The three-hit concept of vulnerability and resilience: toward understanding adaptation to early-life adversity outcome

Abstract

Stressful experiences during early-life can modulate the genetic programming of specific brain circuits underlying emotional and cognitive aspects of behavioral adaptation to stressful experiences later in life. Although this programming effect exerted by experience-related factors is an important determinant of mental health, its outcome depends on cognitive inputs and hence the valence an individual assigns to a given environmental context. From this perspective we will highlight, with studies in rodents, non-human primates and humans, the three-hit concept of vulnerability and resilience to stress-related mental disorders, which is based on gene-environment interactions during critical phases of perinatal and juvenile brain development. The three-hit (i.e., hit-1: genetic predisposition, hit-2: early-life environment, and hit-3: later-life environment) concept accommodates the cumulative stress hypothesis stating that in a given context vulnerability is enhanced when failure to cope with adversity accumulates. Alternatively, the concept also points to the individual's predictive adaptive capacity, which underlies the stress inoculation and match/mismatch hypotheses. The latter hypotheses propose that the experience of relatively mild early-life adversity prepares for the future and promotes resilience to similar challenges in later-life; when a mismatch occurs between early and later-life experience, coping is compromised and vulnerability is enhanced. The three-hit concept is fundamental for understanding how individuals can either be prepared for coping with life to come and remain resilient or are unable to do so and succumb to a stress-related mental disorder, under seemingly identical circumstances.

Keywords: Developmental programming; Early life environment; Epigenetics; Genetic predisposition; HPA axis; Later life environment; Resilience; Stress adaptation; Three hit; Vulnerability.

Figure 1. The newborn rat’s stress system readily habituates to repeated and prolonged maternal separation, while continuing to respond to stressors

Corticosterone (ng/ml) blood plasma levels measured at basal conditions (“basal”; white bars), after 8h of maternal separation (“separated”; gray bars) or 8h of maternal separation with an additional 30min of exposure to novelty (“novelty”; black bars). First separation rat pups (“1st SEP”) had no previous history of treatments. Third separation rat pups (“3rd SEP”) were exposed to 8h of maternal separation on postnatal day (pnd) 3 and 4. For the experiment, Long Evans litters were used. Data represented mean ± SEM. Significance level was set at p < 0.05. * vs. basal, # vs. separated levels of the same treatment group, † vs. basal of 1st HOME SEP, ¥ vs. correspondent value of 1st HOME SEP. n = 14–16 per time point of each treatment group. Adapted from Daskalakis et al., 2011a

Figure 2. The three-hit concept of vulnerability and resilience

Multi-genic inputs (hit-1) interact with early-life environmental inputs and experience-related factors (hit-2), programming phenotypes with differential susceptibility to later-life challenges (hit-3). Depending on the interaction of “programmed phenotypes” with later-life environment vulnerability or resilience may precipitate. Abbreviations: 5-HTTLPR (serotonin-transporter-linked polymorphic region), Aktl(RAC-alpha serine/threonine-protein kinase), BDNF (brain-derived neurotrophic factor), COMT (Catechol-O-methyltransferase), CRHR1 (Corticotropin releasing hormone receptor 1), DAOA (D-amino acid oxidase activator), DRD2 (Dopamine receptor D₂), DRD4 (Dopamine receptor D₄), FKBP5 (FK506 binding protein 5), GR (glucocorticoid receptor), MAOA (Monoamine oxidase A), MR (mineralocorticoid receptor), NPY (neuropeptide Y).