to assess Purkinje cells from the non-manifesting PKCγ-G118D transgenic mouse line.

Results: A significant increase in Rgs8 expression was observed in both slice cultures and primary cerebellar cell cultures derived from the non-manifesting SCA14 mouse line.

Conclusions: Elevated Rgs8 expression in Purkinje cells from symptom-free PKCγ-G118D mice suggests molecular adaptations that may underlie the non-manifesting phenotype, offering insight into the subclinical SCA14 pathophysiology.

Predictive processing asserts that the brain learns a generative model of the world, which it uses to make sensory-updated predictions about reality. While traditional views emphasize the cerebral cortex, prediction is a fundamental brain principle, which underscores the vital role of older subcortical structures. This review offers a framework for understanding the brain as an integrated system of semi-independent cortical and subcortical functional units that collectively enable predictive processing. The cerebral cortex is positioned as the primary driver of subconscious predictions, whereas the thalamus, hippocampal complex, amygdala, basal ganglia, and cerebellum contribute critical indirect roles by translating the predictions into conscious, cohesive, and coordinated experiences and behaviours. Specifically, the thalamus controls and establishes selective attention by synchronizing multiple cortical regions, enabling attended predictions to be expressed into conscious perception and cognition; the hippocampal complex captures novelty and constructs episodic simulations, which represent highly abstract or hypothetical predictions that contribute to the conscious cognitive experience; and the amygdala appraises motivational value and activates emotional states, which predict survival-critical events and prime the brain for action, contributing to a subjective emotional experience. During this translation, the basal ganglia and cerebellum contribute sculpting roles, with the basal ganglia chunking predictions into repertoires, facilitating the cohesive expression of actions, and potentially perceptual, cognitive, and emotional experiences, while the cerebellum generates and adjusts temporal predictions, enabling the coordinated expression of actions and experiences. This integrative framework highlights the essential, often-overlooked contributions of subcortical units to predictive processing, providing a unified model for future research.

Background: Pharmacological treatment for adolescent depression is limited in safety and efficacy. Acupuncture treatment for depression has been endorsed by the World Health Organization. This study aimed to analyze the efficacy and mechanisms of acupuncture in treating adolescent depression.

Methods: An 4-week clinical trial was conducted from February 1, 2022 to June 30, 2024 at three hospitals. Patients aged 12 to 18 years were divided into three treatment groups: Manual acupuncture (MA), antidepressants (ADM), or acupuncture combined with antidepressants (MA+ADM). The 24-item Hamilton Depression scale (HAMD-24) scores, serum neurotransmitters levels, and resting-state functional magnetic resonance imaging (RS-fMRI) data were assessed at baseline (week 0) and after treatment (week 4).

Results: After a 4-week intervention, both the MA and MA+ADM groups showed significant improvement in HAMD-24 scores. The MA+ADM group experienced more improvement, particularly in addressing somatization and sleep disorders. The study revealed that acupuncture increased serum levels of 5-hydroxytryptamine (5-HT), kynurenic acid, dopamine noradrenaline, adrenaline, L-histidine, and picolinic acid in adolescents with depression. Acupuncture was also found to regulate the excitability of depression-related brain regions (frontal lobe, caudate nucleus, anterior cingulate, and paracingulate gyri) and the functional connectivity of depression-related circuits (limbic-cortical-striatal-pallidal-thalamic circuit and hate circuit). Furthermore, significant negative correlations were observed between week 0 and week 4 HAMD-24 scores and up-regulated serum levels of 5-HT and dopamine. Scores were positively associated with increased amplitude of low-frequency fluctuations and regional homogeneity values.

Conclusions: Acupuncture improves adolescents' depressive mood and sleep quality and alleviates somatic symptoms by modulating neurotransmitters levels and brain activity.

Clinical trial registration: No: ChiCTR2200056171. https://www.chictr.org.cn/showproj.html?proj=151197.

