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Mitchell, S. B.

Publications and source records attributed to Mitchell, S. B..

7 recordsLinked to original sources

Coordinated Brain-Network Dynamics of Maternal Adaptation

The maternal brain exhibits impressive plasticity, undergoing many anatomical and functional alterations over the transition to parenting. Such alterations can reflect maternal adaptation to offspring needs, aligning with the onset and maintenance of maternal care behaviors. These brain-wide neural changes occur across stages, starting during pregnancy and continuing through the peripartal transition. We therefore wanted to understand brain changes with pregnancy, parenting, and care behaviors over time. Many brain regions have been implicated in the coordination of maternal adaptation and corresponding care behaviors. We used computational modeling of multi-region neural oscillation data to identify distinct electrical networks during naturally-occurring care behaviors and across multiple maternal stages in outbred, highly maternal mice. This work demonstrates that multi-region oscillatory electrical dynamics at high spatiotemporal resolution reflect these functions. Distinct, discriminative networks predict maternal behavior and stage, showcasing network adaptation with parental transition. Maternal behavior and stage also had substantial effects on other distinct, multi-region oscillatory electrical networks relevant to stress susceptibility, further linking maternal adaptation to the neurophysiology of stress. While these stress networks were perturbed by maternal experience of early life stress, networks trained on maternal behavior and stage remained robust against such perturbation. This suggests a uniquely persistent strength of maternal electrical dynamics. Together, this work supports the role of oscillatory electrical dynamics as networks underlying fundamentally conserved behaviors and transitions, demonstrating wide relevance and significance to brain-behavior discovery.

neuroscience↗

Hepatic stearoyl-CoA desaturase-1 is specifically suppressed by dextran sodium sulfate but does not influence colitis sensitivity

The delta-9 desaturase stearoyl-CoA desaturase-1 (SCD1) catalyzes the conversion of saturated fatty acids to monounsaturated fatty acids (MUFA) and is highly expressed in liver and adipocytes. Previous studies have demonstrated that treating mice with dextran sulfate sodium (DSS), a chemical inducer of ulcerative colitis, results in severe downregulation of SCD1 in the liver. However, the specific role of hepatic SCD1 in modulating colitis severity, as well as the impact of DSS on SCD1 and other lipogenic factors in other tissues has not been investigated. Here we show that downregulation of hepatic SCD1 following DSS treatment is not accompanied by changes to other lipogenic genes in the liver. In contrast, adipose tissue demonstrates coordinated reductions in lipogenic genes, including SCD1 and SCD2, while the colon does not display any perturbation of these targets. Furthermore, we demonstrate that the downregulation of hepatic SCD1 occurs independently of sterol regulatory element binding protein-1c (SREBP-1c) and does not require an intact gut microbiome. Interestingly, a distinct model of colitis induced by IL-10 deficiency does not result in downregulation of hepatic SCD1. Concomitant with transcriptional changes, DSS treatment is associated with significant remodeling of the hepatic lipidome, including reductions in total phospholipids (PLs) and reduced MUFA-containing PLs and triacyglycerols (TAGs), consistent with the observed reduction in SCD1. Interestingly, hepatic cholesterol esters and plasma lipids including free cholesterol and glycerophospholipids were significantly elevated following DSS treatment. Given the significant reduction in hepatic SCD1 following DSS treatment, we tested a role for liver SCD1 in modulating colitis sensitivity. Mice with a targeted deletion of hepatic SCD1 were not more prone to colitis, indicating that the loss of hepatic SCD1, while a consequence of DSS-induced colitis, does not mediate colitis sensitivity in vivo. SynopsisHepatic SCD1 does not modulate colitis severity upon DSS exposure. However, DSS-induced colitis elicits significant lipid metabolism dysfunction, demonstrated by elevated plasma and liver lipids, particularly plasma cholesterol and hepatic cholesterol esters, highlighting a role for gutliver crosstalk following colonic inflammation.

physiology↗

Multiomics Approach to Regionally Profile Zinc-Driven Host-Gut Microbiome Interactions in the Intestinal Tract

