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.

Complement Expression in the Retina is not Influenced by Short-term Pressure Elevation

Purpose: To determine whether short-term pressure elevation affects complement gene expression in the retina in vitro and in vivo. Methods: Muller cell (TR-MUL5) cultures and organotypic retinal cultures from adult mice and monkeys were sub- jected to either 24-h or 72-h of pressure at 0, 15, 30, and 45 mmHg above ambient. C57BL/6 mice were subjected to microbead-induced intraocular pressure (IOP) elevation for 7 days. RNA and protein were extracted and used for analysis of expression levels of complement component genes and complement component 1, q subcomponent (C1q) and comple- ment factor H (CFH) immunoblotting. Results: mRNA levels of complement genes and C1q protein levels in Muller cell cultures remained the same for all pressure levels after exposure for either 24 or 72 h. In primate and murine organotypic cultures, pressure elevation did not produce changes in complement gene expression or C1q and CFH protein levels at either the 24-h or 72-h time points. Pressure-related glial fibrillary acidic protein (GFAP) mRNA expression changes were detected in primate retinal organotypic cultures (analysis of variance [ANOVA]; p0.05 for both) with contralateral control and naïve control eyes. Conclusions: Short-term elevation of pressure in vitro as well as short-term (1 week) IOP elevation in vivo does not seem to dramatically alter complement system gene expression in the retina. Prolonged expression to elevated pressure may be necessary to affect the complement system expression

Maternal Cerebrospinal Fluid Glutamate in Response to Variable Foraging Demand: Relationship to Cerebrospinal Fluid Serotonin Metabolites in Grown Offspring

Background Maternal response to allostatic overload during infant rearing may alter neurobiological measures in grown offspring, potentially increasing susceptibility to mood and anxiety disorders. We examined maternal cerebrospinal fluid (CSF) glutamate response during exposure to variable foraging demand (VFD), a bonnet macaque model of allostatic overload, testing whether activation relative to baseline predicted concomitant CSF elevations of the stress neuropeptide, corticotropin-releasing factor. We investigated whether VFD-induced activation of maternal CSF glutamate affects maternal–infant attachment patterns and offspring CSF 5-hydroxyindoleacetic acid concentrations. Methods Mother–infant dyads were exposed to the “VFD stressor,” a paradigm in which mothers experience 16 weeks of foraging uncertainty while rearing their infant offspring. Through staggering the infant age of VFD onset, both a cross-sectional design and a longitudinal design were used. Maternal CSF glutamate and glutamine concentrations post-VFD exposure were cross-sectionally compared to maternal VFD naive controls. Proportional change in concentrations of maternal glutamate (and glutamine), a longitudinal measure, was evaluated in relation to VFD-induced elevations of CSF corticotropin-releasing factor. The former measure was related to maternal–infant proximity scores obtained during the final phases of VFD exposure. Maternal glutamatergic response to VFD exposure was used as a predictor variable for young adolescent offspring CSF metabolites of serotonin, dopamine, and norepinephrine. Results Following VFD exposure, maternal CSF glutamate concentrations correlated positively with maternal CSF CRF concentrations. Activation relative to baseline of maternal CSF glutamate concentrations following VFD exposure correlated directly with a) increased maternal-infant proximity during the final phases of VFD and b) offspring CSF concentrations of monoamine metabolites including 5-hydroxyindoleacetic acid, which was elevated relative to controls. Conclusions Activation of maternal CSF glutamate in response to VFD-induced allostasis is directly associated with elevations of maternal CSF corticotropin-releasing factor. Maternal CSF glutamate alterations induced by VFD potentially compromise serotonin neurotransmission in grown offspring, conceivably modeling human vulnerability to treatment-resistant mood and anxiety disorders

The relationship between maternal Pre-VFD cortisol and Δ cortisol (Post minus Pre-VFD) in response to maternal variable foraging demand.

<p>The red arrow indicates the maternal pre-VFD and post-VFD plasma cortisol mean (44.36) which was unchanged despite exposure to VFD. The blue lines represent distance from no change (Δ = 0). The red line represents the regression line [r = -0.84, p = 0.0001, n = 22).</p

Cortisol response to VFD exposure in relationship to the “vulnerability index”.

<p>The vulnerability index inversely predicted cortisol change [F_(1,19) = 27.97, p < 0.0001; partial η2 = 0.59] (an effect size over four factors greater than a large effect size. Infant sex played no significant role in the relationship [F_(1,19) = 0.07, p = 0.78]. The red line represents a linear regression (r = -0.77; p <0.001; r² = 0.60).</p

Relationship of infant independent variable to Z-score transformed plasma cortisol and CSF CRF change (Δ = Post—Pre) to VFD exposure infant variables.

<p>Relationship of infant independent variable to Z-score transformed plasma cortisol and CSF CRF change (Δ = Post—Pre) to VFD exposure infant variables.</p

Cluster analysis of eight factors potentially related to core variable associated with a dyadic vulnerability index.

<p>The cluster analysis demonstrates the factors that promote maternal cortisol decrements include lighter, more subordinate mothers with lighter infants at the time of VFD onset, with reduced maternal-infant dyadic distance suggesting an association between socioecological vulnerability and cortisol suppression. The cluster analysis suggests a “core” of vulnerability variables (in red outlined area) that are closely associated. The black arrow indicates that core variables were each less than 50 Euclidian Linkage Units from each other. However, given that the VFD group mean cortisol remains stable, cortisol decrements are evidently exquisitely matched by cortisol increments in relatively advantaged, yet equivalently challenged, dyads, hence the concept of social allostasis. Abbreviations: PRECORT = maternal pre-VFD cortisol (ug/dl), DOM, = social rank score, MOMSWT = maternal weight measured prior to VFD exposure, HFDPROX = maternal-infant proximity aggregated score obtained from the final high foraging demand two week epoch, z cortdiff = standardized z-score of post—pre-VFD cortisol in response to maternal VFD, KIDWT = infant weight at the time of onset of VFD exposure (kg), VFDONSET = age in days at onset of VFD, CRFPRE = maternal CSF CRF concentrations (pg, ml) obtained prior to VFD exposure.</p

“High” versus “Low” baseline cortisol grouping and effects on plasma cortisol change in response to VFD exposure.

<p>A significant pre-VFD cortisol grouping x repeated measures interactive effect was noted [F_(1,20) = 20.36; p = 0.0002, partial η² = 0.54, 3.8 x greater than a large effect size] such that the “high” pre-VFD cortisol group exhibited cortisol decreases whereas the “low” cortisol VFD group showed cortisol increases. Vertical bars indicate ± standard errors. * indicates NK posthoc testing with p < 0.05.</p