Metabolic and Inflammatory Stimuli Impact Vascular Circulation and Cell Proliferation Processes in the Amygdala

Genes Brain & Behavior · 2025-09-24

The amygdala participates in the processing of stimulus signals from stimuli and the coordination of the physiological and behavioral responses. The sexually dimorphic structure of the amygdala also contributes to sex-specific molecular and functional profiles. The present study compares the response of the amygdala molecular mechanisms to different environmental stimuli between sexes. The amygdala of female and male pigs was profiled under control, immunostimulation, and the metabolic stimulus of fasting using RNA-sequencing. Differential expression analysis (False Discovery Rate -adjusted p value < 0.05) identified 958 genes affected by stimulus and 504 genes affected by sex within treatments. The functional categories presenting a predominance of differentially expressed genes included the synaptic vesicle cycle pathway, vascular smooth muscle contraction pathway, epithelial cell proliferation process, chemokine signaling, and apoptosis. Network analysis revealed hub genes, including Stx1a, Cplx1, Clam3, and Myh11, among the gene modules susceptible to stimuli. The regulatory element SUZ12 was associated with differential gene expression between stimuli in both sexes, whereas RELA and IRF1 were uniquely detected in males and females, respectively. The findings from the multifaceted approach provide genomic leads to investigating interventions that can mitigate the effects of stimuli on the amygdala function.

Epigenetic disruptions in the offspring hypothalamus in response to maternal infection

Gene · 2024-02-29 · 5 citations

Immune and metabolic challenges induce changes in pain sensation and related pathways in the hypothalamus

Physiological Genomics · 2024-01-08 · 8 citations

The interaction of infection during gestation and insults later in life influences the molecular mechanisms in the hypothalamus that participate in pain sensation. The response of the hypothalamic transcriptome varies between sexes and can also affect synapses and immune signals. The findings from this study assist in the identification of agonists or antagonists that can guide pretranslational studies to ameliorate the effects of gestational insults interacting with postnatal challenges on physiological or behavioral disorders.

Prophylactic clemastine treatment improves influenza A virus-induced cognitive dysfunction in mice

Brain Behavior & Immunity - Health · 2024-10-09 · 3 citations

Respiratory infection by influenza A virus (IAV) is known to cause systemic inflammation, neuroinflammation, and cognitive impairment. We previously found that experimental infection with IAV affected oligodendrocyte homeostasis, which was associated with altered expression of genes involved in myelin maintenance as well as the lipidome. In this study, we sought to determine if clemastine, an antihistamine with myelin promoting properties, could reverse the effects of IAV on oligodendrocyte (OL) specific genes, as well as mitigate infection-induced cognitive impairment. Male and female C57BL/6J mice were randomized into experimental groups based on clemastine treatment, infection, and sex. Treatment with vehicle or clemastine (10mg/kg/d) commenced seven days prior to inoculation with either saline or IAV and continued throughout the experiment. Body weight was measured throughout the infection. Spatial learning and memory were assessed by Morris water maze. Sickness behavior was assessed by measuring burrowing response. Immune cell responses were determined by flow cytometry, RT-qPCR, antigen recall assays and ELISA, and viral load assessed by RT-qPCR. Hippocampal levels of neuroinflammatory ( Tnf, Cdkn1a ) and myelin ( Plp1 , Mag , Ugt8a ) genes were determined by RT-qPCR. Mice infected with IAV developed weight loss, impaired cognitive flexibility, reduced burrowing behavior, altered lung immune cell infiltration, increased circulating anti-viral IgM and IgG levels and increased T cell responses to IAV epitopes. Infection increased hippocampal levels of genes associated with neuroinflammation and decreased levels of genes involved in myelination. Clemastine treatment resulted in earlier recovery of weight loss in males and increased IgM levels for both sexes, but neither affected expression levels of Tnf or Cdkn1a , nor rescued changes to oligodendrocyte genes. However, treatment mitigated infection-induced neurocognitive impairment.

