Reactivation of early-life stress-sensitive neuronal ensembles contributes to lifelong stress hypersensitivity

Abstract

Early-life stress (ELS) is one of the strongest lifetime risk factors for depression, anxiety, suicide, and other psychiatric disorders, particularly after facing additional stressful events later in life. Human and animal studies demonstrate that ELS sensitizes individuals to subsequent stress. However, the neurobiological basis of such stress sensitization remains largely unexplored. We hypothesized that ELS-induced stress sensitization would be detectable at the level of neuronal ensembles, such that cells activated by ELS would be more reactive to adult stress. To test this, we leveraged transgenic mice to genetically tag, track, and manipulate experience-activated neurons. We found that in both male and female mice, ELS-activated neurons within the nucleus accumbens (NAc), and to a lesser-extent the medial prefrontal cortex, were preferentially reactivated by adult stress. To test whether reactivation of ELS-activated ensembles in the NAc contributes to stress hypersensitivity, we expressed hM4Dis receptor in control or ELS-activated neurons of pups and chemogenetically inhibited their activity during experience of adult stress. Inhibition of ELS-activated NAc neurons, but not control-tagged neurons, ameliorated social avoidance behavior following chronic social defeat stress in males. These data provide evidence that ELS-induced stress hypersensitivity is encoded at the level of corticolimbic neuronal ensembles.

The impact of pubertal stress and adult hormone exposure on the transcriptome of the developing hypothalamus

“…Another future goal will be to merge this cell-type specificity with tracking of the same cells throughout the lifespan, which will overcome our current limitation of examining adolescent and adult outcomes in different animals. Recent work has shown that a stress exposure early, in the form of maternal separation, led to the prolonged sensitivity of a set of cells in the nucleus accumbens to stressors in adulthood (40).…”

“…Another future goal will be to merge this cell-type specificity with tracking of the same cells throughout the lifespan, which will overcome our current limitation of examining adolescent and adult outcomes in different animals. Recent work has shown that a stress exposure early, in the form of maternal separation, led to the prolonged sensitivity of a set of cells in the nucleus accumbens to stressors in adulthood (40). Using a transgenic strategy in mice to permanently mark cells that had increased Arc expression in response to early life stress, Balouek et al showed that neurons tagged by maternal separation were the same cells reactivated by stress later in life and that blocking their activation ameliorated the negative behavioral consequences.…”

Lifelong molecular consequences of high Glucocorticoids exposure during development

“…Early life stress (ELS) affects healthy development and aging as well as susceptibility to psychiatric disorders in humans [1][2][3][4] . Studies in humans and animals suggest ELS may increase risk for psychiatric diseases such as depression by inducing hypersensitivity to future stress exposure [5][6][7][8] . However, mechanism by which ELS sensitizes responses to future stress responses in adulthood remains poorly understood.…”

Gas5 regulates early life stress-induced anxiety and spatial memory

“…Maternal separation, a well-established model of early-life stress, has been extensively studied to investigate the long-term consequences of adverse early life events during this critical period of brain function and behaviour (Taylor et al, 2010; Korosi et al, 2012). Stress due to maternal separation (MS) in rodents leads to anxiety-like behaviours in adulthood as characterized by heightened fear, avoidance, and stress sensitivity (Banqueri et al, 2017; Lundberg et al, 2020; Balouek et al ., 2023). The ventral hippocampus, a key brain area affected by MS (Dimatelis et al, 2014; Marais et al, 2009), has been shown to regulate emotions (Jimenez et al, 2018; H. Li et al, 2022; McNaughton, 1997).…”