Astrocytes undergo phenotypic changes with aging, contributing to neurodegenerative diseases and cognitive impairments in later life. The temporoammonic (TA) pathway terminates at the stratum lacunosum-moleculare (SLM) of the CA1 region, where astrocytic support is crucial for synaptic plasticity and information processing related to spatial learning and memory. This study tested the hypothesis that age-related morphological changes in astrocytes of the SLM affect cognitive performance and we explored whether masticatory activity modulates these changes. Young (6 months) and aged (18 months) female Swiss albino mice were subjected to three distinct masticatory regimens: a hard diet (HD), HD followed by a soft diet (HD/SD), or HD followed by SD and a return to HD (HD/SD/HD). Cognitive performance was assessed using the Morris Water Maze (MWM), with learning rates calculated from escape latencies throughout five days of trials. After behavioral testing, the mice were culled and immunohistochemical analysis of glial fibrillary acidic protein (GFAP) expression was performed. 3D reconstructions of astrocytes within the SLM were generated and analyzed. Hierarchical clustering identified distinct astrocyte morphotypes, revealing a significant age-related shift from high-complexity astrocytes (AST1) toward lower-complexity subtypes (AST2 and AST3). In the AST1 phenotype, aging did not significantly alter astrocytic complexity in animals maintained under normal masticatory conditions (HD group) in the dorsal region, then, AST1 may represent a more stable and aging-driven astrocytic phenotype, with limited sensitivity to masticatory modulation during advanced aging. Therefore, in AST2 of HD group, aged animals exhibited greater complexity compared to young animals, suggesting the occurrence of adaptive or compensatory astroglial remodeling during physiological aging. Behavioral analysis showed an age-dependent reduction in learning performance in the HD group, where 18 M mice exhibited a significantly lower contrast index than 6 M old mice on day 4 of the Morris Water Maze task. These findings highlight that morphological changes in astrocytes within the dorsal SLM may contribute to age-related alterations in hippocampus-dependent learning. Overall, maintaining proper mastication may be an effective approach to maintain astrocytic integrity during aging and preserve hippocampus-dependent cognitive function, particularly in older individuals.

BackgroundAlzheimer’s disease (AD), a complex neurodegenerative disease associated with ageing, is the leading cause of dementia. Few people with early AD are eligible for the novel Food and Drug Administration (FDA)-approved drug treatments. Accordingly, new tools and early diagnosis markers are required to predict subtypes, individual stages, and the most suitable personalized treatment. We previously demonstrated that the regulation of microRNA (miR)-124 is crucial for proper neuronal function and microglia reshaping in human AD cell models.ObjectiveThe aim of this study was to develop an efficient miR-124-3p-loaded exosome strategy and validate its therapeutic potential in using a multi-compartment microfluidic device of neuron–glia that recapitulates age-AD pathological features.Methods and resultsUsing cortical microglia from mouse pups, separated from glial mixed cultures and maintained for 2 days in vitro (stressed microglia), we tested the effects of SH-SY5Y-derived exosomes loaded with miR-124-3p mimic either by their direct transfection with Exo-Fect™ (ET124) or by their isolation from the secretome of miR-124 transfected cells (CT124). ET124 revealed better delivery effciency and higher potent effects in improving the stressed microglia status than CT124. Tricultures of human SH-SY5Y neuroblastoma cells (SH-WT) were established in the presence of the human microglia cell line (HMC3) and immortalized human astrocytes (IM-HA) in tricompartmentalized microfluidic devices. Replacement of SH-WT cells with those transfected with APP695 (SH-SWE) in the tricultures and addition of low doses of hydrogen peroxide were used to simulate late-onset AD. The system mimicked AD-associated neurodegeneration and neuroinflammation processes. Notably, ET124 exhibited neuroprotective properties across the three cell types in the AD model by preventing neuronal apoptosis and neurite deficits, redirecting microglial profiles towards a steady state, and attenuating the inflammatory and miRNA fingerprints associated with astrocyte reactivity.ConclusionTo the best of our knowledge, this is the first study supporting the neuro- and immunoprotective properties of miR-124-engineered exosomes in a microfluidic triculture platform, recapitulating age-related susceptibility to AD. Our system offers potential to develop personalized medicines in AD patient subtypes.