The emergence of inflammatory microglia during gut inflammation is not affected by FFAR2 expression in intestinal epithelial cells or peripheral myeloid cells

Brain Behavior and Immunity · 2024-03-11 · 18 citations

Gut inflammation can trigger neuroinflammation and is linked to mood disorders. Microbiota-derived short-chain fatty acids (SCFAs) can modulate microglia, yet the mechanism remains elusive. Since microglia do not express free-fatty acid receptor (FFAR)2, but intestinal epithelial cells (IEC) and peripheral myeloid cells do, we hypothesized that SCFA-mediated FFAR2 activation within the gut or peripheral myeloid cells may impact microglia inflammation. To test this hypothesis, we developed a tamoxifen-inducible conditional knockout mouse model targeting FFAR2 exclusively on IEC and induced intestinal inflammation with dextran sodium sulfate (DSS), a well-established colitis model. Given FFAR2's high expression in myeloid cells, we also investigated its role by selectively deleting it in these populations of cells. In an initial study, male and female wild-type mice received 0 or 2% DSS for 5d and microglia were isolated 3d later to assess inflammatory status. DSS induced intestinal inflammation and upregulated inflammatory gene expression in microglia, indicating inflammatory signaling via the gut-brain axis. Despite the lack of significant effects of sex in the intestinal phenotype, male mice showed higher microglial inflammatory response than females. Subsequent studies using FFAR2 knockout models revealed that FFAR2 expression in IECs or immune myeloid cells did not affect DSS-induced colonic pathology (i.e. clinical and histological scores and colon length), or colonic expression of inflammatory genes. However, FFAR2 knockout led to an upregulation of several microglial inflammatory genes in control mice and downregulation in DSS-treated mice, suggesting that FFAR2 may constrain neuroinflammatory gene expression under healthy homeostatic conditions but may permit it during intestinal inflammation. No interactions with sex were observed, suggesting sex does not play a role on FFAR2 potential function in gut-brain communication in the context of colitis. To evaluate the role of FFAR2 activated by microbiota-derived SCFAs, we employed the same knockout and DSS models adding fermentable dietary fiber (0 or 2.5% inulin for 8 wks). Despite no genotype or fiber main effects, contrary to our hypothesis, inulin feeding augmented DSS-induced inflammation and signs of colitis, suggesting context-dependent effects of fiber. These findings highlight microglial involvement in colitis-associated neuroinflammation and advance our understanding of FFAR2's role in the gut-brain axis. Although not integral, we observed that the role of FFAR2 differs between homeostatic and inflammatory conditions, underscoring the need to consider different inflammatory conditions and disease contexts when investigating the role of FFAR2 and SCFAs in the gut-brain axis.

Respiratory infection with influenza A virus delays remyelination and alters oligodendrocyte metabolism

iScience · 2024-07-06 · 1 citations

, and found that infection altered brain OL and microglia metabolism in a manner that opposed the metabolic profile induced by remyelination. Specifically, infection increased glycolytic capacity of OLs and microglia, an effect that was recapitulated by lipopolysaccharide (LPS) stimulation of mixed glia cultures. In contrast, mitochondrial dependence was increased in OLs during remyelination, which was similarly observed in OLs of myelinating P14 mice compared to adult and aged mice. Collectively, our data indicate that respiratory viral infection is capable of suppressing remyelination, and suggest that metabolic dysfunction of OLs is implicated in remyelination impairment.

Free fatty acid receptor 2 (FFAR2) expression by intestinal epithelial cells (IEC) is not integral for regulating the microglia response to intestinal inflammation

Brain Behavior and Immunity · 2023-11-01

Effects of an inulin fiber diet on the gut microbiome, colon, and inflammatory biomarkers in aged mice

Experimental Gerontology · 2023-04-07 · 28 citations

Due to the increasing human life expectancy and limited supply of healthcare resources, strategies to promote healthy aging and reduce associated functional deficits are of public health importance. The gut microbiota, which remodels with age, has been identified as a significant contributor to the aging process that is modifiable by diet. Since prebiotic dietary components such as inulin have been shown to impart positive benefits with regards to aging, this study used C57Bl6 mice to investigate whether 8 weeks on a 2.5 % inulin enhanced AIN-93M 1 % cellulose diet could offset age-associated changes in gut microbiome composition and markers of colon health and systemic inflammation in comparison to a AIN 93M 1 % cellulose diet with 0 % inulin. Our results demonstrated that, in both age groups, dietary inulin significantly increased production of butyrate in the cecum and induced changes in the community structure of the gut microbiome but did not significantly affect systemic inflammation or other markers of gastrointestinal health. Aged mice had different and less diverse microbiomes when compared to adult mice and were less sensitive to inulin-induced microbiome community shifts, evidenced by longitudinal differences in differentially abundant taxa and beta diversity. In aged mice, inulin restored potentially beneficial taxa including Bifidobacterium and key butyrate producing genera (e.g. Faecalibaculum). Despite inducing notable taxonomic changes, however, the 2.5 % inulin diet reduced alpha diversity in both age groups and failed to reduce overall community compositional differences between age groups. In conclusion, a 2.5 % inulin enhanced diet altered gut microbiome α and β diversity, composition, and butyrate production in both adult and aged mice, with more potent effects on β diversity and greater number of taxa significantly altered in adult mice. However, significant benefits in age-associated changes in systemic inflammation or intestinal outcomes were not detected.

