Genetic predisposition for high stress reactivity amplifies effects of early-life adversity

McIlwrick, Silja; Rechenberg, Alexandra; Matthes, Mariana; Burgstaller, Jessica; Schwarzbauer, Thomas; Chen, Alon; Touma, Chadi

doi:10.1016/j.psyneuen.2016.04.023

Cited by 37 publications

(43 citation statements)

References 91 publications

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“…Early-life programming may be adaptive in some cases [e.g., the attenuation of the enzyme 11β-HSD 2 can be beneficial to regulate sodium retention in nutrient poor environments ( Yehuda and Seckl, 2011 )]. However, studies in both humans and animal models have shown that programming in response to early-life stress (ELS) exposure can precipitate a dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in later life ( Heim et al, 2000 ; Shea et al, 2005 ; Korosi and Baram, 2010 ; McIlwrick et al, 2016 ). This can be evidenced by alterations in the corticotropin-releasing hormone (CRH) system, exaggerated release of glucocorticoid hormones from the adrenal cortex in response to stressors, and by impaired negative feedback via glucocorticoid and mineralocorticoid receptors (GR and MR) in the brain.…”

Section: Introductionmentioning

confidence: 99%

“…The stress reactivity (SR) mouse model is a genetic animal model, which recapitulates several of the key endophenotypes of the two MDD subtypes described above ( Touma et al, 2008 ; Heinzmann et al, 2014 ), including associated changes in bodyweight ( Touma et al, 2009 ), sleep architecture ( Touma et al, 2009 ; Fenzl et al, 2011 ), stress hormone profiles ( Touma et al, 2008 , 2009 ; Heinzmann et al, 2014 ), and cognitive performance ( Knapman et al, 2010a , b , 2012 ). Using this animal model, our group recently showed that an inherited predisposition for extremes in stress reactivity (high or low) interacts with ELS to shape short-term, as well as lasting consequences at the level of stress-coping behavior, neuroendocrine function, and gene expression ( McIlwrick et al, 2016 ). It remained uncertain, however, to what extent this gene x environment interaction has long-term effects on cognitive function and on the expression of important neurotrophic factors in the hippocampus.…”

Section: Introductionmentioning

confidence: 99%

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Late-Onset Cognitive Impairments after Early-Life Stress Are Shaped by Inherited Differences in Stress Reactivity

McIlwrick

Pohl

Chen

et al. 2017

Front. Cell. Neurosci.

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Early-life stress (ELS) has been associated with lasting cognitive impairments and with an increased risk for affective disorders. A dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis, the body’s main stress response system, is critically involved in mediating these long-term consequences of adverse early-life experience. It remains unclear to what extent an inherited predisposition for HPA axis sensitivity or resilience influences the relationship between ELS and cognitive impairments, and which neuroendocrine and molecular mechanisms may be involved. To investigate this, we exposed animals of the stress reactivity mouse model, consisting of three independent lines selectively bred for high (HR), intermediate (IR), or low (LR) HPA axis reactivity to a stressor, to ELS and assessed their cognitive performance, neuroendocrine function and hippocampal gene expression in early and in late adulthood. Our results show that HR animals that were exposed to ELS exhibited an HPA axis hyper-reactivity in early and late adulthood, associated with cognitive impairments in hippocampus-dependent tasks, as well as molecular changes in transcript levels involved in the regulation of HPA axis activity (Crh) and in neurotrophic action (Bdnf). In contrast, LR animals showed intact cognitive function across adulthood, with no change in stress reactivity. Intriguingly, LR animals that were exposed to ELS even showed significant signs of enhanced cognitive performance in late adulthood, which may be related to late-onset changes observed in the expression of Crh and Crhr1 in the dorsal hippocampus of these animals. Collectively, our findings demonstrate that the lasting consequences of ELS at the level of cognition differ as a function of inherited predispositions and suggest that an innate tendency for low stress reactivity may be protective against late-onset cognitive impairments after ELS.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Late-Onset Cognitive Impairments after Early-Life Stress Are Shaped by Inherited Differences in Stress Reactivity

McIlwrick

Pohl

Chen

et al. 2017

Front. Cell. Neurosci.