Adult neurogenesis is dysregulated in neurological disorders, including depression. Adult neural stem cells (NSCs) are close to the vasculature and the cerebrospinal fluid, placing them in an ideal position to receive extrinsic signals and transmit these cues to the neurogenic niche. Herein, we aimed to explore how different systemic cues influence the regenerative properties of NSC secretome on recipient differentiating cells and microglia, key neurogenic components. To mimic signals that NSCs may sense in pathological conditions, we used the secretome of oxidative damaged cells (acute oxidative damage), and the serum from depressed mice (depression-associated chronic signals). Alternatively, NSCs were conditioned with different mitochondrial metabolic regulators to mimic a pro-metabolic NSC environment. Results showed that both injury and metabolic stimuli triggered the increase of NSC proliferation and mitochondrial fragmentation, along with the delivery of a neuroprotective secretome toward injured recipient cells. However, premature differentiation was only observed in NSCs sensing depression-associated chronic signals. The secretome from metabolic-stimulated NSCs favored neurogenesis of target cells, being enriched in regenerative metabolites. Depression-associated signals promoted a NSC secretome with reduced regenerative metabolites and microRNAs that repressed microglial phagocytosis and differentiation in target NSCs. At last, the reduction of oxidative phosphorylation-related proteins in the neurogenic niche of depressed mice was rescued by physical exercise. Our data indicate a central role of external metabolic and injury signals in regulating the neurogenic niche through NSC paracrine activity, unveiling distinct NSC regenerative responses upon transient acute and chronic injuries, and new cues for physical exercise-induced alleviation of depression.

Visual cortical plasticity during early postnatal life is profoundly shaped by species-specific ocular anatomy and ecological demands. This review synthesizes comparative evidence on how monocular deprivation (MD)—a classical model of amblyopia—affects visual system development in frontal- versus lateral-eyed mammals. Frontal-eyed species, including cats and primates, exhibit extensive binocular field overlaps and columnar architecture in the primary visual cortex (V1), making them highly susceptible to MD-induced shifts in ocular dominance and synaptic remodeling. In contrast, lateral-eyed species such as rodents and ungulates possess limited binocular overlaps and lack well-defined ocular dominance columns yet still demonstrate significant MD-induced plasticity involving callosal reorganization, glial activation, and extracellular matrix remodeling. We examine shared and divergent cellular mechanisms underpinning these responses, including the role of parvalbumin-expressing interneurons, perineuronal nets, and neuromodulators like BDNF and NRG1. Rodent models support the notion that even in the absence of classical columnar organization, lateral-eyed species can undergo region-specific structural remodeling in V1 following MD. These distinctions underscore how binocular integration circuits are fine-tuned through extended critical periods in frontal-eyed species, whereas plasticity in lateral-eyed species is more diffusely distributed. The integration of cross-species data revealed conserved principles of visual cortical plasticity and identified mechanisms potentially targetable for amblyopia therapy. Understanding the ecological and anatomical context of plasticity allows for a more accurate interpretation of animal models and supports the development of precision strategies for visual rehabilitation. This comparative framework expands the scope of amblyopia research and offers new avenues for translational interventions.

