Maternal hypothalamic-pituitary-adrenal axis response to foraging uncertainty: A model of individual vs. social allostasis and the Superorganism Hypothesis

Introduction: Food insecurity is a major global contributor to developmental origins of adult disease. The allostatic load of maternal food uncertainty from variable foraging demand (VFD) activates corticotropin-releasing factor (CRF) without eliciting hypothalamic-pituitary-adrenal (HPA) activation measured on a group level. Individual homeostatic adaptations of the HPA axis may subserve second-order homeostasis, a process we provisionally term “social allostasis.” We postulate that maternal food insecurity induces a “superorganism” state through coordination of individual HPA axis response. Methods: Twenty-four socially-housed bonnet macaque maternal-infant dyads were exposed to 16 weeks of alternating two-week epochs of low or high foraging demand shown to compromise normative maternal-infant rearing. Cerebrospinal fluid (CSF) CRF concentrations and plasma cortisol were measured pre- and post-VFD. Dyadic distance was measured, and blinded observers performed pre-VFD social ranking assessments. Results: Despite marked individual cortisol responses (mean change = 20%) there was an absence of maternal HPA axis group mean response to VFD (0%). Whereas individual CSF CRF concentrations change = 56%, group mean did increase 25% (p = 0.002). Our dyadic vulnerability index (low infant weight, low maternal weight, subordinate maternal social status and reduced dyadic distance) predicted maternal cortisol decreases (p \u3c 0.0001) whereas relatively “advantaged” dyads exhibited maternal cortisol increases in response to VFD exposure. Comment: In response to a chronic stressor, relative dyadic vulnerability plays a significant role in determining the directionality and magnitude of individual maternal HPA axis responses in the service of maintaining a “superorganism” version of HPA axis homeostasis, provisionally termed “social allostasis.

Response to hypoxia involves smad proteins in human endothelial cells

Smad proteins are the downstream substrates of membrane ser/thr kinase TGF-β receptors, and mediate responses of endothelial cells (EC) to mechanical and metabolic stress. Oxygen deprivation (Hypoxia: Hx) is a consistent component of ischémie vascular disorders and induces an inflammatory response in vascular endothelium. This study, performed in human umbilical vein endothelial cells (HUVEC), examined the effect of Hx on activity of Smads and their target gene TGF-β2, a cytokine regulator of inflammation in EC. RNase protection studies showed that exposure to Hx (1% O2) increased mRNA levels of TGF-β2 by 10-fold in a time-dependent fashion (P \u3c .01). Parallel increases in active and latent TGF-β2 protein were found by measuring the response of a TGF-βresponsive luciferase construct in a bioassay. Hx stimulated TGF-β2 transcription in HUVEC, determined by activity of a TGF-β2 CAT promoter construct, by 3-fold; Hxinduced transcription was increased by a further 4-fold (P \u3c .01) after cotransfection of HUVEC with Smad 3/4 expression vectors. Hx also increased transcription from a known TGF-β-responsive promoter, 3TP-lux, by 10-fold (P \u3c .01); cotransfection of Smad 3/4 vectors increased the activity of 3TP-lux by a further 3-fold ( P \u3c .01). Smad association with DNA was shown with EMSA using a Smad-binding oligonucleotide, SEE, as probe. Binding to SBE occurred only with nuclear extracts from hypoxic but not normoxic HUVEC, was not competed by oligonucleotides corresponding to DNA-binding sites of SP1 or HIF-1, and was supershifted with antibody to Smad 3 and 4 but not to HIF-1 or preimmune sera. To further examine the effects of Hx on EC signal transduction and function, total RNA obtained from HUVEC exposed to Hx for increasing time periods was used for mRNA transcript profiling by cDNA arrays (Clonetech, Atlas 1.2). Results were normalized to β-actin and show that mRNA of TGF-β l, -β2, and their upstream regulators such as TGF-β RI and Ang II Rl were induced at 18h after Hx compared to normoxia. Furthermore, Hx induced mRNAs of Smad co-factors SP1 and -2, which cooperate to inhibit Gl cell cycle progression. mRNA levels of Smads, Jak-Stat proteins, or NF-KB were unchanged, but HIF-1 mRNA was increased. In sum, Hx-induced increases in TGF-β2, TGF-β RI, and Smad 3/4 function in EC suggest that this pathway plays an important role in endothelial response to hypoxic stress

Cerebrospinal Fluid Concentrations of Biogenic Amines and Corticotropin-releasing Factor in Adolescent Non-human Primates as a Function of the Timing of Adverse Early Rearing

Adolescent bonnet macaques nursed as infants by mothers facing unpredictable requirements for food procurement (variable foraging demand, VFD) display persistent neurobiological disturbances. This study examined the long-term neurochemical and behavioral effects of adverse rearing initiated later in infancy than in previous cohorts of subjects to test the hypothesis that the timing of an early adverse experience would influence patterns of biobehavioral outcome. Cisternal cerebrospinal fluid (CSF) monoamine and corticotropin-releasing factor (CRF) concentrations were obtained from 20 bonnet macaques (11 VFD-reared and 9 normally reared controls) approximately 2 years after the end of differential rearing. VFD-reared primates displayed on multiple samplings significantly lower CSF CRF concentrations and higher CSF 5-hydroxyindoleacetic acid (5-HIAA) concentration compared to controls. In the VFD-reared, significant inverse correlations between CRF and all three monoamines were found (5-HIAA, 3-methoxy-4-hydroxyphenethyleneglycol and homovanillic acid), most prominently for 5-HIAA. In controls, but not VFD-reared subjects, CSF CRF was positively correlated with changes in "gregariousness" upon presentation of a fear stimulus. VFD-reared subjects displayed greater baseline hierarchical engagement than controls. In contrast to prior findings, in which rearing under VFD conditions at an earlier age led to increased CSF CRF compared with controls, CSF CRF was lower after later exposure to VFD rearing than in controls. Thus, the timing of exposure to VFD conditions early in life evidently determines whether CSF CRF was found to be elevated or decreased, within the context of increased serotonin metabolism, during the course of primate maturation

