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.
Highlights
Life stress (ELS) increases the risk of the development of depression and anxiety disorders in adulthood (Heim and Nemeroff, 2001)
variable foraging demand (VFD) subjects exhibited increased cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) compared to non-VFD controls
Convergent evidence of reduced neurotrophic activity in association with high CSF 5-HIAA in VFD was reflected by reduced fractional anisotropy (FA) of the anterior limb of the internal capsule (ALIC)
Summary
Life stress (ELS) increases the risk of the development of depression and anxiety disorders in adulthood (Heim and Nemeroff, 2001). ELS may increase the risk for developing these disorders later in life, but may precipitate the onset of these illnesses, increase the likelihood of comorbidity, and impair efficacy of treatment (Friedman et al, 2002; Nemeroff et al, 2003; Gladstone et al, 2004). As the serotonergic system has been identified as crucially important to both the pathophysiology and the treatment of mood disorders, alterations in serotonin neurotransmission following ELS may be one key component in determining the contribution of ELS to depression and anxiety (Owens and Nemeroff, 1994). Life stress (ELS) is cited as a risk for mood and anxiety disorders, potentially through altered serotonin neurotransmission. A putatively decreased serotonin neurotransmission would be reflected by reductions in hippocampal volume and white matter (WM) fractional anisotropy (FA)
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