Epigenetic Programming Effects of Early Life Stress: A Dual-Activation Hypothesis

Abstract

Epigenetic processes during early brain development can function as ‘developmental switches’ that contribute to the stability of long-term effects of early environmental influences by programming central feedback mechanisms of the HPA axis and other neural networks. In this thematic review, we summarize accumulated evidence for a dual-activation of stress-related and sensory networks underlying the epigenetic programming effects of early life stress. We discuss findings indicating epigenetic programming of stress-related genes with impact on HPA axis function, the interaction of epigenetic mechanisms with neural activity in stress-related neural networks, epigenetic effects of glucocorticoid exposure, and the impact of stress on sensory development. Based on these findings, we propose that the combined activation of stress-related neural networks and stressor-specific sensory networks leads to both neural and hormonal priming of the epigenetic machinery, which sensitizes these networks for developmental programming effects. This allows stressor-specific adaptations later in life, but may also lead to functional mal-adaptations, depending on timing and intensity of the stressor. Finally, we discuss methodological and clinical implications of the dual-activation hypothesis. We emphasize that, in addition to modifications in stress-related networks, we need to account for functional modifications in sensory networks and their epigenetic underpinnings to elucidate the long-term effects of early life stress.

Stress hormones mediate developmental plasticity in vertebrates with complex life cycles

“…The effect on fitness depends on the context and informational content of the early experiences; some carry-over effects may be beneficial when the early-life experience prepares the organism for conditions encountered later in life (i.e., see the Thrifty Phenotype hypothesis; ( Hales and Barker, 1992 ; Prentice, 2005 ). On the other hand, exposure to stressors early in life can lead to higher probabilities of reproductive dysfunction and adult-onset disease ( Barker, 1997 ; Chen and Baram, 2016 ; Choe et al, 2019 ; Fogelman and Canli, 2019 ; Lux, 2018 ; Malik and Spencer, 2019 ; Murphy et al, 2017 ; Ridout et al, 2018 ; Wakeford et al, 2018 ; Walters and Kosten, 2019 ).…”

“…In mammals, exposure to early life stress can cause a diversity of psychopathologies ( Chen and Baram, 2016 ; Fogelman and Canli, 2019 ; Lux, 2018 ; O'Donnell and Meaney, 2020 ; Vaiserman, 2015 ; Walters and Kosten, 2019 ). Neonatal stress in mammals causes stable, long term alterations in the morphology of CRF neurons in brain areas involved with neuroendocrine and behavioral responses to stress (i.e., PVN, amygdala, bed nucleus of the stria terminalis - BNST, hippocampus, locus coeruleus) ( Buschdorf and Meaney, 2016 ; Meaney, 2001 ).…”

Early-Life m6A RNA Demethylation by Fat Mass and Obesity-Associated Protein (FTO) Influences Resilience or Vulnerability to Heat Stress Later in Life

“…Fine-tuning of the thermal-response set point during the critical postnatal sensory-developmental period can determine future reactions to heat stress, inducing either resilience or vulnerability. Epigenetic modifications are involved in early life environmental programming, establishing a specific chromatin state to specify gene expression patterns associated with cellular memory (Franklin et al, 2012;Braun et al, 2017;Lux, 2018). We have previously shown that specific epigenetic marking of CRH intron (Cramer et al, 2019) and HSP70 promoter (Kisliouk et al, 2017) in response to harsh or mild heat stress at the critical development period underlay their differential expression during heat challenge later in life.…”

“…The exposure to stressful experiences, including heat stress, during the critical sensory development period at early life can change neural architecture and modulate the stress response set point leading to either stress resilience or vulnerability later in life (Franklin et al, 2012;Braun et al, 2017;van Bodegom et al, 2017;Lux, 2018). Thermal control set point is regulated by thermosensitive neurons of the preoptic anterior hypothalamus (PO/AH; Boulant, 2006;Wang et al, 2019).…”

The Basis For A Neurobiological-Associative Model of Personality and Group Cohesion: The Evolutionary And System Biological Origins Of Social Exclusion, Hierarchy, and Structure

“…Neuroepigenetics is a subfield of epigenetics which deals with neural cells based on the experience-dependent epigenome regulation, which contributes to gene expression in nondividing neural cells as well as contributing to cell fate determination and differentiation. Further, it has been shown that early life stress can change both gene expression and brain structure in both animals and human models (Lux, 2018).…”