Elevated cerebrospinal fluid 5-hydroxyindoleacetic acid in macaques following early life stress and inverse association with hippocampal volume: preliminary implications for serotonin-related function in mood and anxiety disorders

Abstract

Background: Early life stress (ELS) is cited as a risk for mood and anxiety disorders, potentially through altered serotonin neurotransmission. We examined the effects of ELS, utilizing the variable foraging demand (VFD) macaque model, on adolescent monoamine metabolites. We sought to replicate an increase in cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) observed in two previous VFD cohorts. We hypothesized that elevated cisternal 5-HIAA was associated with reduced neurotrophic effects, conceivably due to excessive negative feedback at somatodendritic 5-HT1A autoreceptors. A putatively decreased serotonin neurotransmission would be reflected by reductions in hippocampal volume and white matter (WM) fractional anisotropy (FA).Methods: When infants were 2–6 months of age, bonnet macaque mothers were exposed to VFD. We employed cisternal CSF taps to measure monoamine metabolites in VFD (N = 22) and non-VFD (N = 14) offspring (mean age = 2.61 years). Metabolites were correlated with hippocampal volume obtained by MRI and WM FA by diffusion tensor imaging in young adulthood in 17 males [10 VFD (mean age = 4.57 years)].Results: VFD subjects exhibited increased CSF 5-HIAA compared to non-VFD controls. An inverse correlation between right hippocampal volume and 5-HIAA was noted in VFD- but not controls. CSF HVA and MHPG correlated inversely with hippocampal volume only in VFD. CSF 5-HIAA correlated inversely with FA of the WM tracts of the anterior limb of the internal capsule (ALIC) only in VFD.Conclusions: Elevated cisternal 5-HIAA in VFD may reflect increased dorsal raphe serotonin, potentially inducing excessive autoreceptor activation, inducing a putative serotonin deficit in terminal fields. Resultant reductions in neurotrophic activity are reflected by smaller right hippocampal volume. Convergent evidence of reduced neurotrophic activity in association with high CSF 5-HIAA in VFD was reflected by reduced FA of the ALIC.

Understanding the molecular mechanisms of aggression in BALB/c and TPH2-deficient mice

“…These data are in line with studies on mice (Browne et al, 2011) and macaque monkeys, subjected to early life variable foraging demand stress, where increased 5-HIAA concentrations in the cerebrospinal fluid were found (Coplan et al, 2014). Similar changes for both measures were shown in CF-1 mice exposed to the cold swim stress (Thurmond & Brown, 1984).…”

Effects of anxiety on suicidal ideation

“…The efficacy of SSRIs in treating a number of anxiety disorders indicates a role of serotonin dysfunction in anxiety as well (Kent et al ., 1998). Other studies have linked serotonin function, including 5-HT 1A and 5-HT 2A serotonin receptors, to anxiety (Coplan et al ., 2014; Ramboz et al ., 1998; Sullivan et al ., 2013; Sullivan et al ., 2005; Weisstaub et al ., 2006). Thus, paroxetine’s modulation of serotonin functioning may be specifically beneficial for suicidal depressed individuals who present with high anxiety.…”

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

“…For the VFD rearing exposure [ 15 ], mothers were confronted with an environment in which an adequate amount of food was always available yet the amount of time and effort necessary to obtain daily rations leading to a perception of foraging uncertainty, with persistent psychobiological effects observed in grown offspring [ 33 ]. The maternal food procurement schedule consisted of alternating blocks of 2-weeks in which food was easy to find (Low Foraging Demand; LFD), and 2-weeks in which food procurement was difficult, involving more time and effort (High Foraging Demand; HFD).…”