Journal of integrative neuroscience最新文献

Neurocognitive disorders represent a significant global health challenge and are characterized by progressive cognitive decline across conditions including Alzheimer's disease, mild cognitive impairment, and diabetes-related cognitive impairment. The hippocampus is essential for learning and memory and requires intact neuroplasticity to maintain cognitive function. Recent evidence has identified the brain insulin signaling pathway as a key regulator of hippocampal neuroplasticity through multiple cellular processes including synaptic plasticity, neurotransmitter regulation, and neuronal survival. Dysregulation of this pathway contributes substantially to the pathophysiology of cognitive dysfunction in various disorders. Mechanistically, insulin modulates hippocampal neuroplasticity primarily through the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) cascades, both of which promote synaptic plasticity and support neurogenesis. Beyond its neuronal effects, insulin signaling also regulates glial and endothelial cell function, orchestrating a coordinated multicellular response that is critical for hippocampal integrity. Emerging therapeutic approaches that target this pathway include intranasal insulin administration, glucagon-like peptide-1 (GLP-1) receptor agonists, and peroxisome proliferator-activated receptor (PPAR) agonists. These have demonstrated promising efficacy in restoring hippocampal function and improving cognitive outcomes in both preclinical and clinical studies. This review synthesizes current knowledge on the relationship between brain insulin signaling and hippocampal neuroplasticity. In addition, we highlight the therapeutic potential of insulin-targeted interventions for neurocognitive disorders, including quantifiable outcomes and sex-specific considerations.

Nasal cytology is evolving into a promising tool for diagnosing neurological and psychiatric disorders, especially those such as Alzheimer's and Parkinson's diseases. Moreover, recent research has indicated that biomarkers differ greatly between samples taken before and after death. Nasal cytology might help to identify the early stages of cognitive decline. The association of olfactory disturbances with a host of these neurological disorders is remarkable. This means that the nose, something we probably take for granted, could well be the best means of establishing important biomarkers for earlier diagnoses in these conditions. The nose is a source of epithelial and neuroepithelial cells that can be used in in vitro cultured models and nasal cytology provides new avenues for translational, integrative neuroscientific research. The future incorporation of artificial intelligence into cytological analyses would facilitate the acceptance of nasal cytology as a screening platform for neurodegenerative and psychiatric conditions, facilitating early diagnosis and better management for patients.

Background: Germinal matrix hemorrhage (GMH) is a common complication of premature infants with lifelong neurological consequences. Inflammation-mediated blood-brain barrier (BBB) disruption has been implicated as a main mechanism of secondary brain injury after GMH. The cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) pathway plays a crucial role in inflammation, yet its involvement in GMH pathophysiology remains unclear.

Methods: Collagenase was injected into the right germinal matrix of postnatal day 5 (P5) mouse pups to induce GMH. Either RU.521, or RU.521 combined with a STING agonist SR-717 was administered to the mice after GMH. The number of microglia, proinflammatory cytokines, microglial polarization, BBB permeability, demyelination, and axon degeneration were analyzed by immunofluorescence staining, western blotting, and quantitative real-time PCR. Neurobehavioral functions were evaluated using novel object recognition, Y-maze, and rotarod tests.

Results: After induction of GMH, cGAS and STING were upregulated in the peri-hematomal area with a peak at 24 h, and they were mainly expressed in microglia. RU.521 treatment decreased the number of microglia, proinflammatory cytokines and microglial polarization, preserved BBB integrity, and decreased its permeability after GMH. Moreover, RU.521 decreased GMH-mediated upregulation of STING, phosphorylated TANK-binding kinase 1 (phospho-TBK1), phosphorylated interferon regulatory factor 3 (phospho-IRF3), and interferon-β (IFN-β), diminished demyelination, axon degeneration, and neurological deficits. The STING agonist SR-717 blunted RU.521-induced downregulation of phospho-TBK1, phospho-IRF3 and IFN-β and blocked RU.521-mediated inhibition of inflammation, protected against BBB breakdown, white matter lesions, and neurological dysfunction after GMH.

Conclusions: Inhibition of cGAS improved white matter lesions and neurological dysfunction by modulating the microglial polarization towards decreased neuroinflammation and maintaining BBB integrity through STING-mediated type I IFN-β production. Thus, cGAS may be a potential therapeutic target for the treatment of GMH.

Background: Excessive stress leads to stress injury but the underlying mechanism is not completely understood and current preventive protocols are inadequate. This study aimed to investigate if glucocorticoid (GC) reduces nerve damage in the hypothalamus caused by stress and to clarify the mechanisms involved.

Methods: Behavioral alterations in stressed rats were observed using the open field test. Changes in the levels of stress hormones, inflammatory factors, and stress-related injury factors were detected using enzyme-linked immunosorbent assay (ELISA). Pathological alterations in the hypothalamus were observed using thionine staining and hematoxylin & eosin (HE) staining. The expression levels of proteins linked to pyroptosis were determined using western blotting.

Results: Stressed rats presented obvious anxiety-like behavior; the levels of stress hormones, inflammatory factors, and injury-related factors fluctuated abnormally. Morphological findings indicated substantial damage in the hypothalamus. Stress-induced nerve injury was alleviated by low-dose GC treatment, which also dramatically decreased the concentrations of inflammation-associated markers and expression of the gasdermin D (GSDMD)-related pyroptosis pathway.

Conclusions: Low-dose GC alleviates hypothalamic nerve injury by inhibiting the GSDMD-dependent pyroptosis pathway in stressed rats.

