Journal of integrative neuroscience最新文献

Background: Hypothalamic corticotropin-releasing factor (CRF) has been implicated in the formation of false contextual fear memory. Here, we examined the involvement of glucocorticoid (GR) and mineralocorticoid receptors (MR) in this process.

Methods: Adult male C57BL/6J mice were exposed to Context B, similar but distinct from Context A, 3 h (B-3 h) after electric foot shock (FS) in Context A, and re-exposed to Context B either 24 h (B-24 h) or 9 days (B-9 d) after FS in Context A. To assess the effect of B-3 h exposure on the specificity of original memory, freezing levels were also measured in Context A (A-24 h or A-9 d) in a separate group, following the B-3 h exposure after FS. GR and MR protein levels in the hippocampal nuclear fractions were analyzed by western blotting. In pharmacological studies, dexamethasone (a GR agonist), fludrocortisone (an MR agonist), and mifepristone (a GR antagonist) were subcutaneously administered to hypothalamic CRF knockdown mice.

Results: When mice were exposed to B-3 h after FS, they exhibited increased freezing at B-24 h compared with B-3 h and showed further increases at B-9 d compared with B-24 h, indicating a time-dependent intensification of false contextual fear memory. In contrast, freezing behavior in Context A was reduced at A-24 h and A-9 d after B-3 h exposure compared with mice that were not exposed to B-3 h, suggesting diminished precision of the original memory. Immunoblotting revealed increased nuclear GR levels at B-3 h and decreased MR levels at B-24 h and B-9 d. In CRF knockdown mice, dexamethasone enhanced freezing at B-3 h, whereas fludrocortisone reduced freezing at B-24 h and B-9 d. Co-administration of mifepristone and fludrocortisone suppressed both the formation of false memory at B-3 h and its subsequent enhancement. However, this treatment increased freezing in Context A at A-24 h and A-9 d following B-3 h exposure.

Conclusion: Exposure to a similar but distinct context shortly after FS induces false contextual fear memory via GR activation and promotes its time-dependent potentiation through MR inactivation. Such early exposure may also impair the specificity of the original fear memory.

Encoding a key 'hub' scaffolding protein, the 'Disrupted-In-Schizophrenia-1' (DISC1) gene has been strongly implicated in brain development and functions. Genetic variance in this gene is associated with major neuropsychiatric disorders, including schizophrenia, bipolar disorder, and major depression. DISC1 is abundantly expressed in the brain of humans and various model organisms. Here, we discuss currently available animal models of DISC1-related brain deficits and their clinical relevance. We focus on evolutionarily conserved (shared) mechanisms and species-specific phenotypes, especially in newly developed zebrafish (Danio rerio) models, to better understand the uniquely complex role of DISC1 in the molecular pathogenesis of neurobehavioral abnormalities relevant to human neuropsychiatric disorders.

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.