Journal of Neurochemistry最新文献

Obesity is a worldwide epidemic disease marked by changes in the function of various tissue and organs, driven by excessive fat accumulation. In recent years obesity was characterized not just by the increase of fat, but also an imbalance of energy homeostasis mechanisms. In parallel with global rise in obesity, the incidence of obesity during pregnancy and lactation had also been steadily increasing. Maternal obesity is a public health issue that affects the child and the mother, in acute and chronic term, being a risk factor for the development of metabolic, hormonal, neurodevelopmental, and psychiatric disorders in offspring. Obesity during the gestation can reprogram the fetal immune, metabolic, endocrine, and neurological systems, influencing offspring's metabolism and mental health. This is supported by the Developmental Origins of Health and Disease (DOHaD) theory, which proposes that environmental factors during critical periods of early development (as the fetal period) can influence the risk of developing diseases later in life. In this review, we focused on how maternal obesity can affect the brain offspring neurodevelopment, neural circuits, synapses, glial cells, and neuroinflammation, which all can influence offspring behavioral disorders.

General anesthesia produces a rapid and reversible loss of consciousness, yet the neural circuits through which chemically unrelated agents achieve this state remain largely unknown. Here, we combined Targeted Recombination in Active Populations (TRAP), Clear, Unobstructed Brain/Body Imaging Cocktails and Computational analysis (CUBIC) tissue clearing, and light-sheet microscopy to generate a hemisphere-wide, single-cell atlas of neurons activated by three mechanistically distinct anesthetics in adult Fos^2A-iCreER/+; R26^Ai14/+ (TRAP2; Ai14) female mice. Automated alignment to the Atlas and unbiased effect-size analysis across 252 regions revealed a striking convergence. Vermal cerebellar lobules and their deep nuclei ranked at the top for every drug, whereas neocortical and thalamic areas showed mixed or drug-specific patterns. Within the cerebellum, the major population of tdTomato-labeled cells was the Purkinje cells, as confirmed by manual counting. Two additional subcortical hubs, the lateral paragigantocellular nucleus and external globus pallidus, were activated by all three agents, suggesting a broader cerebello-autonomic network. These results position Purkinje cells as a commonly activated population by chemically divergent anesthetics, raising the possibility that general anesthesia produces a state of loss of consciousness through the activation of Purkinje cells.

During aging, the brain's lipid composition and the cerebrospinal fluid (CSF) secreted by the choroid plexus (ChP) undergo significant modifications. The ChP, an epithelial tissue located in each brain ventricle, experiences a decline in key functions, including protein secretion and CSF production. A critical gap in our understanding of the ChP lies in its lipid composition and the potential impact of age-related changes on its physiology. This study hypothesized that the lipidome of the lateral ventricle choroid plexus (LVCP) is modulated during aging, potentially generating pro-inflammatory mediators. To address this, we performed quantitative lipidomics on LVCP from male and female mice across aging and investigated whether pro-inflammatory lipid mediators increase with age. LVCP and cortex tissues from C57BL/6 mice aged 6, 12, 18, and 24 months (n = 5/age/sex) were analyzed using liquid chromatography–tandem mass spectrometry, and data were processed using Lipidr and univariate statistical methods. Given the pronounced sex differences, analyses were stratified by sex. During aging, 9 lipids in males and 19 in females were significantly modulated. In males, most changes occurred at 24 months and involved higher levels of arachidonic acid (ARA) in alkyl ether and plasmalogen phosphatidylcholine species. In females, most changes occurred at 18 months and were characterized by lower levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), whereas at 24 months, females exhibited higher levels of EPA, DHA, and ARA in alkyl ether and plasmalogens compared to other ages. Additionally, younger females showed higher levels of oxygenated derivatives of linoleic acid compared to older females. These findings reveal dynamic, sex-specific remodeling of the LVCP lipidome during aging, suggesting that lipid homeostasis in this structure is tightly regulated and may influence inflammatory signaling and barrier function in an age-dependent manner.

The oligopeptidase Ndel1 (NudE neurodevelopment protein 1 like 1) is a multifunctional protein implicated in neurodevelopmental processes, intensively investigated as a potential biomarker in psychiatric disorders. While its roles in regulating the cytoskeleton are well-studied, the global consequences of its loss on the brain's peptide landscape are unknown. This study presents a comprehensive, region-resolved peptidomic resource detailing the consequences of postnatal Ndel1 loss in the mouse cortex, hippocampus, striatum, and cerebellum. We also validated this method of microwave protease inactivation followed by acidic and organic extractions by means of this peptidome analysis across several brain regions. More specifically, using a conditional knockout mouse model with Ndel1 deletion in forebrain excitatory neurons, we employed complementary acidic and alcoholic extraction workflows coupled to liquid chromatography–tandem mass spectrometry (LC–MS/MS). We generated a comparative atlas of differentially abundant peptides (DAPs), identifying hundreds of peptide changes across the different brain regions and extraction methods. Gene Ontology analysis of the inferred source proteins revealed alterations in pathways related to cytoskeletal organization, synaptic function, and cellular metabolism. This dataset provides a foundational resource for generating new hypotheses about Ndel1's region-specific functions and serves as a valuable reference for the neurodevelopmental and neuropeptidomics communities. Understanding these Ndel1-driven changes is crucial, providing valuable insights into the pathophysiology of neurodevelopmental and mental disorders linked to reduced Ndel1 activity, such as schizophrenia, autism, and bipolar disorder. This holistic view may reveal novel therapeutic targets for these complex conditions.