Background: The dorsolateral prefrontal cortex (DLPFC) is a critical node in the working memory (WM) neural circuit, established through neurophysiology, neuropsychology, and neuroimaging studies in humans and nonhuman primates. While most of the neurophysiological evidence for the role of the DLPFC in WM comes from visuospatial WM paradigms, evidence for its role in auditory WM has been suggested by the fact that large lateral prefrontal cortex lesions in nonhuman primates cause auditory discrimination deficits. Moreover, DLPFC neurons demonstrate task-related neuronal responses during auditory WM. In contrast, other studies have proposed that the ventrolateral prefrontal cortex (VLPFC) plays a pivotal role in auditory and audiovisual processing, integration, and mnemonic processing, since VLPFC neurons are responsive to complex acoustic stimuli and are robustly active during auditory WM tasks. Furthermore, inactivation of the VLPFC impairs audiovisual and auditory WM. In these inactivation studies the cortical region that was inactivated by cortical cooling included areas 12/47, 45 and 46 ventral. It is possible that inclusion of area 46 ventral may account for the auditory WM performance deficit previously observed while inactivating VLPFC so further experiments are needed.

Methods: In the present study we examined whether transient inactivation of the DLPFC, including areas 46v and 46d, and 9, in rhesus macaques would effect auditory WM. The DLPFC was inactivated by cortical cooling while two rhesus macaques performed an auditory working memory task. This was followed by permanent ibotenic acid lesions and assessment of behavioral performance post-lesion.

Results: Our experiments demonstrated that inactivation of DLPFC by cortical cooling in two macaques did not result in a significant decrease in performance of an auditory WM task. The inactivation resulted in an increase in dropped gaze events during the latter half of the task, in one subject, which could be due to a loss of attention or motivation. The ibotenic acid lesions of the DLPFC did not significantly alter performance on the auditory WM task.

Conclusions: Our results showed that DLPFC transient inactivation with cortical cooling and ibotenic acid lesions did not significantly alter overall auditory working memory performance, which differs from the impairment seen when the VLPFC is inactivated. Our data suggest that the DLPFC and VLPFC may play different roles in auditory working memory.

Background: Anatomical studies have indicated that the brain and the heart are connected through multiple pathways. However, the functional interplay between them is unclear, especially for different task states. This study explored the brain-heart interplay under reflexive and voluntary saccade tasks.

Methods: The Synthetic Data Generation model was used to quantify the interplay between the brain and heart.

Results: Bidirectional interplay patterns were found between the brain and heart under different frequency bands for the two types of saccade task. There were significant variations in the interplay coupling across saccade tasks, particularly in the prefrontal and parietal lobes. This phenomenon can be explained by the complexity and cognition load among the saccade tasks.

Conclusions: This study shed light on the dynamic bidirectional interplay mechanisms between the brain and heart, contributing to the understanding of brain-heart interaction.

Aging is a multifaceted biological process characterized by numerous physiological and molecular alterations that profoundly impact health and susceptibility to disease. Among the genetic determinants influencing aging, the apolipoprotein E (APOE) gene cluster has emerged as a critical focus of research. This study explored the diverse roles of APOE in both normal and pathological aging, with particular emphasis on its involvement in Alzheimer's disease (AD). We first examined the "physiological" aspects of aging, highlighting cellular and systemic adaptations that support organismal homeostasis. This was followed by an analysis of the pathophysiological deviations underlying neurodegenerative disorders, with AD as a key example. The role of APOE in normative aging was then discussed, including its contributions to lipid metabolism, synaptic plasticity, and neuroprotection-functions essential for maintaining both cerebral and systemic health. However, the pathological implications of APOE genetic variants, particularly the ε4 allele, were considered in relation to the increased risk of AD and other age-related diseases. Additionally, the APOE gene cluster, which includes adjacent regulatory and interactive genes, was examined for its potential to modulate APOE expression and function, thereby influencing the aging process. This synthesis underscores the pivotal role of the APOE gene cluster in elucidating the genetic and molecular mechanisms underlying aging and age-related diseases, providing a foundation for the development of targeted therapeutic interventions.

Background: Dyslipidemia during midlife represents a significant risk factor for neuropathological alterations associated with cognitive decline. Given the currently incurable nature of dementia, implementation of preventive strategies and early therapeutic interventions prior to disease progression are paramount. Emerging evidence suggests that hyperbaric oxygen (HBO) therapy exhibits neuroprotective properties in various neurological conditions. However, whether HBO treatment modulates lipid metabolism dysregulation and subsequent neurodegeneration remains unanswered. This investigation aimed to elucidate the therapeutic potential of HBO treatment in ameliorating cerebral dysfunction and metabolic perturbations using apolipoprotein E (ApoE)-deficient (ApoE^-/-) mice.

Methods: ApoE^-/- mice received HBO treatment for 10 consecutive days, and then behavioral assessment tests were performed. Serum and brain tissue were collected to measure oxidative stress levels and inflammatory factors.

Results: Compared with ApoE^-/- group, cognitive declines was significantly reversed in mice of the ApoE^-/-+HBO mice. The blood lipid profiles of ApoE^-/- mice were also improved after HBO treatment, accompanied by a reduction in body weight. Moreover, HBO treatment was found to ameliorates neuronal injury and amyloid-β deposition in the hippocampus of ApoE^-/- mice. Further studies have revealed that the benefits of HBO treatment occurred through the reduction of inflammatory factors and attenuation of oxidative stress.

Conclusions: These findings indicate that HBO treatment effectively improves the intracerebral microenvironment of ApoE^-/- mice, providing a novel regulatory mechanism of protection against dyslipidemia-associated brain deficits by HBO treatment.