Early Rearing Conditions Affect Monoamine Metabolite Levels During Baseline and Periods of Social Separation Stress: A Non-human Primate Model (Macaca mulatta).

Elizabeth K Wood,Christina S Barr,Melanie L Schwandt,Stephen J Suomi,Natalia Gabrielle,J Dee Higley,Stephen G Lindell,Andrea N Skowbo,Jacob Hunter

doi:10.3389/fnhum.2021.624676

Abstract

A variety of studies show that parental absence early in life leads to deleterious effects on the developing CNS. This is thought to be largely because evolutionary-dependent stimuli are necessary for the appropriate postnatal development of the young brain, an effect sometimes termed the “experience-expectant brain,” with parents providing the necessary input for normative synaptic connections to develop and appropriate neuronal survival to occur. Principal among CNS systems affected by parental input are the monoamine systems. In the present study, N = 434 rhesus monkeys (233 males, 201 females) were reared in one of two conditions: as mother-reared controls (MR; n = 269) or without adults with 24-h access to same-aged peers (PR; n = 165). When subjects were six-months-old, they underwent a separation paradigm involving 4, sequential, four-day social separations from their mothers or peers, with each separation followed by three-day reunions with their mothers or their peers. Prior to the separation paradigm, baseline cisternal CSF samples were obtained, as well as at the end of each the four social separations, and after final separation, during a recovery period. CSF was assayed for concentrations of monoamine metabolites and a blood sample was genotyped for the serotonin transporter (5-HTT) genotype. Replicating earlier landmark findings, PR subjects with the s allele exhibited lower baseline concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), when compared to PR subjects homozygous for the L allele. MR subjects were undifferentiated by genotype. PR subjects exhibited lower CSF 5-HIAA concentrations during baseline, but higher CSF 5-HIAA during social separations, when compared to MR subjects. There were rearing effects for the dopamine metabolite homovanillic acid (HVA) and for the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG), with PR subjects showing higher HVA and lower MHPG when compared to MR subjects. These findings indicate that there are long-term deficits in the response of monoamines following early maternal absence. The results of this study confirm and extend earlier findings that early parental absence has deleterious consequences for the development of the monoamine systems, and that these consequences are modulated by the 5-HTT genotype.

Highlights

In primates, most cortical brain development occurs postnatally (Bakken et al, 2016)
There was a significant two-way separation-by-rearing condition interaction on CSF 5-HIAA concentrations [F(1,173) = 5.97, p = 0.02], with MR subjects exhibiting higher CSF 5-HIAA concentrations during Baseline, when compared to PR subjects (p = 0.007). This effect reversed during the stress of the social separations, with MR subjects showing lower CSF 5-HIAA concentrations during Separation 1 (p = 0.04), Separation 2 (p = 0.003), Separation 3 (p = 0.04), and Separation 4 (p = 0.007), when compared to the PR subjects
PR subjects showed an increase in CSF 5-HIAA concentrations, but PR and MR subjects showed no difference from Separation 4 to Recovery (p = 0.60), and neither group returned to Baseline levels during Recovery

Summary

Introduction

Most cortical brain development occurs postnatally (Bakken et al, 2016). Studies of humans raised in institutions exhibit fewer synaptic connections relative to their typically-reared peers, resulting in smaller brains (Dobrova-Krol et al, 2008), reduced white matter (Eluvathingal et al, 2006; Mehta et al, 2009), reduced functional connections between structures in the limbic system (Chugani et al, 2001; Daniels et al, 2013; Kumar et al, 2014), increased amygdalae volume (Rutter et al, 2007; Mehta et al, 2009; Tottenham et al, 2010), and decreased corpus callosum volume (Mehta et al, 2009) They tend to show a dysregulated stress response (Gunnar et al, 2001; Tarullo and Gunnar, 2006). While Nelson et al (2011) makes the case that it is difficult to tease out the deficits resulting from impoverished early environments and the deficits resulting from poor social experiences, Studies of children with less severe early experiences, who develop in homes with more stimulating surroundings but whose mothers are less responsive to their infants’ needs, for instance, mothers who suffer from depression, show deficits in CNS development and functioning (Ashman and Dawson, 2002; Pruessner et al, 2004; Qiu et al, 2015); albeit, not as extreme as those seen in institutionallyreared children

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