Abstract
Background
Social defeat, which refers to experiences of loss during a confrontation among conspecific animals or during a hostile dispute among humans, can occur in either dyadic or group–individual encounters. Various animal models have been used to study the molecular mechanisms underpinning major depressive disorder. Among these, the social defeat paradigm has emerged as among the best approaches to evaluating depressed behavior. People frequently encounter stimuli generated by interactions with other people, and social challenges appear to be the most prevalent stressor in humans and other social animals. Furthermore, this procedure may also be considered an animal model of schizophrenia given that social defeat results in deficits in prepulse inhibition, an enhanced mesocorticolimbic dopamine response, increased phasic activity in the ventral tegmental area (VTA) dopaminergic neurons, and behavioral and neuronal cross-sensitization to amphetamines. Metabolomics is well suited for elucidating the systemic changes associated with stress because the systems underlying the stress response need to respond rapidly to threatening stimuli, and the initial events associated with the acute stress response are primarily metabolite-based. Moreover, metabolic changes have been reported in animals using a social defeat stress procedure. Specifically, the metabolism of lipids, amino acids, and energy was significantly perturbed by such a procedure. We hypothesized that measurement of the metabolomes in several key brain regions implicated in psychiatric disorders would illuminate the endogenous metabolic perbutations related to stress vulnerability and resilience, leading towards specific biomarker discovery.
Methods
Adult C57BL/6N mice were subjected social defeat stress for 10 days. Defeated mice were classified into unsusceptible (stress resilient) and susceptible (stress susceptible). Using high-resolution magic angle spinning 1H nuclear magnetic resonance (HR-MAS 1H NMR), untargeted metabolomes were measured in the amygdala (AMY), dorsal hippocampus (dHIP), dorsal striatum (dST), and prefrontal cortex (PFC).
Results
We observed perturbations of glutamine in the AMY; glutamate in the dHIP; glycine and myo-inositol in the dST; and aspartate, choline, and phosphoethanolamine in the PFC of susceptible and/or unsusceptible groups compared to the control group. The susceptible and unsusceptible groups significantly differed with regard to three metabolites: glutamine, glycine, and choline.
Discussion
To deepen our understanding of the pathophysiology of stress-related disorders, we measured metabolites in the AMY, dST, dHIP, and PFC of mice exposed to social defeat stress. Significant perturbations were observed in the metabolism of amino acids, lipids, and neurotransmitters. It was of great interest to observe that the Cho, Glu, and Gly levels of the susceptible and unsusceptible groups differed significantly.
Using HR-MAS 1H NMR, we observed perturbations of Gln in the AMY, of Glu in the dHIP, of Gly and m-Ins in the dST, and of Asp, Cho, and PE in the PFCs of susceptible and/or unsusceptible groups compared with the control group. Interestingly, three metabolites, Glu, Gly, and Cho, differed significantly between susceptible and unsusceptible groups. These findings suggest that social defeat stress induces disturbances in the metabolism of amino acids, lipids, and neurotransmitters in several brain areas. Furthermore, the resulting understanding of susceptibility-related metabolites may move us a step closer to elucidating the factors underpinning resistance to stress-related mental illnesses and identifying diagnostic biomarkers.