Transcriptomic profiles of stress susceptibility and resilience in the amygdala and hippocampus

Abstract

A single, severe episode of stress can bring about myriad responses amongst individuals, ranging from cognitive enhancement to debilitating and persistent anxiety; however, the biological mechanisms that contribute to resilience versus susceptibility to stress are poorly understood. The dentate gyrus (DG) of the hippocampus and the basolateral nucleus of the amygdala (BLA) are key limbic regions that are susceptible to the neural and hormonal effects of stress. Previous work has also shown that these regions contribute to individual variability in stress responses; however, the molecular mechanisms underlying the role of these regions in susceptibility and resilience are unknown. In this study, we profiled the transcriptomic signatures of the DG and BLA of rats with divergent behavioral outcomes after a single, severe stressor. We subjected rats to three hours of immobilization with exposure to fox urine and conducted a behavioral battery one week after stress to identify animals that showed persistent, high anxiety-like behavior. We then conducted bulk RNA sequencing of the DG and BLA from susceptible, resilient, and unexposed control rats. Differential gene expression analyses revealed that the molecular signatures separating each of the three groups were distinct and non-overlapping between the DG and BLA. In the amygdala, key genes associated with insulin and hormonal signaling corresponded with vulnerability. Specifically, Inhbb, Rab31, and Ncoa3 were upregulated in the amygdala of stress-susceptible animals compared to resilient animals. In the hippocampus, increased expression of Cartpt - which encodes a key neuropeptide involved in reward, reinforcement, and stress responses - was strongly correlated with vulnerability to anxiety-like behavior. However, few other genes distinguished stress-susceptible animals from control animals, while a larger number of genes separated stress-resilient animals from control and stress-susceptible animals. Of these, Rnf112, Tbx19, and UBALD1 distinguished resilient animals from both control and susceptible animals and were downregulated in resilience, suggesting that an active molecular response in the hippocampus facilitates protection from the long-term consequences of severe stress. These results provide novel insight into the mechanisms that bring about individual variability in the behavioral responses to stress and provide new targets for the advancement of therapies for stress-induced neuropsychiatric disorders.

The double-edged sword of the hippocampus-ventromedial prefrontal cortex resting-state connectivity in stress susceptibility and resilience: A prospective study

“…While its involvement in stress susceptibility is well-documented, the amygdala's role in stress resilience remains less clear. For instance, in a rodent study, it was found that, unlike the hippocampus, which played a role in both stress vulnerability and resilience, the amygdala was primarily associated with stress vulnerability ( Long et al, 2023 ). Similar results had been observed in human cohorts, where the amygdala and its associated connectivity network were linked to stress responses during the COVID-19 pandemic but did not demonstrate the same significance in stress resilience ( Zhou et al, 2023 ).…”

“…Conversely, many individuals possess the capacity to adapt to stressors and employ adaptive responses, showing resilience (Franklin, Saab et al 2012; van der Werff et al, 2013 ). Investigating the neurobiological mechanisms underlying both stress susceptibility and resilience contributes to a deeper understanding of the processes involved in stress-related disorders and might pave the way for new approaches to the prevention and treatment of these conditions ( Charney 2004 , Long et al, 2023 ).…”

“…While having found the distinct roles of the hippocampus playing in the molecular mechanisms of stress vulnerability and stress resilience in rodent researches ( Henningsen et al, 2012 ; Larosa and Wong 2022 , Long et al, 2023 ), there is a significant lack of studies that has directly assessed and compared the role of the hippocampus, especially its connectivity with the vmPFC, in stress susceptibility versus stress resilience following trauma in humans. However, such investigations are of paramount importance for gaining a comprehensive understanding of these stress-related processes and furthering our knowledge of stress-related disorders ( Franklin, Saab et al 2012 ).…”