The oxytocinergic system is highly responsive to early-life experiences, playing a crucial role in regulating social behaviors. In this study, we examined the effects of a neonatal experience modeling maternal neglect on the oxytocinergic system in the adult rat brain. To investigate this, rat pups were exposed to a T-maze during Postnatal Days 10–13, where prohibition of contact with the mother—which served as the expected reward—constituted a mildly aversive experience (Denial of Expected Reward, DER). Our findings revealed that adult males subjected to the DER experience exhibited reduced levels of close social interaction, which could be ameliorated by acute intranasal oxytocin administration. Moreover, adult DER males had decreased expression of oxytocin receptors (OTR) in the medial nucleus of the amygdala (MeA) accompanied by alterations in the methylation profile of the OTR gene proximal promoter in MeA, specifically increased methylation levels of cytosines at positions −65, −19 and −11. No such effects were detected in the hippocampus or the medial-orbital prefrontal cortex (MO PFC). Notably, in adult females the DER experience did not affect OTR expression in the brain areas examined (MeA, hippocampus and MO PFC) or their social interaction. These results suggest that the aversive early-life experience of DER has affected the epigenetic regulation of OTR expression in a sexually dimorphic, brain region-specific manner, leading to a reduction in oxytocinergic activity within the adult male amygdala, accompanied by impaired social interactions.

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder characterized by balance and gait disturbance, muscle coordination deficits, and dysarthria as a primary symptom. SCA1 is caused by the expansion of CAG repeats in the ATXN1 gene, leading to a polyglutamine(polyQ) tract in the Ataxin-1 protein. In this study, the effects of KDS2010, an inhibitor of monoamine oxidase-B (MAO-B), were evaluated in a transgenic mouse model of SCA1 (SCA1^154Q/2Q) disease model using the rotarod, hindlimb, and open field tests. In both males and females, oral administration of KDS2010 significantly improved latency in the rotarod test and the hindlimb clasping phenotype without changing muscle weight. In the open field test, a notable improvement in moving distance was observed particularly in females. Treatment with KDS2010 slowed molecular layer atrophy and restored the reduced number of Purkinje cells in the cerebellum of SCA1 model mice, accompanied by decreased levels of glial fibrillary acidic protein (GFAP) and reduced expression of monoamine oxidase-B (MAO-B). These results indicate that KDS2010 ameliorated the behavioral pathology of SCA1 by attenuating GFAP upregulation and preventing Purkinje cell loss. Our findings demonstrate that KDS2010 improves SCA1-related behavioral deficits by reducing GFAP expression, preserving Purkinje cell numbers, and decreasing cerebellar MAO-B levels—molecular markers of SCA1, without affecting muscle size.

Hyperhomocysteinemia (HHcy), a condition characterized by elevated plasma levels of the sulfur-containing amino acid homocysteine, has emerged as a multifactorial and systemic risk factor with profound effects on neural and vascular integrity. This review integrates recent findings from epidemiological studies, clinical data, and mechanistic research to provide a comprehensive overview of HHcy's contribution to neurovascular dysfunction. We examine how nutritional deficits, aging, genetic polymorphisms—such as in the methylenetetrahydrofolate reductase (MTHFR) and cystathionine beta-synthase (CBS) genes—pharmacological agents, and comorbid conditions shape homocysteine homeostasis and susceptibility to pathology. Emphasis is placed on molecular pathways, including oxidative and nitrative stress, inflammasome activation, autophagy, and epigenetic modulation, which link HHcy to cognitive decline, memory impairment, endothelial dysfunction, and increased disease burden in neurodegenerative disorders. By consolidating multidisciplinary evidence, we position HHcy as a pivotal but under-recognized target for intervention in neurochemical and vascular health.

Retinitis Pigmentosa (RP) is a group of rare, inherited, neurodegenerative diseases of the retina that primarily affect rod photoreceptors. The initial loss of rods is followed by a secondary cone photoreceptor degeneration and eventually legal blindness. Despite several attempts, RP still remains essentially untreatable. In recent years, inhibition of poly (ADP-ribose) polymerase (PARP) has been proposed as a potential therapeutic strategy for autosomal-recessive RP, based on promising work in preclinical animal models. However, the effects of PARP inhibitors in autosomal-dominant RP are still largely unknown. Here, we employed a novel, human-homologous rhodopsin-mutant Rho^I255del/+ mouse model for autosomal dominant RP to assess the impact of different PARP inhibitors on the progression of photoreceptor degeneration. The PARP inhibitors used –olaparib, saruparib, INO1001, and nicotinamide–target different PARP isoforms, and their potentially differential effects were evaluated in organotypic retinal explants cultivated under entirely defined conditions. Readouts comprised in situ activity assays for PARP and calpain-type proteases, the TUNEL assay for cell death, as well as immunostaining for activated calpain-2, activated caspase-3, rhodopsin, and cone arrestin-3. Unexpectedly, and in contrast to previous findings in animal models for recessive RP, all of the PARP inhibitors used led to marked and dose-dependent rod photoreceptor toxicity in the Rho^I255del dominant RP model. Furthermore, this effect appeared to be independent of rhodopsin expression. On the other hand, cone photoreceptors were apparently unaffected by PARP inhibition. The present study thus demonstrates the importance of PARP activity for rod photoreceptor viability in a dominant rhodopsin mutant, highlights the need for a deeper understanding of the mechanisms underlying photoreceptor degeneration in different RP forms, and cautions against the indiscriminate use of PARP inhibitors for the treatment of RP.