Zinc deficiency (ZnD) is a major risk factor for metabolic and inflammatory diseases associated with gut microbial alterations, such as obesity, type 2 diabetes, and inflammatory bowel disease. Despite its importance, there are no established dietary recommendations for zinc supplementation in individuals with these conditions, except in cases of severe diarrhea in children. This gap stems from inconsistent outcomes in zinc supplementation trials, suggesting an incomplete understanding of zinc-mediated spatial and temporal regulation within the host-microbiome interface. This study employed a multiomics approach to investigate zinc-driven host-gut microbial interactions in the intestinal tract of mice fed zinc-adequate or ZnD diets. Radio tracing and metallomics analyses uncovered differential zinc abundance across intestinal tissues, with conventionalized germ-free mice displaying significantly lower zinc levels than germ-free mice, highlighting the reciprocal regulation of zinc between host tissues and gut microbes. Transcriptomic analyses revealed region-specific effects of ZnD, including altered energy metabolism and apoptosis in the small intestine, and impaired barrier function and redox processes in the colon. Metagenomics profiling revealed that ZnD reduced microbial diversity in the small intestine, while the cecum and colon were protected from diversity loss but exhibited an increased abundance of pathogenic bacteria. Correlation analyses linked tissue-specific host gene expression to shifts in microbial populations, identifying potential microbial mediators of host transcription changes under ZnD. Collectively, these findings emphasize the critical role of zinc in spatially regulating host-microbiome interactions, advancing our understanding of region-specific impacts of ZnD on the GI tract and disease risk. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=146 SRC="FIGDIR/small/662895v1_ufig1.gif" ALT="Figure 1"> View larger version (71K): org.highwire.dtl.DTLVardef@235941org.highwire.dtl.DTLVardef@b8f1deorg.highwire.dtl.DTLVardef@f283eorg.highwire.dtl.DTLVardef@11b039a_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

Transcriptomic Evaluation of Stress Vulnerability Network using Single Cell RNA-Seq in mouse Prefrontal Cortex

Increased vulnerability to stress is a major risk factor for the manifestation of several mood disorders, including major depressive disorder (MDD). Despite the status of MDD as a significant donor to global disability, the complex integration of genetic and environmental factors that contribute to the behavioral display of such disorders has made a thorough understanding of related etiology elusive. Recent developments suggest that a brain-wide network approach is needed, taking into account the complex interplay of cell types spanning multiple brain regions. Single cell RNA-sequencing technologies can provide transcriptomic profiling at the single-cell level across heterogenous samples. Furthermore, we have previously used local field potential oscillations and machine learning to identify an electrical brain network that is indicative of a predisposed vulnerability state. Thus, this study combined single cell RNA-sequencing (scRNA-Seq) with electrical brain network measures of the stress-vulnerable state, providing a unique opportunity to access the relationship between stress network activity and transcriptomic changes within individual cell types. We found especially high numbers of differentially expressed genes between animals with high and low stress vulnerability brain network activity in astrocytes and glutamatergic neurons but we estimated that vulnerability network activity depends most on GABAergic neurons. High vulnerability network activity included upregulation of microglia and mitochondrial and metabolic pathways, while lower vulnerability involved synaptic regulation. Genes that were differentially regulated with vulnerability network activity significantly overlapped with genes identified as having significant SNPs by human GWAS for depression. Taken together, these data provide the gene expression architecture of a previously uncharacterized stress vulnerability brain state, enabling new understanding and intervention of predisposition to stress susceptibility. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=91 SRC="FIGDIR/small/540705v2_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@1ebe036org.highwire.dtl.DTLVardef@cd2131org.highwire.dtl.DTLVardef@13e3519org.highwire.dtl.DTLVardef@1100e62_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

Metal transporter SLC39A14/ZIP14 modulates regulation between the gut microbiome and host metabolism

