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The three-hit concept of vulnerability and resilience: Toward understanding adaptation to early-life adversity outcome
Open accessAbstract
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.
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“Accordingly, this shift from a hyper- to a hypo-responsive stress axis in the first 5 years in life may be represent an particularly crucial stress-sensitive period, especially in the absence of a nurturing caregiver (104).”
From Developmental Trajectories of Early Life Stress and Trauma: A Narrative Review on Neurobiological Aspects Beyond Stress System Dysregulation (2019) · cites this paper as [104]
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“After an initial hyper-responsive period, the HPA axis may later transition into a stress hypo-responsive period (SHRP) with lower basal cortisol levels and blunted stress-induced cortisol reactivity (101, 104–106).”
From Developmental Trajectories of Early Life Stress and Trauma: A Narrative Review on Neurobiological Aspects Beyond Stress System Dysregulation (2019) · cites this paper as [104]
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“The classical vulnerabilitystress model of mental disorders, arguably one of the most influential models of disorder development, as well as conceptually similar approaches such as the”
From The applied implications of epigenetics in anxiety, affective and stress-related disorders - A review and synthesis on psychosocial stress, psychotherapy and prevention (2020) · cites this paper as Daskalakis, Bagot, Parker, Vinkers, & de Kloet, 2013
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“Taken together, enduring changes in the transcriptome may facilitate the response to early developmental challenges and thus play a central role in the long-term (and sometimes transgenerational) biological trajectories of stress-related disease through programming effects for stress reactivity after ELS/CT exposure (104, 413, 414).”
From Developmental Trajectories of Early Life Stress and Trauma: A Narrative Review on Neurobiological Aspects Beyond Stress System Dysregulation (2019) · cites this paper as [104]
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“Recently, Daskalakis et al. (104) have expanded this model suggesting a three-hit concept for vulnerability and resilience.”
From Developmental Trajectories of Early Life Stress and Trauma: A Narrative Review on Neurobiological Aspects Beyond Stress System Dysregulation (2019) · cites this paper as [104]
The cited source says what the claim attributes to it.
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“Accordingly, vulnerability in a given context is enhanced when failure to cope with adversity accumulates.”
From Developmental Trajectories of Early Life Stress and Trauma: A Narrative Review on Neurobiological Aspects Beyond Stress System Dysregulation (2019) · cites this paper as [104]
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“The interaction of the individual genetic background (hit-1) with ELS/CT exposure (hit-2) results in an evolving phenotype with altered stress axis regulation and sensitivity due to early developmental programming, which, in turn, interacts with later-life challenges (hit-3) to result in a higher or lower vulnerability risk according to the type of challenge experienced.”
From Developmental Trajectories of Early Life Stress and Trauma: A Narrative Review on Neurobiological Aspects Beyond Stress System Dysregulation (2019) · cites this paper as [104]
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Metadata
- Authors
- Daskalakis, N. P., Bagot, R. C., Parker, K. J., Vinkers, C. H., & de Kloet, E. R.
- Affiliations
- Leiden University (NL)
- Douglas Mental Health University Institute (CA)
- Stanford Medicine (US)
- Utrecht University (NL)
- Corresponding author
- Daskalakis, Nikolaos P.
- Venue
- Psychoneuroendocrinology
- Publisher
- Elsevier BV
- Published
- 2013-09
- Volume
- 38
- Issue
- 9
- Pages
- 1858-1873
- ISSN
- 0306-4530 (ISSN-L)
- PMC
- PMC3773020
- OpenAlex
- W2150581383
- Semantic Scholar
- 803eaa44fe6fdff1f9eccd7886ac5a72114899e7
- Cited by
- 579
- References
- 202
- Citations by year
- 2026: 34 · 2025: 29 · 2024: 62 · 2023: 49 · 2022: 52 · 2021: 58 · 2020: 54 · 2019: 50 · 2018: 45 · 2017: 44 · 2016: 41 · 2015: 34 · 2014: 22 · 2013: 4
- FWCI
- 14.94
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Psychoneuroendocrinology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- Funders
- Dutch Top-Institute Pharma T5-209
- NIH-R01HD67175
- Royal Netherlands Academy for Sciences
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Social Sciences › Psychology › Clinical Psychology › Resilience and Mental Health
- Social Sciences › Psychology › Clinical Psychology › Child Abuse and Trauma
- Keywords
- vulnerability and resilience, childhood adversity, stress-related disorders, gene-environment interaction, match-mismatch hypothesis, coping
- MeSH terms
- Adaptation, Psychological, Animals, Avoidance Learning, Disease Models, Animal, Female, Glucocorticoids, Humans, Hypothalamo-Hypophyseal System, Maternal Behavior, Maternal Deprivation, Models, Neurological, Models, Psychological, Neuronal Plasticity, Pituitary-Adrenal System, Pregnancy, Prenatal Exposure Delayed Effects, Primates, Stress Disorders, Post-Traumatic, Stress, Psychological, Genetic Predisposition to Disease, Vulnerable Populations, Epigenesis, Genetic, Rats, Resilience, Psychological, Gene-Environment Interaction
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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