Metabolomics reveals distinct neurochemical profiles associated with stress resilience

Abstract

Acute social defeat represents a naturalistic form of conditioned fear and is an excellent model in which to investigate the biological basis of stress resilience. While there is growing interest in identifying biomarkers of stress resilience, until recently, it has not been feasible to associate levels of large numbers of neurochemicals and metabolites to stress-related phenotypes. The objective of the present study was to use an untargeted metabolomics approach to identify known and unknown neurochemicals in select brain regions that distinguish susceptible and resistant individuals in two rodent models of acute social defeat. In the first experiment, male mice were first phenotyped as resistant or susceptible. Then, mice were subjected to acute social defeat, and tissues were immediately collected from the ventromedial prefrontal cortex (vmPFC), basolateral/central amygdala (BLA/CeA), nucleus accumbens (NAc), and dorsal hippocampus (dHPC). Ultra-high performance liquid chromatography coupled with high resolution mass spectrometry (UPLC-HRMS) was used for the detection of water-soluble neurochemicals. In the second experiment, male Syrian hamsters were paired in daily agonistic encounters for 2 weeks, during which they formed stable dominant-subordinate relationships. Then, 24 h after the last dominance encounter, animals were exposed to acute social defeat stress. Immediately after social defeat, tissue was collected from the vmPFC, BLA/CeA, NAc, and dHPC for analysis using UPLC-HRMS. Although no single biomarker characterized stress-related phenotypes in both species, commonalities were found. For instance, in both model systems, animals resistant to social defeat stress also show increased concentration of molecules to protect against oxidative stress in the NAc and vmPFC. Additionally, in both mice and hamsters, unidentified spectral features were preliminarily annotated as potential targets for future experiments. Overall, these findings suggest that a metabolomics approach can identify functional groups of neurochemicals that may serve as novel targets for the diagnosis, treatment, or prevention of stress-related mental illness.

Chemogenetic activation of an infralimbic cortex to basolateral amygdala projection promotes resistance to acute social defeat stress

“…All animals were tested for a CD response 24 hours later. During acute social defeat stress, subjects were consecutively placed in the home cages of three separate resident aggressors for 5-min each with 5-min inter-trial intervals, as described previously 27,28 . No defeat control animals were treated identically except that the aggressors were removed from their cages to control for olfactory and environmental exposure.…”

“…www.nature.com/scientificreports www.nature.com/scientificreports/ Dominant-subordinate encounters. To allow the establishment of dominance relationships, subjects were individually housed for 1 week following stereotaxic surgery and were then weight-matched into resident-intruder dyads and paired in daily social encounters for 14 days as described previously 27,28 . Briefly, subjects were randomly assigned as a resident or intruder, and all social encounters occurred in the resident's home cage.…”

“…CNO or vehicle (5% DMSO in saline) was administered by intraperitoneal injection to each hamster (3 mg/kg; 0.3 ml volume injection). Acute social defeat stress consisted of subjects being placed in the home cages of three separate resident aggressors, as described previously 27,28 . Briefly, resident aggressors were prescreened to ensure that they reliably attacked and defeated intruders.…”

Activity of a vmPFC-DRN Pathway Corresponds With Resistance to Acute Social Defeat Stress

“…In another animal model, optogenetic stimulation of the vmPFC-DRN circuit during an acute forced swim stressor promotes proactive behavioral responses (Warden et al, 2012), which have been argued to index stress resilience (e.g., Wood et al, 2010). In our laboratory, we have shown that male Syrian hamsters who maintain social dominance for 2 weeks exhibit fewer negative behavioral (Morrison et al, 2014), neuroendocrine (Dulka et al, 2018b), and neurochemical (Dulka et al, 2017) consequences of social defeat stress compared to subordinates or controls. Importantly, such status-dependent changes in behavior require recruitment of vmPFC neurons (Morrison et al, 2013) and correspond with reduced activity of the DRN during social and non-social acute stress (Cooper et al, 2017).…”

Prelimbic-amygdala overexcitability mediates trait vulnerability in a novel mouse model of acute social defeat stress

“…Various forms of acute social stress have been described [22,63,83], but a standardized ASDS protocol resulting in distributions of resilience and susceptibility similar to CSDS has not previously been validated to the best of our knowledge. Experimental mice were placed into the cages of three aggressive CD1 mice for 2 min each sequentially, without rest periods.…”