Zinc (Zn) plays a critical role in maintaining intestinal homeostasis by regulating intestinal epithelial cells, host immune cells, and gut microbiome community composition. Deletion of metal transporter Slc39a14/Zip14 causes spontaneous intestinal permeability with low-grade chronic inflammation, mild hyperinsulinemia, and greater body fat with insulin resistance in adipose, suggesting a role for ZIP14-mediated intestinal metal transport in regulating both intestinal homeostasis and systemic metabolism. Here, we showed the function of ZIP14-mediated Zn transport in the gut microbiome composition and how ZIP14-linked changes to gut microbiome community composition are correlated with changes in host metabolism. Deletion of Zip14 generated Zn-deficient epithelial cells and luminal content in the entire intestinal tract; reduced bacterial diversity and Saccharomyces cerevisiae (S. cerevisiae) overgrowth; altered host metabolome; and shifted host energy metabolism toward glucose utilization. This work provides evidence for the regulation of gut microbiome composition, host metabolome, and energy metabolism by metal transporter ZIP14. SignificanceIntestinal permeability, gut dysbiosis, and Zn dyshomeostasis are emerging signatures of inflammatory bowel diseases and metabolic disorders such as type-2-diabetes and obesity. Zn deficiency is a common clinical finding among these diseases. Zn is essential for the regulation of the intestinal epithelial cells, host immune cells, and the gut microbiome. Transporter-mediated mobilization of Zn plays a critical role in maintaining intestinal homeostasis by facilitating the targeted tissue/cell-specific function. However, studies are lacking in linking transporter-mediated Zn mobilization, gut microbiome, hosts intestinal health, and metabolism. Using the systems-level approach, this study revealed novel findings that deletion of Slc39a14/Zip14 resulted in altered intestinal Zn homeostasis, gut microbiome composition, host metabolome and energy metabolism.

physiology↗

Calcium-induced calcium release in noradrenergic neurons of the locus coeruleus

The locus coeruleus (LC) is a nucleus within the brainstem that consists of norepinephrine-releasing neurons. It is involved in broad processes including autonomic regulation, and cognitive and emotional functions such as arousal, attention and anxiety. Understanding the mechanisms that control the excitability of LC neurons is important because they innervate widespread regions of the central nervous system. One of the key regulators is the cytosolic calcium concentration ([Ca2+]c), the increases in which can be amplified by calcium-induced calcium release (CICR) from the intracellular calcium stores. Although the electrical activities of LC neurons are regulated by changes in [Ca2+]c, the extent of CICR involvement in this regulation has remained unclear. Here we show that CICR hyperpolarizes acutely dissociated LC neurons of the rat brain and demonstrate the pathway whereby it does this. When CICR was activated by extracellular application of 10 mM caffeine, LC neurons were hyperpolarized in the current-clamp mode of the patch-clamp recording, and the majority of neurons showed an outward current in the voltage-clamp mode. This outward current was accompanied by an increase in membrane conductance, and its reversal potential was close to the K+ equilibrium potential, indicating that it is mediated by the opening of K+ channels. The outward current was generated in the absence of extracellular calcium and was blocked when the calcium stores were inhibited by applying ryanodine. Pharmacological experiments indicated that the outward current was mediated by Ca2+-activated K+ channels of the non-small conductance type. Finally, the application of caffeine led to an increase in the [Ca2+]c in these neurons, as visualized by fluorescence microscopy. These findings delineate a mechanism whereby CICR suppresses the electrical activity of LC neurons, and indicate that it could play a dynamic role in modulating the LC-mediated noradrenergic tone in the brain.

neuroscience↗

Transcriptome profiles in brains of mice heterozygous for a DYT1 dystonia-associated mutation in the endogenous Tor1a gene

In patients with the brain disorder dystonia, body movement is severely affected - with involuntary muscle contractions and abnormal postures, causing extensive deterioration of the patients quality of life. The most common inherited form of this disorder is DYT1 dystonia, which is caused by a mutation in TOR1A gene and autosomal dominant. The molecular mechanisms that underlie the effects of the TOR1A mutation on brain function remain unclear. To understand these, we examined the gene expression profiles (transcriptome) in four brain regions (cerebral cortex, hippocampus, striatum and cerebellum) in a mouse model, the heterozygous {Delta}E-torsinA knock-in mice which genetically reproduce the mutation in DYT1 dystonia. The samples were obtained at 2 to 3 weeks of age, a period during which synaptic abnormalities have been reported. Pairwise comparisons of brain regions revealed differential gene expression irrespective of genotype. A comparison of heterozygous to wild-type mice failed to reveal genotype-dependent differences in gene expression in any of the four brain regions when examined individually. However, genotype-dependent differences became apparent when the information for all brain regions was combined. These results suggest that any changes in the transcriptome within a brain region were subtle at this developmental stage, but that statistically significant changes occur across all brain regions. Such changes in the transcriptome, although subtle in degree, could underlie the processes that give rise to DYT1 dystonia.

neuroscience↗