OBJECTIVE:We sought to investigate the plasticity of diet-induced changes in astrocyte morphology of stratum lacunosum-moleculare (SLM) in CA1. DESIGN:Three diet regimes were adopted in 15 mice, from the 21st postnatal day to 6 months. The first diet regimen was pellet feed, called Hard Diet (HD). The second, with reduced masticatory, received a pellet-diet followed by a powdered-diet, and it was identified as Hard Diet/Soft Diet (HD/SD). Finally, the group with rehabilitated masticatory was named Hard Diet/Soft Diet/Hard Diet (HD/SD/HD). In the end, euthanasia and brain histological processing were performed, in which astrocytic immunoreactivity to glial-fibrillary-acidic-protein (GFAP) was tested. In reconstructed astrocytes, morphometric analysis was performed. RESULTS:Astrocyte morphometric revealed that changes in masticatory regimens impact astrocyte morphology. In the dorsal CA1, switching from a hard diet to a soft diet led to reductions in most variables, whereas in the ventral, fewer variables were affected, highlighting regional differences in astrocyte responses. Cluster analysis further showed that diet-induced changes in astrocyte morphology were reversible in the dorsal region, but not in the ventral region, indicating a persistent impact on astrocyte diversity and complexity in the ventral even after rehabilitation. Correlation tests between astrocyte morphology and behavioral performance demonstrated disrupted relationships under masticatory stress, with effects persisting after rehabilitation. CONCLUSION:Changes in the diet result in significant alterations in astrocyte morphology, suggesting a direct link between dietary modulation and cellular structure. Morphometric analyses revealed distinct alterations in astrocyte morphology in response to changes in the masticatory regimen, with both dorsal/ventral regions displaying notable changes. Moreover, the regional differential effects on astrocytes underscore the complexity of mastication on neuroplasticity and cognitive function.

The dentate gyrus plays a crucial role in learning and spatial memory, particularly in its middle third molecular layer, which receives the primary afferent input via the medial perforant path. Interestingly, changes in masticatory activity are described to affect this region with visible astrogliosis, release of pro-inflammatory cytokines and oxidative stress, affecting synaptic physiology, and cognition. This study aimed to investigate the impact of altered masticatory activity on spatial memory in young Swiss albino mice, correlating these effects with morphological changes in astrocytes. The mice were divided into three groups: Hard diet with pellets (HD), hard diet/soft diet (HD/SD, reduced masticatory activity), and HD/SD/HD (rehabilitated). The Morris water maze test was used to measure escape latency, while three-dimensional microscopic reconstruction methods provided morphometric data on the astrocytes. Hierarchical clustering analysis validated the existence of four morphological subtypes with decreasing complexity (AST1, AST2, AST3, and AST4), in the outer, middle, and inner thirds of the dentate gyrus molecular layer. Changes in masticatory activity affected the number and distribution of astrocytes subtypes excepting AST3 in the middle third layer. Canonical discriminant function analysis indicated that complexity was the variable most influencing cluster formation. Correlation tests between complexity and escape latency for each animal group showed a significant correlation with a large effect size of 60 % [Pearson's R: 0.605, p < 0.0011 in the HD group in the middle third, which was disrupted by altered masticatory activity. AST3 morphotype in the middle third showed a linear correlation with learning and spatial memory functions in the HD group [Pearson's R: 0.624, p < 0.0011 that disappeared with a reduction in masticatory activity, and nor restored by diet rehabilitation. This finding was not observed for inner and outer layers, supporting the contribution of middle third AST3 to learning and spatial memory. Group comparison tests also revealed that diet differentially impacts astrocyte subpopulations on each third of the dentate gyrus molecular layer. Data validate the influence of the masticatory activity on astrocyte complexity and suggest the existence of AST3 association with spatial memory and learning tasks in young female mice. Further research on the underlying mechanisms of these relationships is essential to identify potential therapeutic targets for cognitive disorders and to develop effective interventions to preserve cognitive function.

