Altered development of the Hurst Exponent in medial prefrontal cortex in preschoolers with autism.

BACKGROUND: Atypical balance of excitation (E) and inhibition (I) in the brain is thought to contribute to the emergence and symptomatology of autism spectrum disorders (ASD). E/I ratio can be estimated from resting state functional magnetic resonance imaging (fMRI) using the Hurst Exponent (H). A recent study reported decreased ventromedial prefrontal cortex (vmPFC) H in male adults with ASD. Part of the default mode network (DMN), vmPFC plays an important role in emotion regulation, decision making, and social cognition. It frequently shows altered function and connectivity in autistic individuals. METHODS: The current study presents the first fMRI evidence of altered early development of vmPFC H and its link to DMN functional connectivity (FC) and emotional control in toddlers and preschoolers with ASD. 83 children (n=45 ASD), ages 1½ - 5 years, underwent natural sleep fMRI as part of a longitudinal study. RESULTS: In a cross-sectional analysis, vmPFC H decreased with age in children with ASD, reflecting increasing E/I ratio, but not in typically developing children. This effect remained significant when controlling for gestational age at birth, socioeconomic status, or ethnicity. The same pattern was also observed in a subset of children with longitudinal fMRI data acquired two years apart on average. Lower vmPFC H was further associated with reduced FC within the DMN as well as with higher emotional control deficits (though only significant transdiagnostically). CONCLUSIONS: These results suggest an early onset of E/I imbalances in vmPFC in ASD with likely consequences for the maturation of the DMN.

Catestatin Inhibits Obesity-Induced Macrophage Infiltration and Inflammation in the Liver and Suppresses Hepatic Glucose Production, Leading to Improved Insulin Sensitivity.

The activation of Kupffer cells (KCs) and monocyte-derived recruited macrophages (McMΦs) in the liver contributes to obesity-induced insulin resistance and type 2 diabetes. Mice with diet-induced obesity (DIO mice) treated with chromogranin A peptide catestatin (CST) showed several positive results. These included decreased hepatic/plasma lipids and plasma insulin, diminished expression of gluconeogenic genes, attenuated expression of proinflammatory genes, increased expression of anti-inflammatory genes in McMΦs, and inhibition of the infiltration of McMΦs resulting in improvement of insulin sensitivity. Systemic CST knockout (CST-KO) mice on normal chow diet (NCD) ate more food, gained weight, and displayed elevated blood glucose and insulin levels. Supplementation of CST normalized glucose and insulin levels. To verify that the CST deficiency caused macrophages to be very proinflammatory in CST-KO NCD mice and produced glucose intolerance, we tested the effects of (sorted with FACS) F4/80+Ly6C- cells (representing KCs) and F4/80-Ly6C+ cells (representing McMΦs) on hepatic glucose production (HGP). Both basal HGP and glucagon-induced HGP were markedly increased in hepatocytes cocultured with KCs and McMΦs from NCD-fed CST-KO mice, and the effect was abrogated upon pretreatment of CST-KO macrophages with CST. Thus, we provide a novel mechanism of HGP suppression through CST-mediated inhibition of macrophage infiltration and function.

Isolation and Analysis of Stromal Vascular Cells from Visceral Adipose Tissue.

The obesity epidemic is the underlying driver of the type 2 diabetes mellitus epidemic. A remarkable accumulation of various pro-inflammatory immune cells in adipose tissues is a hallmark of obesity and leads to pathogenesis of tissue inflammation and insulin resistance. Here, we describe a detailed protocol to isolate adipose tissue stromal vascular cells (SVCs), which enrich various immune cells of adipose tissues. These SVCs can be used to examine the population and activation status of immune cells by tracking their cell surface antigens, gene expression, and activation of specific signaling pathways.