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

Abstract

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.

Chronic Psychosocial Stress and Experimental Pubertal Delay Affect Socioemotional Behavior and Amygdala Functional Connectivity in Adolescent Female Rhesus Macaques

“…The overall pattern of amygdala FC (Fig. 5A) was consistent with previous FC studies (e.g., Grayson et al, 2016; Reding et al, 2019) and the known anatomical connectivity of macaque amygdala (Höistad and Barbas, 2008), which is reciprocally interconnected with medial temporal pole, hippocampus, parahippocampal cortex, anterior insula, posterior orbitofrontal and medial PFC. In voxelwise, whole-brain analyses with stringent correction for multiple comparisons, we observed only one significant effect – subordinate status was associated with increased FC between left amygdala and right temporal pole (Fig.…”

“…3B), consistent with observations that subordinate monkeys engage less in affiliative social behavior (Michopoulos et al, 2012; Snyder-Mackler et al, 2016). Affiliative behavior (e.g., seeking proximity, grooming) serves an important social bonding function amongst unrelated group-living female macaques, and the relatively reduced opportunities for prosocial interactions experienced by subordinate-ranking animals may be a critical factor that accounts for the adverse effects of chronic stress on neurobehavioral and health related outcomes (Howell et al, 2014; Reding et al, 2019; Sapolsky, 2005; Snyder-Mackler et al, 2016).…”

“…Socially housed female macaques organize into a linear social dominance hierarchy in which subordinate members are subject to constant unpredictable harassment, mimicking the uncontrollable and unpredictable nature of human psychosocial stress (Wilson, 2016). Subordinate group-living macaques experience continuous exposure to subordination stress from early in life and exhibit a range of stress-related neurobehavioral (Godfrey et al, 2016; e.g., Howell et al, 2014; Reding et al, 2019) and health outcomes (Sapolsky, 2005; e.g., Snyder-Mackler et al, 2016).…”

“…Imaging data were preprocessed per published protocols (Reding et al, 2019) using an in-house Nipype pipeline incorporating tools from the FMRIB Software Library (FSL; RRID: SCR_002823) and 4dfp tools. The pipeline performs: 1) slice-time correction, 2) one-step resampling of rigid body head motion correction, distortion correction using diffusion field maps, structural-functional co-registration, and non-linear registration of the T1-weighted structural image to the 112RM-SL atlas in F99 space at 1.5×1.5×1.5mm 3 resolution, 4) signal normalization to a mode of 1000, 5) detrending, 6) regression of rigid body head motion parameters, whole-brain, ventricle, and white matter signal, and all first-order derivatives, and 7) low-pass filtering (< 0.1 Hz).…”

“…Studies with non-human primates offer a translational bridge from rodent work. In a recent example, Reding et al (Reding et al, 2019) showed that, in ovariectomized adult female rhesus monkeys, treatment with E2 differentially modulated amygdala-medial PFC functional connectivity in chronically stressed (subordinate) relative to non-stressed (dominant) animals. This suggests that, even during adulthood, exposure to E2 interacts with chronic stress to alter macroscale brain circuits of relevance to human psychopathology.…”