With the aging of the global population, neurodegenerative diseases are emerging as a major public health issue. The adoption of a less sedentary lifestyle has been shown to have a beneficial effect on cognitive decline, but the molecular mechanisms responsible are less clear. Here we provide a detailed analysis of the complex molecular, cellular, and systemic mechanisms underlying age-related cognitive decline and how lifestyle choices influence these processes. A review of the evidence from animal models, human studies, and postmortem analyses emphasizes the importance of integrating physical exercise with cognitive, multisensory, and motor stimulation as part of a multifaceted approach to mitigating cognitive decline. We highlight the potential of these non-pharmacological interventions to address key aging hallmarks, such as genomic instability, telomere attrition, and neuroinflammation, and underscore the need for comprehensive and personalized strategies to promote cognitive resilience and healthy aging.

MicroRNAs (miRNAs) play a crucial role in the regulation of gene expression levels and have been implicated in the pathogenesis of autism spectrum disorder (ASD) and schizophrenia (SCZ). In this study, we examined the adult expression profiles of specific miRNAs in the prefrontal cortex (PFC) of a neurodevelopmental mouse model for ASD and SCZ that mimics perinatal pathology, such as NMDA receptor hypofunction, and exhibits behavioral and neurophysiological phenotypes related to these disorders during adulthood. To model the early neuropathogenesis of the disorders, mouse pups were administered subcutaneously with ketamine (30 mg/Kg) at postnatal days 7, 9, and 11. We focused on a set of miRNAs most frequently altered in ASD (miR-451a and miR-486-3p) and in SCZ (miR-132-3p and miR-137-3p) according to human studies. Additionally, we explored miRNAs whose alterations have been identified in both disorders (miR-21-5p, miR-92a-2-5p, miR-144-3p, and miR-146a-5p). We placed particular emphasis on studying the sexual dimorphism in the dynamics of these miRNAs. Our findings revealed significant alterations in the PFC of this ASD- and SCZ-like mouse model. Specifically, we observed upregulated miR-451a and downregulated miR-137-3p. Furthermore, we identified sexual dimorphism in the expression of miR-132-3p, miR-137-3p, and miR-92a-2-5p. From a translational perspective, our results emphasize the potential involvement of miR-92a-2-5p, miR-132-3p, miR-137-3p, and miR-451a in the pathophysiology of ASD and SCZ and strengthen their potential as biomarkers and therapeutic targets of such disorders.

Since the identification of human immunodeficiency virus type 1 (HIV-1) in 1983, many improvements have been made to control viral replication in the peripheral blood and to treat opportunistic infections. This has increased life expectancy but also the incidence of age-related central nervous system (CNS) disorders and HIV-associated neurodegeneration/neurocognitive impairment and depression collectively referred to as HIV-associated neurocognitive disorders (HAND). HAND encompasses a spectrum of different clinical presentations ranging from milder forms such as asymptomatic neurocognitive impairment or mild neurocognitive disorder to a severe HIV-associated dementia (HAD). Although control of viral replication and suppression of plasma viral load with combination antiretroviral therapy has reduced the incidence of HAD, it has not reversed milder forms of HAND. The objective of this review, is to describe the mechanisms by which HIV-1 invades and disseminates in the CNS, a crucial event leading to HAND. The review will present the evidence that underlies the relationship between HIV infection and HAND. Additionally, recent findings explaining the role of neuroinflammation in the pathogenesis of HAND will be discussed, along with prospects for treatment and control.

As the global population ages, the prevalence of neurodegenerative diseases has become a major public health concern. The adoption of a less sedentary lifestyle has been shown to have a beneficial effect on cognitive decline, but the molecular mechanisms responsible are less clear. Here we provide a detailed analysis of the complex molecular, cellular, and systemic mechanisms underlying age-related cognitive decline and how lifestyle choices influence these processes. A review of the evidence from animal models, human studies, and postmortem analyses emphasizes the importance of integrating physical exercise with cognitive, multisensory, and motor stimulation as part of a multifaceted approach to mitigating cognitive decline. We highlight the potential of these non-pharmacological interventions to address key aging hallmarks—such as genomic instability, telomere attrition, and neuroinflammation—and underscore the need for comprehensive and personalized strategies to promote cognitive resilience and healthy aging.

