Neuroscience Insights最新文献

The human brain contains multiple cell types that are spatially organized into functionally distinct regions. The proper development of the brain requires complex gene regulation mechanisms in both neurons and the non-neuronal cell types that support neuronal function. Studies across the last decade have discovered that the 3D nuclear organization of the genome is instrumental in the regulation of gene expression in the diverse cell types of the brain. In this review, we describe the fundamental biochemical mechanisms that regulate the 3D genome, and comprehensively describe in vitro and ex vivo studies on mouse and human brain development that have characterized the roles of the 3D genome in gene regulation. We highlight the significance of the 3D genome in linking distal enhancers to their target promoters, which provides insights on the etiology of psychiatric and neurological disorders, as the genetic variants associated with these disorders are primarily located in noncoding regulatory regions. We also describe the molecular mechanisms that regulate chromatin folding and gene expression in neurons. Furthermore, we describe studies with an evolutionary perspective, which have investigated features that are conserved from mice to human, as well as human gained 3D chromatin features. Although most of the insights on disease and molecular mechanisms have been obtained from bulk 3C based experiments, we also highlight other approaches that have been developed recently, such as single cell 3C approaches, as well as non-3C based approaches. In our future perspectives, we highlight the gaps in our current knowledge and emphasize the need for 3D genome engineering and live cell imaging approaches to elucidate mechanisms and temporal dynamics of chromatin interactions, respectively.

Stroke remains a leading cause of mortality and disability, with ischemic stroke being the most common type. It occurs due to reduced cerebral blood flow, leading to a cascade of events initiated by oxygen and nutrient deprivation, triggering excitotoxicity, oxidative stress, and inflammation and finally culminating in neuronal injury and death. Key molecular players in ischemic stroke include glutamate receptors, acid-sensing ion channels, and purinergic receptors, exacerbating cellular damage through calcium influx, oxidative stress, and mitochondrial dysfunction. Understanding these mechanisms has shaped therapeutic strategies, such as neuroprotective agents and stem cell therapies. Current treatments such as tissue plasminogen activator (tPA) emphasize timely intervention, yet challenges persist in patient-specific variability and accessibility. This review provides an overview of ischemic stroke pathophysiology, emphasizing cellular responses to ischemia and current and future therapeutic approaches including stem cell therapies aimed at mitigating stroke-induced disabilities and improving long-term outcomes.

Increasing evidence documents turnover of the resting-state blood-oxygen-level dependent signal (TBOLD) as a key measure of local cortical brain status. Here we evaluated contemporaneous and lagged associations between TBOLD and cognitive function in 711 participants in the Human Connectome Project on Aging (HCP-A; 316 males and 395 females, age range 36-90 years). We found that TBOLD was negatively associated with Montreal Cognitive Assessment (MoCA) Total scores and with performance on 2 subscales, Delayed Recall and Visuospatial/Executive Function, controlling for sex, age, and handedness. This negative association was largely documented across brain areas and was significantly stronger in the left hemisphere compared to the right. In addition, analyses evaluating forward lagged crosscorrelations between TBOLD and cognitive performance demonstrated that TBOLD predicted decrements in future performance on MoCA Total score, Delayed Recall, and Visuospatial/Executive Function subscales, controlling for sex and handedness. Taken together, we found that increased TBOLD is associated with decreased cognitive performance contemporaneously and in the future. On the hypothesis that increased TBOLD is the outcome of neuroinflammatory processes, these findings provide a mechanism linking neuroinflammation with decreased cognitive performance.

Cerebral amyloid angiopathy (CAA) is a common disorder of the elderly, a prominent comorbidity of Alzheimer's disease, and causes vascular cognitive impairment and dementia. Previously, we generated a novel transgenic rat model (rTg-D) that produces human familial CAA Dutch E22Q mutant amyloid β-protein (Aβ) in brain and develops arteriolar CAA type-2. Here, we show that deposition of fibrillar Aβ promotes arteriolar smooth muscle cell loss and cerebral microhemorrhages that can be detected by magnetic resonance imaging and confirmed by histopathology. Aged rTg-D rats also present with cognitive deficits. Cerebral proteomic analyses revealed 241 proteins that were significantly elevated with an increase of >50% in rTg-D rats presenting with CAA compared to wild-type rats. Fewer proteins were significantly decreased in rTg-D rats. Of note, high temperature requirement peptidase A (HTRA1), a proteinase linked to transforming growth factor beta 1 (TGF-β1) signaling, was elevated and found to accumulate in cerebral vessels harboring amyloid deposits. Pathway analysis indicated elevation of the TGF-β1 pathway and increased TGF-β1 levels were detected in rTg-D rats. In conclusion, the present findings provide new molecular insights into the pathogenesis of CAA and suggest a role for interactions between HTRA1 and TGF-β1 in the disease process.