Peripheral nerve injury is a relatively common clinical condition that predominantly results from sensory, motor, and nutritional disorders. These can be due to aging, external forces, diseases, or changes in physical and chemical environments. Although interventions, including relevant drugs and surgeries, have led to advancements in peripheral nerve repair, achieving complete recovery remains a challenge. Untimely treatment and rehabilitation can lead to lifelong disabilities and neurological pain. Exercise is a low-cost intervention that plays an active role in the rehabilitation of patients with many diseases, including peripheral nerve injuries. This narrative review, conducted in accordance with the Scale for the Assessment of Narrative Review Articles guidelines, synthesized evidence from searches of PubMed, Scopus, Web of Science, and Google Scholar databases to summarize the molecular mechanisms of exercise and adjuvant therapies in peripheral nerve injury rehabilitation and the synergistic benefits of combined exercise and adjuvant therapy for peripheral nerve repair. This study revealed that the combination of exercise with either physical therapy or traditional Chinese medicine yielded superior therapeutic outcomes for peripheral nerve injuries attributable to aging, pathological conditions, and environmental factors. These benefits appear to be mediated by the suppression of oxidative stress and inflammatory responses, upregulation of neurotrophic factor expression, activation of autophagic pathways, modulation of endocrine homeostasis, and promotion of vascular network reconstruction. Furthermore, this study provides a theoretical foundation and a potential research direction for elucidating the targeted molecular mechanisms through which exercise ameliorates peripheral nerve injury.

Alzheimer's disease (AD) is the most common cause of dementia in older adults, marked by a gradual and irreversible deterioration of cognitive abilities, including memory and thinking skills. AD is highly heterogeneous, with variations in amyloid and tau pathology, symptoms, proteostasis, neuroinflammation, and genetics. Dysregulated proteostasis and neuroinflammation, though usually protective, contribute significantly to disease progression. Proteostasis refers to the network that maintains the integrity of both intracellular and extracellular proteins, while neuroinflammation is the biological response to harmful stimuli. Proteostasis stress can activate immune responses and cause excessive inflammation, while impaired microglia and astrocyte function can further disrupt proteostasis and worsen disease progression. While numerous reviews on AD exist, this review focuses on the complex interplay between proteostasis and neuroinflammation in AD and their integral roles in disease pathology. Additionally, we will explore current and promising therapeutics targeting these processes, potential biomarkers, and the clinical trials conducted over the past 5 years, particularly those that address neuroinflammation and proteostasis, as identified through a PubMed search.

Aims: Parkinson's disease (PD) is characterized by dopaminergic neuron degeneration and disruption to mitochondria-associated endoplasmic reticulum membranes (MAMs). This study explores whether electroacupuncture (EA) can alleviate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced PD symptoms and investigates the underlying mechanisms using RNA sequencing (RNA-seq).

Methods: A PD mouse model was established using MPTP, followed by EA treatment at governing vessel 20 (GV20) and gallbladder meridian 34 (GB34) acupoints, with sham EA treatments as a control. Behavioral assays, immunohistochemistry, and Western blotting assessed neuroprotective effects. MAM integrity was assessed using Western blot, immunofluorescence staining, and transmission electron microscopy. RNA-seq and protein-protein interaction (PPI) analysis identified differentially expressed genes which were validated by real-time fluorescence quantitative polymerase chain reaction (qRT-PCR).

Results: EA treatment improved motor performance, increased substantia nigra (SN) and striatum tyrosine hydroxylase expression, reduced SN alpha-synuclein, and improved SN dopamine neuron MAM structure. Transcriptomic analysis identified 32 MAM-associated genes, of which fibronectin-1 (Fn1) was identified as a key regulator. EA was found to upregulate Fn1 expression, suggesting its involvement in MAM stabilization and neuroprotection.

Conclusion: EA at GV20 and GB34 alleviated motor and neural impairments in a PD mouse model potentially through modulation of Fn1 and its role in MAM-associated pathways.

