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Oligodendrocyte precursor cells (OPCs) account for 5% of the resident parenchymal central nervous system glial cells. OPCs are not only a back-up for the loss of oligodendrocytes that occurs due to brain injury or inflammation-induced demyelination (remyelination) but are also pivotal in plastic processes such as learning and memory (adaptive myelination). OPC differentiation into mature myelinating oligodendrocytes is controlled by a complex transcriptional network and depends on high metabolic and mitochondrial demand. Mounting evidence shows that OPC dysfunction, culminating in the lack of OPC differentiation, mediates the progression of neurodegenerative disorders such as multiple sclerosis, Alzheimer’s disease and Parkinson’s disease. Importantly, neurodegeneration is characterised by oxidative and carbonyl stress, which may primarily affect OPC plasticity due to the high metabolic demand and a limited antioxidant capacity associated with this cell type. The underlying mechanisms of how oxidative/carbonyl stress disrupt OPC differentiation remain enigmatic and a focus of current research efforts. This review proposes a role for oxidative/carbonyl stress in interfering with the transcriptional and metabolic changes required for OPC differentiation. In particular, oligodendrocyte (epi)genetics, cellular defence and repair responses, mitochondrial signalling and respiration, and lipid metabolism represent key mechanisms how oxidative/carbonyl stress may hamper OPC differentiation in neurodegenerative disorders. Understanding how oxidative/carbonyl stress impacts OPC function may pave the way for future OPC-targeted treatment strategies in neurodegenerative disorders.

The ongoing fight against mosquito-borne diseases such as dengue, Zika, and chikungunya is increasingly challenged by Aedes aegypti resistance to pyrethroid insecticides. This resistance is primarily driven by knockdown resistance (kdr) mutations in the voltage-gated sodium channel ( Vgsc ) gene, which have been identified in different regions with significant variability in their prevalence and impact. Managing Ae. aegypti populations in the face of this resistance require in-depth understanding of the global distribution of kdr mutations and their relationship to insecticide use patterns. This narrative review identifies a diverse landscape of kdr mutations, with common mutations such as V1016I, F1534C, and L982W, the latter of which has recently gained attention as an important mutation contributing to resistance in various regions, often co-occurring with other mutations and leading to enhanced resistance phenotypes. Additional mutations including V410L, G923V, S989P, I1011M/V, and D1763Y further complicate the resistance profile, indicating a dynamic evolution of resistance in response to pyrethroid use. This review also highlights significant gaps in current research, particularly in understanding the interaction between kdr mutations and other resistance mechanisms, such as metabolic detoxification by enzymes like cytochrome P450s, glutathione S -transferases (GST), and esterases, and the need for more standardized methodologies for data collection and reporting. The widespread use of pyrethroids has significantly contributed to the global spread of kdr mutations in Ae. aegypti , thereby challenging the efficacy of the current chemical vector control strategies. Despite these challenges, pyrethroids remain essential for mosquito control owing to their proven efficacy, rapid action, and versatility. However, the rising levels of resistance highlight the need for an integrated approach to vector management that combines chemical, biological, and community-based strategies. Future research should address these gaps through longitudinal studies and the development of new insecticides and resistance management strategies to address the growing threat of insecticide resistance in Ae. aegypti and protect public health. Graphical Abstract

Background In response to brain injury or inflammation, astrocytes undergo hypertrophy, proliferate, and migrate to the damaged zone. These changes, collectively known as \"astrogliosis\", initially protect the brain; however, astrogliosis can also cause neuronal dysfunction. Additionally, these astrocytes undergo intracellular changes involving alterations in the expression and localization of many proteins, including α v β 3 integrin. Our previous reports indicate that Thy-1, a neuronal glycoprotein, binds to this integrin inducing Connexin43 (Cx43) hemichannel (HC) opening, ATP release, and astrocyte migration. Despite such insight, important links and molecular events leading to astrogliosis remain to be defined. Methods Using bioinformatics approaches, we analyzed different Gene Expression Omnibus datasets to identify changes occurring in reactive astrocytes as compared to astrocytes from the normal mouse brain. In silico analysis was validated by both qRT-PCR and immunoblotting using reactive astrocyte cultures from the normal rat brain treated with TNF and from the brain of a hSOD1 G93A transgenic mouse model. We evaluated the phosphorylation of Cx43 serine residue 373 (S373) by AKT and ATP release as a functional assay for HC opening. In vivo experiments were also performed with an AKT inhibitor (AKTi). Results The bioinformatics analysis revealed that genes of the PI3K/AKT signaling pathway were among the most significantly altered in reactive astrocytes. mRNA and protein levels of PI3K, AKT, as well as Cx43, were elevated in reactive astrocytes from normal rats and from hSOD1 G93A transgenic mice, as compared to controls. In vitro, reactive astrocytes stimulated with Thy-1 responded by activating AKT, which phosphorylated S373Cx43. Increased pS373Cx43 augmented the release of ATP to the extracellular medium and AKTi inhibited these Thy-1-induced responses. Furthermore, in an in vivo model of inflammation (brain damage), AKTi decreased the levels of astrocyte reactivity markers and S373Cx43 phosphorylation. Conclusions Here, we identify changes in the PI3K/AKT molecular signaling network and show how they participate in astrogliosis by regulating the HC protein Cx43. Moreover, because HC opening and ATP release are important in astrocyte reactivity, the phosphorylation of Cx43 by AKT and the associated increase in ATP release identify a potential therapeutic window of opportunity to limit the adverse effects of astrogliosis.