Early-life stress, corticotropin-releasing factor, and serotonin transporter gene: A pilot study

Recent studies have indicated a gene-by-environment interaction between serotonin transporter gene (5-HTTLPR) polymorphism and childhood abuse on depressive symptoms. In addition, persistent elevation of cerebrospinal fluid (CSF) corticotropin-releasing factor (CRF) concentrations following early-life adversity has been posited to underlie the subsequent development of major depression. This pilot study tested the hypothesis that elevations of juvenile CSF CRF concentrations are, in part, determined by an interaction between polymorphisms of the 5-HTTLPR and early-life stress. Nine juvenile male bonnet macaques ( Macaca radiata) had been raised under variable foraging demand (VFD) conditions, a nonhuman primate model of early-life stress, whereas nine subjects were normatively raised under LFD (low foraging demand) conditions. Genotyping revealed that four (44.4%) of the VFD-reared monkeys possessed at least one “s” allele whereas five VFD monkeys were of the l/l genotype. Of the nine LFD subjects, two (22%) had the s/l genotype and seven had the l/l genotype. A “juvenile” CSF sample was obtained at approximately 3 years of age. CSF CRF concentrations were elevated specifically in the VFD “s/s” and “s/l” allele group in comparison to each of the remaining three groups, indicating a gene-by-environment (G × E) interaction

Metabolic syndrome and neurometabolic asymmetry of hippocampus in adult bonnet monkeys

Obesity is associated with the insulin resistance metabolic syndrome, postulated to be mediated by stress-induced alterations within the hypothalamic–pituitary–adrenal (HPA) axis. In adult bonnet macaques we examined relationships between components of the metabolic syndrome, hippocampal neurometabolic asymmetry, an indicator of negative affect, and juvenile cerebrospinal fluid (csf) corticotropin-releasing factor (CRF) levels obtained after stress exposure associated with maternal food insecurity and in controls. Eleven adult male monkeys (seven with early life stress) who had undergone csf-CRF analyses as juveniles had magnetic resonance spectroscopic imaging (MRSI) of bilateral hippocampus, morphometry (body mass index, BMI; sagittal abdominal diameter, SAD) and determination of fasting plasma glucose and insulin as adults. Neurometabolite ratios included N-acetyl-aspartate as numerator (NAA; a marker of neuronal integrity) and choline (Cho; cell turnover) and creatine (Cr; reference analyte) as denominators. Elevated juvenile csf-CRF levels positively predicted adult BMI and SAD and were associated with right>left shift of NAA ratio within the hippocampus. Adult visceral obesity and insulin level correlated with right>left shift in hippocampal NAA concentrations, controlling for age and denominator. Juvenile csf-CRF levels, a neuropeptide associated with early life stress, predict adult visceral obesity and hippocampal asymmetry supporting the hypothesis that metabolic syndrome in adults may be related to early life stress. Furthermore, this study demonstrates asymmetrical hippocampal alterations related to obesity. ► Juvenile CRF levels positively predicted adult BMI and sagittal abdominal diameter. ► CRF levels were associated with right>left hippocampal N-acetyl-aspartate (NAA). ► BMI and insulin level correlated with right>left hippocampal NAA concentrations. ► These data associate hippocampal NAA with primate metabolic syndrome. ► Asymmetrical hippocampal alterations are presumably a result of or leading to obesity

Metabolic syndrome and neurometabolic asymmetry of hippocampus in adult bonnet monkeys

OBJECTIVE: Obesity is associated with the insulin resistance metabolic syndrome, postulated to be mediated by stress-induced alterations within the hypothalamic-pituitary-adrenal (HPA) axis. In adult bonnet macaques we examined relationships between components of the metabolic syndrome, hippocampal neurometabolic asymmetry, an indicator of negative affect, and juvenile cerebrospinal fluid (csf) corticotropin-releasing factor (CRF) levels obtained after stress exposure associated with maternal food insecurity and in controls. METHODS: Eleven adult male monkeys (seven with early life stress) who had undergone csf-CRF analyses as juveniles had magnetic resonance spectroscopic imaging (MRSI) of bilateral hippocampus, morphometry (body mass index, BMI; sagittal abdominal diameter, SAD) and determination of fasting plasma glucose and insulin as adults. Neurometabolite ratios included N-acetyl-aspartate as numerator (NAA; a marker of neuronal integrity) and choline (Cho; cell turnover) and creatine (Cr; reference analyte) as denominators. RESULTS: Elevated juvenile csf-CRF levels positively predicted adult BMI and SAD and were associated with right > left shift of NAA ratio within the hippocampus. Adult visceral obesity and insulin level correlated with right > left shift in hippocampal NAA concentrations, controlling for age and denominator. CONCLUSION: Juvenile csf-CRF levels, a neuropeptide associated with early life stress, predict adult visceral obesity and hippocampal asymmetry supporting the hypothesis that metabolic syndrome in adults may be related to early life stress. Furthermore, this study demonstrates asymmetrical hippocampal alterations related to obesity