Autonomic medicine is a rapidly evolving field focused on understanding diseases and processes that affect the autonomic nervous system (ANS). The ANS regulates essential involuntary physiologic processes such as heart rate, blood pressure, and digestion. This review introduces the key anatomical structures, physiological mechanisms, and biochemical processes underlying autonomic function. The anatomy section focuses on the peripheral components of the ANS, including the sympathetic and parasympathetic divisions. The physiological section explores the process of homeostasis and the intricate feedback systems that maintain this balance within the body. Finally, the biochemistry of autonomic signaling, focusing on the neurotransmitters acetylcholine, norepinephrine, and epinephrine, and their receptors, is reviewed. Pertinent clinical points are highlighted throughout, emphasizing the importance of the basic science to the clinical world. This review aims to provide a comprehensive basic science foundation for clinicians and researchers exploring the field of autonomic medicine.

Background: Remote ischemic conditioning (RIC), a novel neuroprotective therapy, has broad potential for reducing the occurrence and recurrence of cerebrovascular events, yet its mechanisms are not incompletely understood. The aim of this study is to investigate whether RIC alleviates apoptosis, inflammation, and reperfusion injury in rat models of ischemic stroke by regulating the Elabela (ELA)-apelin-Apelin receptor (APJ) system.

Methods: We established a rat model of middle cerebral artery occlusion (MCAO) with ischemia-reperfusion injury, and RIC was administered twice daily for 3 days post-MCAO. Cerebral infarct volume was measured and neuronal damage was assessed. Apoptosis-related caspase-3 expression was detected by Terminal deoxynucleotidyl Utransferase nick-End Labeling (TUNEL) and Western blotting (WB). WB was also used to measure apelin, signal transducer and activator of transcription 3 (STAT3), and p-STAT3 protein levels in infarcted brain tissue. ELA miRNA expression was evaluated. Immunofluorescence was used to detect hypoxia-inducible factor 1α (HIF-1α) and activating transcription factor 4 (ATF4) expression. Serum levels of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were measured using enzyme-linked immunosorbent assay (ELISA).

Results: RIC reduced the cerebral infarct volume and neuronal damage in MCAO rats. Compared with the MCAO group, the RIC-treated group (MCAO+RIC) presented significantly lower caspase-3, TNF-α, IL-1β, p-STAT3, HIF-1α, and ATF4 expression (p < 0.05), whereas STAT3 and ELA miRNA expression and apelin protein levels were increased (p < 0.05). While positively correlated with STAT3 expression, Elabela and apelin levels exhibited a negative correlation with caspase-3 (p < 0.05).

Conclusions: RIC mitigates MCAO-induced neuronal apoptosis, inflammation, and reperfusion injury by modulating the ELA-apelin-APJ system, highlighting its therapeutic potential for ischemic stroke.

Background: Epilepsy, a significant neurological condition marked by the occurrence of repeated seizures, continues to pose a substantial health challenge. Previous studies have indicated that Dipeptidyl Peptidase-4 (DPP4) inhibitors may possess antiepileptic properties. Ferroptosis, a newly discovered type of programmed cell death, has recently surfaced as a promising therapeutic target in the management of epilepsy. Nevertheless, the exact mechanisms responsible for the effects of DPP4 inhibitors have not yet been fully elucidated.

Methods: The anti-epileptic effect was evaluated through electroencephalogram (EEG) recordings, behavioral assessments, and immunohistochemical analysis in a mouse model of epilepsy induced by LiCl/Pilocarpine. Public RNA-sequencing data was used to search the key targets of epilepsy. Neuronal ferroptosis was assessed through western blotting and immunofluorescence in an epilepsy rat model and a glutamate-induced neuronal cell model.

Results: Administration of the DPP4 inhibitor sitagliptin was observed to markedly reduce seizure severity in an animal model of epilepsy. Furthermore, sitagliptin effectively diminished epileptiform activity, as assessed by EEG. Additionally, pretreatment with sitagliptin led to a notable decrease in the expression of heme oxygenase-1 (HO-1), reactive oxygen species (ROS) production, and mitochondrial damage, while increasing glutathione peroxidase 4 (GPX4) expression in the epilepsy rat model. Similar effects were observed in cell-based experiments, where sitagliptin pretreatment enhanced GPX4 expression in glutamate-induced neuronal models.

Conclusions: The DPP4 inhibitor sitagliptin mitigates ferroptosis in epilepsy models. These findings highlight new potential targets and treatment modalities for epilepsy.