Frontiers in Molecular Neuroscience最新文献

In recent years, there has been growing interest in the study of gut microbiota and its relationship with multiple diseases, ranging from digestive problems to cognitive disorders. The composition of this microbiota is determined by external and internal factors-such as psychosocial or environmental aspects-and is closely linked to diet, since the foods we consume provide nutrients and establish the conditions of the intestinal environment. The gut-brain axis describes how the intestinal microbial flora and the compounds it produces generate and transmit signals that act on our nervous system and regulate multiple processes in the body. This systematic review aims to explore the impact of the Mediterranean Diet on the composition of the gut microbiota and to analyze its effects on various cognitive conditions, such as memory. Based on a review of 20 articles, we examined how the Mediterranean Diet-characterized by high consumption of olive oil, fruits, vegetables, legumes, and fish-modulates the microbiota in the human gut. The results showed that adherence to the Mediterranean Diet is associated with an increase in beneficial bacteria such as Faecalibacterium prausnitzii and Bifidobacterium, and with greater production of short-chain fatty acids (SCFAs), especially butyrate. The Mediterranean Diet appears to exert a neuroprotective role in disorders such as mild cognitive impairment, schizophrenia, Parkinson's disease, and metabolic diseases. This protective function, derived from changes in the gut microbiota, leads to improvements in cognitive function. Overall, the findings underscore the direct relationship between nutrition and mental health and reinforce the value of the Mediterranean Diet as a preventive strategy and a modulator of cognition through the gut-brain axis, promoting brain health across the lifespan.

Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD420251273990.

Introduction: Apolipoprotein E (ApoE), reelin, and several other proteins bind ApoE-receptor 2 (apoER2), distinguished from other members of its receptor family by signal transduction which enhances the activity of N-methyl D-aspartate (NMDA) receptors. Evidence indicates that this signal transduction depends upon apoER2 forming dimers or other high-order clusters. It seems noteworthy therefore that protein products of major APOE gene variants differ in their numbers of cysteines capable of forming disulfide dimers, with the allele (ε4) associated with highest rates of Alzheimer's disease (AD) possessing none. Thus, lower AD risk may be associated with the ability of ApoE to dimerize and thereby promote apoER2 dimerization and signaling.

Methods: We examined calcium fluxes via the NMDA receptor in neurons derived from the NTera2 cell line in response to conditioned medium from human astrocytes differing in APOE genotype, recombinant ApoE proteins, reelin, amyloid β-peptide (Aβ) preparations differing in their aggregation states, and secreted amyloid precursor protein (sAPP). Signaling through apoER2 was inhibited by receptor-associated protein (RAP) or siRNA directed against apoER2.

Results: Reelin, fibrillar Aβ, ApoE3, and conditioned medium from APOE ε3 astrocytes elevated calcium fluxes, and this phenomenon required apoER2. By contrast, ApoE4 and oligomeric Aβ antagonized activation. sAPP showed high-affinity binding to apoER2 and enhanced responses to reelin.

Discussion: These findings suggest a comprehensive hypothesis for the pathogenesis of AD whereby the common factor in development of disease is antagonism of apoER2, likely to include agents that cannot promote the receptor's dimerization yet competitively inhibit those ligands that can cause dimerization.

Neural organoids can be integrated with AI models in various formats, termed AI-NO systems. Neural organoids and AI are each high impact research fields which may play significant roles in biological research and clinical decision making. However, their potential benefits, pitfalls and associated governance structures are often overshadowed by highly speculative discourse over the possibility of them developing some form of consciousness and subsequently acquiring a level of moral status. This article examines the cause for this speculative discourse, arguing for a focus on more immediate, empirically grounded ethical issues. It describes potential ethical issues when data obtained from AI models is used for research planning and drug discovery on neural organoids; when AI models are used to analyze data obtained from neural organoids; and when AI models are used to control interventions on neural organoids in open- or closed-loop configurations. It concludes with an investigation on how AI-NO systems may impact clinical decision making.

Background: Notch overactivation and aberrant neurogenesis following status epilepticus (SE) has been identified by our previous study. The current study further supplements this by exploring additional pathological changes during epileptogenesis post-SE, as well as the potential role of Notch in these processes.

Methods: Rats were administered N-[N-(3,5-difluorophenacetyl)-L-alanyl)]-S-phenylglycine t-butyl ester (DAPT) immediately after SE induction. Spontaneous recurrent seizures were monitored via electroencephalogram (EEG). Hippocampal synaptic ultrastructure was analyzed using transmission electron microscopy. Nissl staining and Timm staining were performed at 28 days post-SE to evaluate neuronal loss and mossy fiber sprouting (MFS), respectively.