Influence of Maternal Immune Activation and Stressors on the Hippocampal Metabolome

Metabolites · 2023-07-25 · 4 citations

Prenatal stress often results in maternal immune activation (MIA) that can impact prenatal brain development, molecular processes, and substrates and products of metabolism that participate in physiological processes at later stages of life. Postnatal metabolic and immunological stressors can affect brain metabolites later in life, independently or in combination with prenatal stressors. The effects of prenatal and postnatal stressors on hippocampal metabolites were studied using a pig model of viral MIA exposed to immunological and metabolic stressors at 60 days of age using gas chromatography mass spectrometry. Postnatal stress and MIA elicited effects (FDR-adjusted p-value &lt; 0.1) on fifty-nine metabolites, while eight metabolites exhibited an interaction effect. The hippocampal metabolites impacted by MIA or postnatal stress include 4-aminobutanoate (GABA), adenine, fumarate, glutamate, guanine, inosine, ornithine, putrescine, pyruvate, and xanthine. Metabolites affected by MIA or postnatal stress encompassed eight significantly (FDR-adjusted p-value &lt; 0.1) enriched Kyoto Encyclopedia of Genes and Genomes Database (KEGG) pathways. The enriched arginine biosynthesis and glutathione metabolism pathways included metabolites that are also annotated for the urea cycle and polyamine biosynthesis pathways. Notably, the prenatal and postnatal challenges were associated with disruption of the glutathione metabolism pathway and changes in the levels of glutamic acid, glutamate, and purine nucleotide metabolites that resemble patterns elicited by drugs of abuse and may underlie neuroinflammatory processes. The combination of MIA and postnatal stressors also supported the double-hit hypothesis, where MIA amplifies the impact of stressors later in life, sensitizing the hippocampus of the offspring to future challenges. The metabolites and pathways characterized in this study offer evidence of the role of immunometabolism in understanding the impact of MIA and stressors later in life on memory, spatial navigation, neuropsychiatric disorders, and behavioral disorders influenced by the hippocampus.

Genes Participating in the Ensheathment of Neurons Are Affected by Postnatal Stress and Maternal Immune Activation in the Pituitary Gland

Genes · 2023-04-28 · 7 citations

Immune challenges during gestation are associated with neurodevelopmental disorders and can interact with stress later in life. The pituitary gland participates in endocrine- and immune-related processes that influence development, growth, and reproduction and can modulate physiological and behavioral responses to challenges. The objective of this study was to investigate the effect of stressors at different time points on the molecular mechanisms of the pituitary gland and detect sex differences. RNA sequencing was used to profile the pituitary glands of female and male pigs exposed to weaning stress and virally induced maternal immune activation (MIA), relative to unchallenged groups. Significant effects (FDR-adjusted p-value &lt; 0.05) of MIA and weaning stress were detected in 1829 and 1014 genes, respectively. Of these, 1090 genes presented significant interactions between stressors and sex. The gene ontology biological process of the ensheathment of neurons (GO:0007272), substance abuse, and immuno-related pathways, including the measles disease (ssc05162), encompasses many genes with profiles impacted by MIA and weaning stress. A gene network analysis highlighted the under-expression of myelin protein zero (Mpz) and inhibitors of DNA binding 4 (Id4) among the non-stressed males exposed to MIA, relative to the control and non-MIA males exposed to weaning stress, relative to non-stressed pigs. The detection of changes in the molecular mechanisms of the pituitary gland could advance our understanding of disruptions in the formation of the myelin sheath and the transmission of neuron-to-neuron signals in behavioral disorders associated with maternal immune activation and stress.