The SARS-CoV-2 virus is primarily a respiratory virus, but, as it spread worldwide, it became apparent that there are multiple extrapulmonary manifestations. Reports arose of young and otherwise healthy patients presenting to emergency departments with large-vessel occlusions. Because of a rapidly evolving pandemic, conflicting data sometimes arose regarding the impact of the pandemic on strokes. COVID-19 can induce a hypercoagulable and a proinflammatory state through the interactions with the ACE-2 receptor. These mechanisms may lead to the strokes, both ischemic and hemorrhagic, that are seen in this infection. Strokes, in conjunction with COVID-19 infection, tended to be more disabling and portended a higher mortality. Treatment of these strokes was challenging, as emergency departments were strained with the high burden of COVID-19 admissions. Finally, vaccines against COVID-19 were widely administered, and their potential to cause stroke as an adverse event are discussed. This article will provide an in depth review of the recent updates about the incidence, epidemiology, pathophysiology, clinical presentation and treatment of strokes that are associated with COVID-19.

Psychedelic therapies are an emerging class of treatments in psychiatry with great potential, however relatively little is known about their interactions with other commonly used psychiatric medications. As psychedelic therapies become more widespread and move closer to the clinic, they likely will need to be integrated into existing treatment models which may include one or more traditional pharmacological therapies, meaning an awareness of potential drug-drug interactions will become vital. This commentary outlines some of the issues surrounding the study of drug-drug interactions of this type, provides a summary of some of the relevant key results to date, and charts a way forward which relies crucially on multimodal neuroimaging investigations. Studies in humans which combine Positron Emission Tomography (PET) and functional Magnetic Resonance Imaging (fMRI), plus ancillary measures, are likely to provide the most comprehensive assessment of drug-drug interactions involving psychedelics and the relevant effects at multiple levels of the drug response (molecular, functional, and clinical).

The global growth of an aging population is expected to coincide with an increase in aging-related pathologies, including those related to brain health. Thus, the potential for accelerated cognitive health declines due to adverse aging is expected to have profound social and economic implications. However, the progression to pathological conditions is not an inevitable part of aging. In fact, engaging in activities that improve cardiovascular fitness appears to be a means that offers the benefits of maintaining and/or improving cognitive health in older age. However, to date, the underlying mechanisms responsible for improved central nervous system health and function with exercise are not yet fully elucidated. Consequently, there is considerable interest in studies aimed at understanding the neurophysiological benefits of exercise on aging. One such area of study suggests that the improvements in brain health via exercise are, in part, driven by the recovery of inhibitory processes related to the neurotransmitter gamma-aminobutyric acid (GABA). In the present review, we highlight the opposing effects of aging and exercise on cortical inhibition and the GABAergic system's functional integrity. We highlight these changes in GABA function by reviewing work with in vivo measurements: transcranial magnetic stimulation (TMS) and magnetic resonance spectroscopy (MRS). We also highlight recent and significant technological and methodological advances in assessing the GABAergic system's integrity with TMS and MRS. We then discuss potential future research directions to inform mechanistic GABA study targeted to improve health and function in aging. We conclude by highlighting the significance of understanding the effects of exercise and aging, its influence on GABA levels, and why a better understanding is crucial to allow for more targeted and effective interventions aimed to ultimately improve age-related decline in aging.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus, emerged in December 2019, sparking a global health crisis. While initially recognized as a respiratory illness, it has become evident that Coronavirus disease 2019 (COVID-19) also affects the central nervous system. This comprehensive review focuses on the neurological manifestations of COVID-19 and its impact on patients with preexisting neurological disorders, particularly those with multiple sclerosis (MS) receiving disease-modifying therapies. Advancements in management, including vaccinations, antiviral therapy, and targeted prophylaxis, have led to a decline in the incidence and severity of COVID-19. Nevertheless, significant complications persist, particularly in patients with advanced MS, who are highly vulnerable to infectious agents like SARS-CoV-2. This review explores the evolving understanding of MS and its association with SARS-CoV-2, encompassing neuroinvasiveness, pathogenesis, disease severity, and outcomes. Research findings reveal substantial neurological implications for some MS patients with COVID-19, with a potential risk of disease relapse and severity. A notable proportion of MS patients experiencing COVID-19 may manifest new symptoms, experience exacerbation of existing symptoms, or encounter both simultaneously, underscoring the diverse neurological effects of the virus. While vaccination and therapeutics have mitigated the overall impact, specific subgroups, especially those on anti-CD20 therapy and with existing disability, remain at higher risk, necessitating ongoing vigilance and tailored care.