Results: EEG recordings demonstrated that DAPT treatment significantly reduced the severity of epileptiform discharges post-SE. Transmission electron microscopy revealed decreased presynaptic active zone length and postsynaptic density thickness in the hippocampal CA1 region of DAPT-treated rats. Nissl staining indicated attenuated hippocampal neuronal loss and partial structural restoration following DAPT administration. Notably, Timm staining showed no significant effect of DAPT on MFS compared to controls.

Conclusion: Inhibition of Notch signaling alleviates EEG epileptic activity, mitigates synaptic damage, and partially preserves hippocampal neuronal structure in adolescent rats post-SE, without altering MFS. These findings suggest Notch signaling as a potential therapeutic target for post-SE neuroprotection, though its role in MFS remains unclear.

Lactate, traditionally regarded as a byproduct of glycolysis, has emerged as a key metabolic substrate and signaling molecule in the brain. Through the astrocyte-neuron lactate shuttle, lactate provides an essential link between energy metabolism and neuronal function. Beyond its metabolic role, lactate influences synaptic plasticity, neuroinflammation, mitochondrial dynamics, and epigenetic regulation, thereby exerting multifaceted effects on cognitive processes. Accumulating evidence demonstrates that lactate acts as a double-edged regulator: under certain conditions, it promotes neuronal resilience and cognitive enhancement, whereas excessive accumulation or impaired transport may contribute to dysfunction. This review synthesizes current knowledge of lactate metabolism in the central nervous system, highlighting its physiological functions, bidirectional impact on cognition, and emerging role as both a biomarker and therapeutic target. A deeper understanding of lactate-mediated mechanisms may pave the way for novel strategies in the prevention and intervention of cognitive impairment. Clinically, lactate is best interpreted as a context-sensitive metabolic readout rather than a standalone disease-specific biomarker.

CB1 and GPR55 receptors form heteromers in striatal neurons; however, the effects of these heteromers on GABA release at their terminals and their impact on motor behavior remain unknown. In this study, we investigate the presence of CB1-GPR55 heteromers on striatonigral neurons and their axon terminals, and also assess their impact on cAMP accumulation, GABA release, and motor behavior. Furthermore, we explore the effects of sequential receptor activation to examine the phenomenon of increased dimerization induced by receptor activation. A PLA assay combined with Substance P immunofluorescence demonstrated the presence of CB1-GPR55 heteromers in the dorsal striatum and substantia nigra of rats. The kainic acid lesion in the striatum leads to a decrease in PLA dots in both regions. Sequential activation of CB1R, followed by GPR55 activation (CB1→GPR55), increased cAMP accumulation and GABA release at the nigral terminals more compared to GPR55 alone activation. In contrast, simultaneous activation (CB1 + GPR55) or the reverse (GPR55→CB1) did not affect the stimulation effects of GPR55 on cAMP accumulation or GABA release. Additionally, CB1/GPR55 immunoprecipitation in synaptosomes revealed an increase during the sequential activation of CB1→GPR55. Treatments with PTx or ChTx did not alter the effects of CB1→GPR55 sequential activation on GABA release. Finally, intranigral injections of a CB1→GPR55 agonist induced more contralateral turns than GPR55 activation alone. These findings indicate that the sequential activation of CB1→GPR55 within CB1/GPR55 heteromers in striatonigral neurons enhances cAMP accumulation, GABA release, and motor behavior by increasing heteromerization via CB1 activation.

Background: This study analyzed 57 patients with glioblastoma treated at the General University Hospital of Castellon, Spain, focusing on clinical, tumor-specific and genetic factors influencing disease outcome. Variables included age, sex, BMI, extent of surgical resection, and use of radiotherapy or chemotherapy. Tumor characteristics assessed included location, size, proximity to the ventricular system and surgical approach. Genetic mutations in the EGFR, TP53 and CDKN2A genes were also analyzed.

Methods: Kaplan-Meier survival analysis was used to assess the impact of clinical, tumor-related, treatment, lifestyle and genetic variables on overall survival and progression-free survival, with group differences evaluated using log-rank tests. Given the exploratory nature of the study and the sample size, multivariable modeling was not performed. Patients with IDH1/2-mutant tumors were excluded in accordance with the 2021 World Health Organization (WHO) classification, which no longer defines IDH-mutant grade 4 astrocytomas as glioblastoma.

Results: A significant finding was the strong association between extent of resection, tumor proximity to the ventricular system and survival: patients with tumors closer to the ventricles had significantly shorter survival, highlighting the critical role of spatial tumor characteristics in glioblastoma outcomes.

Conclusion: These results suggest that integrating clinical, genetic and spatial tumor data into personalized treatment approaches could improve prognosis.

Introduction: Substance use disorder (SUD) is a complex neurobiological disorder characterized by the consolidation of maladaptive neuroplasticity affecting dopaminergic, glutamatergic, and neurotrophic systems, as well as cortical and subcortical networks critical for executive control, emotional regulation, and associative learning.