Our study investigated the innate immune response to Toxoplasma gondii infection by assessing microglial phenotypic changes and sickness behavior as inflammatory response markers post-ocular tachyzoite instillation. Disease progression in Swiss albino mice was compared with the previously documented outcomes in BALB/c mice using an identical ocular route and parasite burden (2 × 105 tachyzoites), with saline as the control. Contrary to expectations, the Swiss albino mice displayed rapid, lethal disease progression, marked by pronounced sickness behaviors and mortality within 11–12 days post-infection, while the survivors exhibited no apparent signs of infection. Comparative analysis revealed the T. gondii-infected BALB/c mice exhibited reduced avoidance of feline odors, while the infected Swiss albino mice showed enhanced avoidance responses. There was an important increase in microglial cells in the dentate gyrus molecular layer of the infected Swiss albino mice compared to the BALB/c mice and their respective controls. Hierarchical cluster and discriminant analyses identified three microglial morphological clusters, differentially affected by T. gondii infection across strains. The BALB/c mice exhibited increased microglial branching and complexity, while the Swiss albino mice showed reduced shrunken microglial arbors, diminishing their morphological complexity. These findings highlight strain-specific differences in disease progression and inflammatory regulation, indicating lineage-specific mechanisms in inflammatory responses, tolerance, and resistance. Understanding these elements is critical in devising control measures for toxoplasmosis.

Alzheimer’s disease (AD), the leading cause of dementia, is a multifactorial disease influenced by aging, genetics, and environmental factors. miRNAs are crucial regulators of gene expression and play significant roles in AD onset and progression. This exploratory study analyzed the expression levels of 28 genes and 5 miRNAs (miR-124-3p, miR-125b-5p, miR-21-5p, miR-146a-5p, and miR-155-5p) related to AD pathology and neuroimmune responses using RT-qPCR. Analyses were conducted in the prefrontal cortex (PFC) and the hippocampus (HPC) of the 5xFAD mouse AD model at 6 and 9 months old. Data highlighted upregulated genes encoding for glial fibrillary acidic protein (Gfap), triggering receptor expressed on myeloid cells (Trem2) and cystatin F (Cst7), in the 5xFAD mice at both regions and ages highlighting their roles as critical disease players and potential biomarkers. Overexpression of genes encoding for CCAAT enhancer-binding protein alpha (Cebpa) and myelin proteolipid protein (Plp) in the PFC, as well as for BCL2 apoptosis regulator (Bcl2) and purinergic receptor P2Y12 (P2yr12) in the HPC, together with upregulated microRNA(miR)-146a-5p in the PFC, prevailed in 9-month-old animals. miR-155 positively correlated with miR-146a and miR-21 in the PFC, and miR-125b positively correlated with miR-155, miR-21, while miR-146a in the HPC. Correlations between genes and miRNAs were dynamic, varying by genotype, region, and age, suggesting an intricate, disease-modulated interaction between miRNAs and target pathways. These findings contribute to our understanding of miRNAs as therapeutic targets for AD, given their multifaceted effects on neurons and glial cells.

The hippocampus is important for memory formation and is severely affected in the brain with Alzheimer disease (AD). Our understanding of early pathogenic processes occurring in hippocampi in AD is limited due to tissue unavailability. Here, we report a chemical approach to rapidly generate free-floating hippocampal spheroids (HSs), from human induced pluripotent stem cells. When used to model AD, both APP and atypical PS1 variant HSs displayed increased A beta 42/A beta 40 peptide ratios and decreased synaptic protein levels, which are common features of AD. However, the two variants differed in tau hyperphosphorylation, protein aggregation, and protein network alterations. NeuroD1-mediated gene therapy in HSs-derived progenitors resulted in modulation of expression of numerous genes, including those involved in synaptic transmission. Thus, HSs can be harnessed to unravel the mechanisms underlying early pathogenic changes in the hippocampi of AD patients, and provide a robust platform for the development of therapeutic strategies targeting early stage AD.