Background The brain cortex is responsible for many higher-level cognitive functions. Disruptions during cortical development have long-lasting consequences on brain function and are associated with the etiology of brain disorders. We previously found that the protein tyrosine phosphatase receptor delta Ptprd, which is genetically associated with several human neurodevelopmental disorders, is essential to cortical brain development. Loss of Ptprd expression induced an aberrant increase of excitatory neurons in embryonic and neonatal mice by hyper-activating the pro-neurogenic receptors TrkB and PDGFRβ in neural precursor cells. However, whether these alterations have long-lasting consequences in adulthood remains unknown. Results Here, we found that in Ptprd+/- or Ptprd-/- mice, the developmental increase of excitatory neurons persists through adulthood, affecting excitatory synaptic function in the medial prefrontal cortex. Likewise, heterozygosity or homozygosity for Ptprd also induced an increase of inhibitory cortical GABAergic neurons and impaired inhibitory synaptic transmission. Lastly, Ptprd+/- or Ptprd-/- mice displayed autistic-like behaviors and no learning and memory impairments or anxiety. Conclusions These results indicate that loss of Ptprd has long-lasting effects on cortical neuron number and synaptic function that may aberrantly impact ASD-like behaviors.

Schizophrenia (SZ) is associated with changes in the structure and function of several brain areas. Several findings suggest that these impairments are related to a dysfunction in γ-aminobutyric acid (GABA) neurotransmission in brain areas such as the medial prefrontal cortex (mPFC), the hippocampus (HPC) and the primary auditory cortex (A1); however, it is still unclear how the GABAergic system is disrupted in these brain areas. Here, we examined the effect of ketamine (Ket) administration during late adolescence in rats on inhibition in the mPFC-, ventral HPC (vHPC), and A1. We observe that Ket treatment reduced the expression of the calcium-binding protein parvalbumin (PV) and the GABA-producing enzyme glutamic acid decarboxylase 67 (GAD67) as well as decreased inhibitory synaptic efficacy in the mPFC. In addition, Ket-treated rats performed worse in executive tasks that depend on the integrity and proper functioning of the mPFC. Conversely, we do not find such changes in vHPC or A1. Together, our results provide strong experimental support for the hypothesis that during adolescence, the function of the mPFC is more susceptible than that of HPC or A1 to NMDAR hypofunction, showing apparent structure specificity. Thus, the impairment of inhibitory circuitry in mPFC could be a convergent primary site of SZ-like behavior during the adulthood.

The excitatory amino acid transporter EAAT3 plays an important role in the neuronal uptake of glutamate regulating the activation of glutamate receptors. Polymorphisms in the gene-encoding EAAT3 have been associated with obsessive–compulsive disorder (OCD), although the mechanisms underlying this relationship are still unknown. We recently reported that mice with increased EAAT3 expression in forebrain neurons (EAAT3 g lo /CMKII) display behavioral and synaptic features relevant to OCD, including increased grooming, higher anxiety-like behavior and altered cortico-striatal synaptic function. The dopamine neurotransmitter system is implicated in ritualistic behaviors. Indeed, dopaminergic neurons express EAAT3, and mice lacking EAAT3 exhibit decreased dopamine release and decreased expression of the dopamine D1 receptor. Moreover, EAAT3 plays a role on the effect of the psychostimulant amphetamine. As such, we sought to determine if the OCD-like behavior in EAAT3 g lo /CMKII mice is accompanied by altered nigro-striatal dopaminergic transmission. The aim of this study was to analyze dopamine transmission both in basal conditions and after an acute challenge of amphetamine, using behavioral, neurochemical, molecular, and cellular approaches. We found that in basal conditions, EAAT3 g lo /CMKII mice performed more grooming events and that they remained in phase 1 of the grooming chain syntax compared with control littermates. Administration of amphetamine increased the number of grooming events in control mice, while EAAT3 g lo /CMKII mice remain unaffected. Interestingly, the grooming syntax of amphetamine-control mice resembled that of EAAT3 g lo /CMKII mice in basal conditions. Using in vivo microdialysis, we found decreased basal dopamine levels in EAAT3 g lo /CMKII compared with control mice. Unexpectedly, we found that after acute amphetamine, EAAT3 g lo /CMKII mice had a higher release of dopamine compared with that of control mice, suggesting that EAAT3 overexpression leads to increased dopamine releasability. To determine postsynaptic effect of EAAT3 overexpression over dopamine transmission, we performed Western blot analysis of dopaminergic proteins and found that EAAT3 g lo /CMKII mice have higher expression of D2 receptors, suggesting a higher inhibition of the indirect striatal pathway. Together, the data indicate that EAAT3 overexpression impacts on dopamine transmission, making dopamine neurons more sensitive to the effect of amphetamine and leading to a disbalance between the direct and indirect striatal pathways that favors the performance of repetitive behaviors.

