Social subordination alters estradiol-induced changes in cortico-limbic brain volumes in adult female rhesus monkeys.

Women have a higher risk of developing stress-related disorders compared to men and the experience of a stressful life event is a potent risk-factor. The rodent literature suggests that chronic exposure to stressors as well as 17ß-estradiol (E2) can result in alterations in neuronal structure in corticolimbic brain regions, however the translation of these data to humans is limited by the nature of the stressor experienced and issues of brain homology. To address these limitations, we used a well-validated rhesus monkey model of social subordination to examine effects of E2 treatment on subordinate (high stress) and dominant (low stress) female brain structure, including regional gray matter and white matter volumes using structural magnetic resonance imaging. Our results show that one month of E2 treatment in ovariectomized females, compared to control (no) treatment, decreased frontal cortex gray matter volume regardless of social status. In contrast, in the cingulate cortex, an area associated with stress-induced emotional processing, E2 decreased grey matter volume in subordinates but increased it in dominant females. Together these data suggest that physiologically relevant levels of E2 alter cortical gray matter volumes in females after only one month of treatment and interact with chronic social stress to modulate these effects on brain structure.

Effects of social subordination and oestradiol on resting-state amygdala functional connectivity in adult female rhesus monkeys.

Preclinical studies demonstrate that chronic stress modulates the effects of oestradiol (E2) on behaviour through the modification of the amygdala and the medial prefrontal cortex (mPFC) neuronal structure. Clinical studies suggest that alterations in amygdala functional connectivity (FC) with the mPFC may be associated with stress-related phenotypes, including mood and anxiety disorders. Thus, identifying the effects of stress and E2 on amygdala-mPFC circuits is critical for understanding the neurobiology underpinning the vulnerability to stress-related disorders in women. In the present study, we used a well-validated rhesus monkey model of chronic psychosocial stress (subordinate social rank) to examine effects of E2 on subordinate (SUB) (i.e. high stress) and dominant (DOM) (i.e. low stress) female resting-state amygdala FC with the mPFC and with the whole-brain. In the non-E2 treatment control condition, SUB was associated with stronger left amygdala FC to subgenual cingulate (Brodmann area [BA] 25: BA25), a region implicated in several psychopathologies in people. In SUB females, E2 treatment strengthened right amygdala-BA25 FC, induced a net positive amygdala-visual cortex FC that was positively associated with frequency of submissive behaviours, and weakened positive amygdala-para/hippocampus FC. Our findings show that subordinate social rank alters amygdala FC and the impact of E2 on amygdala FC with BA25 and with regions involved in visual processing and memory encoding.

Social subordination impairs hypothalamic-pituitary-adrenal function in female rhesus monkeys.

Linear dominance hierarchies organize and maintain stability in female rhesus macaque (Macaca mulatta) social groups regardless of group size. As a consequence of their low social status, subordinate females suffer from an array of adverse outcomes including reproductive compromise, impaired immune function, and poor cardiovascular health. However, data that differentiate limbic-hypothalamic-pituitary-adrenal axis (LHPA) parameters between dominant from subordinate female monkeys are inconsistent, bringing into question whether social subordination alters the LHPA axis in female macaques. One difficulty in examining LHPA function in macaques may be the confounding effects of cycling ovarian steroids that are known to modulate LHPA activity. The current study used ovariectomized dominant and subordinate female rhesus monkeys to examine the effect that social subordination has on LHPA function by measuring morning and diurnal serum cortisol levels, dexamethasone (Dex) suppression of cortisol, metabolic clearance of Dex, and ACTH stimulation of adrenal cortisol release and cortisol response following exposure to acute social isolation. Compared to dominant females, subordinate females showed diminished morning peak cortisol secretion, weakened glucocorticoid negative feedback, and decreased adrenal cortisol response to an ACTH challenge as well as a restrained cortisol response following social isolation. However, the metabolism of Dex did not account for differences in Dex suppression between dominant and subordinate females. These results indicate that the ability to mount and limit glucocorticoid release is significantly reduced by psychosocial stress in female rhesus macaques, suggesting a hyporesponsive LHPA phenotype which resembles that observed in several human psychopathologies.

Evidence for ape and human specializations in geniculostriate projections from VGLUT2 immunohistochemistry.

Vesicular glutamate transporters (VGLUTs) reuptake glutamate into synaptic vesicles at excitatory synapses. VGLUT2 is localized in the cortical terminals of neuronal somas located in the main sensory nuclei of the thalamus. Thus, immunolabeling of cortex with antibodies to VGLUT2 can reveal geniculostriate terminal distributions in species in which connectivity cannot be studied with tract-tracing techniques, permitting broader comparative studies of cortical specializations. Here, we used VGLUT2 immunohistochemistry to compare the organization of geniculostriate afferents in primary visual cortex in hominid primates (humans, chimpanzees, and an orangutan), Old World monkeys (rhesus macaques and vervets), and New World monkeys (squirrel monkeys). The New and Old World monkeys had a broad, dense band of terminal-like labeling in cortical layer 4C, a narrow band of labeling in layer 4A, and additional labeling in layers 2/3 and 6, consistent with results from conventional tract-tracing studies in these species. By contrast, although the hominid primates had a prominent layer 4C band, labeling of layer 4A was sparse or absent. Labeling was also present in layers 2/3 and 6, although labeling of layer 6 was weaker in hominids and possibly more individually variable than in Old and New World monkeys. These findings are consistent with previous observations from cytochrome oxidase histochemistry and a very small number of connectivity studies, suggesting that the projections from the parvocellular layers of the lateral geniculate nucleus to layer 4A were strongly reduced or eliminated in humans and apes following their evolutionary divergence from the other anthropoid primates.