Background: Alzheimer's disease (AD) is a progressive neurological disorder characterized by a wide range of cognitive and non-cognitive impairments. The present study was designed to investigate the potential effects of cacao on cognitive and non-cognitive performance and to identify the role of oxidative stress in an AD animal model induced by unilateral intracerebroventricular (U-ICV) injection of amyloid beta_1-42 (Aβ_1-42).

Methods: Oral administration of cacao (0.5 g/kg/day) was performed for 60 consecutive days. Following 60 days, the open-field (OF) test, elevated plus-maze (EPM) test, novel object recognition (NOR) test, Barnes maze (BM) test, and Morris water maze (MWM) test were used to evaluate locomotor activity, anxiety-like behavior, recognition memory, and spatial memory, respectively. Total oxidant status (TOS) and total antioxidant capacity (TAC) in plasma were also examined. Furthermore, the number of healthy cells in the hippocampus's dentate gyrus (DG), CA1, and CA3 regions were identified using hematoxylin and eosin staining.

Results: The results indicated that the injection of Aβ_1-42 in rats led to recognition memory and spatial memory impairments, as well as increased anxiety. This was accompanied by decreased total antioxidant capacity (TAC), increased total oxidative stress (TOS), and increased neuronal death. Conversely, cacao treatment in AD rats improved memory function, reduced anxiety, modulated oxidative stress balance, and decreased neuronal death.

Conclusion: The findings suggest that cacao's ability to improve the balance between oxidants and antioxidants and prevent neuronal loss may be the mechanism underlying its beneficial effect against AD-related cognitive and non-cognitive impairments.

Pelizaeus-Merzbacher disease (PMD, currently known as hypomyelinating leukodystrophy type 1 [HLD1]) is a hereditary hypomyelinating and/or demyelinating disease associated with the proteolipid protein 1 (plp1) gene in the central nervous system (CNS). One of the major causes of this condition is incomplete or defective oligodendroglial cell myelin sheath formation triggered by endoplasmic reticulum (ER) stress and subsequent unfolded protein response (UPR). The HLD1-associated Ala-243-to-Val mutation (p.Ala243Val) of PLP1 is widely recognized to trigger defective oligodendroglial cell morphological differentiation, primarily due to ER stress. We have previously reported that knockdown of Rab7B (also known as Rab42), a small GTP/GDP-binding protein involved in intracellular vesicle trafficking around the lysosome, can recover chemical ER stress-induced incomplete cell shapes in the FBD-102b cell line, a model of oligodendroglial cell morphological differentiation. Here, we present findings indicating that incomplete cell shapes induced by PLP1 p.Ala243Val can be restored by knockdown of Rab7B using the clustered regularly interspaced short palindromic repeats (CRISPR) and CasRx (also known as Cas13d) system. Also, the knockdown promoted the trafficking of PLP1 p.Ala243Val to lysosome-associated membrane protein 1 (LAMP1)-positive organelles. These results highlight the unique role of Rab7B knockdown in modulating oligodendroglial cell morphological changes and potentially facilitating the transport of mutated PLP1 to LAMP1-positive organelles, suggesting its potential as a therapeutic target for alleviating HLD1 phenotypes, at least in part, at the molecular and cellular levels.