In this special issue, O. Khalaf and J. Gräff provided a comprehensive review on the mechanisms mediating the transformation from an unstable memory to a lasting one, including neural circuits and subpopulations of cells that can be recruited into a memory trace, as well as the structural changes occurring at synapses during memory formation. P. Espinosa et al. examined the effect of neonatal exposure to sex hormones in the programming of dopaminergic neurons resulting in increased expression of tyrosine hydroxylase in ventral tegmental area and substantia nigra. In particular, in the article by B. Seifert et al., they elegantly demonstrated that the amyloid-beta peptide causes a dysfunction in vesicular transport of brain derived neurotrophic factor in transgenic mouse models of Alzheimer’s disease. Understanding the precise interaction of synaptically relevant transcriptional regulation can have therapeutic potential for treatments and possibly improving these conditions, and the work by P. Lobos et al. fits within this premise: since it is known that oxidative stress contributes to the development of Alzheimer’s disease, they studied the effect of astaxanthin, an antioxidant having free access to the brain, on the aberrant calcium signaling and decreased expression of type-2 ryanodine receptors (RyR2) induced by amyloid-β peptide oligomers (AβOs).

There is a growing interest in investigating the effects of physical exercise on cognitive performance, particularly episodic memory. Similarly, an increasing number of studies in recent decades have studied the effects of physical activity on mood and anxiety disorders. Moreover, the COVID-19 pandemic has raised awareness of the importance of regular physical activity for both mental and physical health. Nevertheless, the exact mechanisms underlying these effects are not fully understood. Interestingly, recent findings suggest that the serotonergic system may play a key role in mediating the effects of physical exercise on episodic memory and anxiety. In this review, we discuss the impact of physical exercise on both episodic memory and anxiety in human and animal models. In addition, we explore the accumulating evidence that supports a role for the serotonergic system in the effects of physical exercise on episodic memory and anxiety.

Background Obsessive–compulsive disorder (OCD) is a severe neuropsychiatric condition affecting 1–3% of the worldwide population. OCD has a strong genetic component, and the SLC1A1 gene that encodes neuronal glutamate transporter EAAT3 is a strong candidate for this disorder. To evaluate the impact of reduced EAAT3 expression in vivo, we studied male EAAT3 heterozygous and wild-type littermate mice using a battery of behavioral paradigms relevant to anxiety (open field test, elevated plus maze) and compulsivity (marble burying), as well as locomotor activity induced by amphetamine. Using high-performance liquid chromatography, we also determined tissue neurotransmitter levels in cortex, striatum and thalamus—brain areas that are relevant to OCD. Results Compared to wild-type littermates, EAAT3 heterozygous male mice have unaltered baseline anxiety-like, compulsive-like behavior and locomotor activity. Administration of acute amphetamine (5 mg/kg intraperitoneally) increased locomotion with no differences across genotypes. Tissue levels of glutamate, GABA, dopamine and serotonin did not vary between EAAT3 heterozygous and wild-type mice. Conclusions Our results indicate that reduced EAAT3 expression does not impact neurotransmitter content in the corticostriatal circuit nor alter anxiety or compulsive-like behaviors.

Scientific evidence shows that dietary patterns are a key environmental determinant of mental health. Dietary constituents can modify epigenetic patterns and thus the gene expression of relevant genetic variants in various mental health conditions. In the present work, we describe some nutrigenomic effects of dietary fiber, phenolic compounds (plant secondary metabolites), and fatty acids on mental health outcomes, with emphasis on their possible interactions with genetic and epigenetic aspects. Prebiotics, through their effects on the gut microbiota, have been associated with modulation in the neuroendocrine response to stress and the facilitation of the processing of positive emotions. Some of the genetic and epigenetic mechanisms include the serotonin neurotransmitter system (TPH1 gene) and the brain-derived neurotrophic factor (inhibition of histone deacetylases). The consumption of phenolic compounds exerts a positive role in neurocognitive domains. The evidence showing the involvement of genetic and epigenetic factors comes mainly from animal models, highlighting the role of epigenetic mechanisms through miRNAs and methyltransferases as well as the effect on the expression of apoptotic-related genes. Long-chain n-3 fatty acids (EPA and DHA) have been mainly related to psychotic and mood disorders, but the genetic and epigenetic evidence is scarce. Studies on the genetic and epigenetic basis of these interactions need to be promoted to move towards a precision and personalized approach to medicine.