Methods: This systematic review was conducted in accordance with PRISMA 2020 guidelines and integrated 57 studies published between 2020 and 2025 to analyze neuroplastic mechanisms involved in vulnerability to substance use disorder and brain recovery following chronic substance exposure.

Results: The findings revealed consistent alterations in synaptic density, BDNF/TrkB signaling, glutamatergic homeostasis, and epigenetic regulation, along with structural and functional neuroimaging changes in regions such as the prefrontal cortex (PFC), nucleus accumbens (NAc), and amygdala. Four core therapeutic domains for neuroplastic restoration were identified: neuromodulation approaches (including repetitive transcranial magnetic stimulation, transcranial direct current stimulation, and deep brain stimulation), compounds that promote neuroplasticity via neurotrophic signaling, epigenetic and anti-inflammatory interventions, and psychological therapies based on memory reconsolidation processes. These strategies demonstrated the capacity to normalize prefrontal activity, modulate reward networks, strengthen emotional regulation, and reduce craving.

Conclusion: Despite significant advances, important gaps remain, including methodological heterogeneity, scarcity of longitudinal studies, and limited clinical generalizability. Overall, the evidence suggests that recovery from substance use disorder requires multimodal interventions simultaneously targeting molecular, synaptic, and circuit-level plasticity, with growing emphasis on personalized approaches guided by neurobiological biomarkers.

Peroxisomes are dynamic organelles that play a crucial role in cellular metabolism, particularly in fatty acid degradation, cholesterol homeostasis and reactive oxygen species metabolism. Their dysfunction is associated with severe neurological disorders, including Zellweger spectrum disorders (ZSD) and X-linked adrenoleukodystrophy (X-ALD). In this study, we investigated the relationship between cholesterol homeostasis and myelination in postnatal peroxisome-deficient Pex2 knockout mice. We dissected the central nervous system (CNS) of 10-day-old (P10) control and Pex2 ^-/- mice into five regions: spinal cord, brainstem, cerebellum, diencephalon and cerebral cortex. Catalase activity, a marker enzyme of peroxisomes, was significantly increased in CNS regions of Pex2 ^-/- mice, indicating an oxidative imbalance. Proteomic analysis revealed significant alterations in peroxisomal proteins and pathways related to neurodegenerative diseases, cholesterol and fatty acid metabolism and mRNA processing. Cholesterol biosynthesis was particularly dysregulated: enzyme activities, mRNA, and protein levels were reduced in white matter regions but increased in the cerebral cortex. The elevated desmosterol levels in the brain of Pex2 ^-/- mice indicate impaired cholesterol synthesis. Sphingolipid metabolism was also altered in the peroxisome-deficient CNS, as the protein levels of enzymes dihydroceramide desaturase 1, ceramide synthase 2, fatty acid 2-hydroxylase, and UDP-glycosyltransferase 8 were significantly decreased. Myelination was significantly reduced throughout the CNS, as evidenced by decreased activities of the myelin marker 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP) and decreased mRNA and protein levels of myelin-associated proteins. The consistent decrease in ribosomal protein S6 phosphorylation in the CNS of Pex2 ^-/- mice suggests that decreased mechanistic target of rapamycin complex 1 (mTORC1) activity contributes to hypomyelination. Gene expression analysis revealed an upregulation of pro-inflammatory cytokines and altered expression of some homeostatic and disease-associated microglial (DAM) genes. However, full DAM activation was not yet observed in Pex2 ^-/- mice at P10. In conclusion, this study shows that systemic peroxisome deficiency leads to severe hypomyelination and dysregulation of cholesterol and fatty acid metabolism in the CNS, providing new insights into the pathophysiology of peroxisomal disorders.

Mesenchymal stem cells (MSCs) have been studied as a potential therapy for a wide range of conditions for approximately 30 years. MSCs have shown promise in treating pathologies of or affecting the central nervous system (CNS), specifically Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), stroke, spinal cord injury (SCI), traumatic brain injury (TBI), degenerative disc disease (DDD), and sepsis/meningitis. The therapeutic benefits of MSCs derive primarily from their arsenal of secreted factors that promote anti-inflammatory and pro-survival pathways while attenuating harmful immune responses, thus making them powerful immunomodulatory entities which are also capable of affecting a diverse range of cellular functions to promote endogenous mechanisms of repair. This review summarizes the current state of clinical trials research regarding pathologies of the CNS with a focus on historical progression and upcoming trials. We take a mechanistic approach to explain the therapeutic basis of MSCs and how this has informed clinical trials. We also mention the role of the MSC secretome and MSC exosomes in the treatment of CNS pathologies as well as their increasing use in clinical trials. Finally, we address the challenges inherent to the clinical translation and implementation of MSC therapies along with future directions of the field.