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“…Recent work in sheep suggests that ewes with high cortisol responses (HR) to ACTH gain more adipose tissue in response to a highenergy diet than ewes with low cortisol responses (LR) [73] . This contrasts that of HR mice, which have reduced body weight compared to LR mice [83] . In sheep, however, this innate difference in the susceptibility to gain weight is underpinned by a compilation of neuroendocrine, metabolic, and behavioural traits [73][74][75] .…”

Section: Cortisol Responsiveness Identifies Obesity-prone Individualsmentioning

confidence: 69%

“…A series of behavioural tests show that LR animals exhibit proactive coping strategies [74] . This contrasts work in mice, in that HR mice show hyper-activity in response to stress [83] . Nonetheless, LR ewes show greater physical activity in response to isolation stress, reduced fear towards humans, reduced freezing and increased initiative to reach a food reward [74] .…”

Section: Divergent Metabolic and Behavioural Responses To Stress In Lmentioning

confidence: 81%

Innate Obesity, Revealed by Selection Markers, Confers Significant Imprint of Hypothalamic Genes Controlling Energy Expenditure

Henry¹

2016

Neuroendocrinology

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The incidence of obesity is rapidly escalating and has reached epidemic proportions. In all species, including rodents, humans, and sheep, there is large variation in the degree of weight gain across individuals in response to an obesogenic environment. This individual variation is, at least in part, determined by innate differences in energy expenditure, of which adaptive thermogenesis is a key component. The hypothalamus is essential to the control of body weight and adiposity. Appetite-regulating peptides within the hypothalamus exert reciprocal effects on food intake and energy expenditure, such that neuropeptides that stimulate food intake inhibit thermogenesis and vice versa. This review discusses the role of the hypothalamic neuropeptides in determining innate predisposition to obesity in 3 animal models being obesity-prone and obesity-resistant rodents, genetically lean and obese sheep, and animals selected for high/low cortisol responsiveness. In rodents, leptin resistance is a primary feature of the propensity to become obese. This contrasts that of larger mammals, such as sheep, where altered susceptibility to obesity manifests within the melanocortin and/or orexin pathways. This review highlights fundamental species differences within the hypothalamus that lead to altered susceptibility to weight gain and increased propensity to become obese.

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“…Two additional observations in the current study are worth noting. First, the interindividual differences observed in mitochondrial respiration likely arise through a combination of experimental variability in the measures, including the documented variation in OCR measures by Seahorse across plates and experimental day (Sakamuri 2019; Yepez, 2018; Hubbard, 2018), and by well-known heterogeneous responses of different litters to ELS, as reported using different measures, including behavioral outcomes (for example (Bolton et al, 2018b;Goodwill et al, 2019;Heun-Johnson and Levitt, 2017;McIlwrick et al, 2016). We emphasize, however, that the statistically determined large effect sizes (w 2 ), even in light of such variation, indicate the robustness of the ELS adaptations reported here.…”

Section: Discussionmentioning

confidence: 99%

Proteomic and mitochondrial adaptations to early-life stress are distinct in juveniles and adults

Eagleson

Villaneuva

Southern

et al. 2020

Preprint

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Exposure to early-life stress (ELS) increases risk for poor mental and physical health outcomes that emerge at different stages across the lifespan. Yet, how age interacts with ELS to impact the expression of specific phenotypes remains largely unknown. An established limited-bedding paradigm was used to induce ELS in mouse pups over the early postnatal period. Initial analyses focused on the hippocampus, based on documented sensitivity to ELS in humans and various animal models, and the large body of data reporting anatomical and physiological outcomes in this structure using this ELS paradigm. An unbiased discovery proteomics approach revealed distinct adaptations in the non-nuclear hippocampal proteome in male versus female offspring at two distinct developmental stages: juvenile and adult. Gene ontology and KEGG pathway analyses revealed significant enrichment in proteins associated with mitochondria and the oxidative phosphorylation (OXPHOS) pathway in response to ELS in female hippocampus only. To determine whether the protein adaptations to ELS reflected altered function, mitochondrial respiration (driven through complexes II-IV) and complex I activity were measured in isolated hippocampal mitochondria using a Seahorse X96 Flux analyzer and immunocapture ELISA, respectively. ELS had no effect on basal respiration in either sex at either age. In contrast, ELS increased OXPHOS capacity in juvenile males and females, and reduced OXPHOS capacity in adult females but not adult males. A similar pattern of ELS-induced changes was observed for complex I activity. These data suggest that initial adaptations in juvenile hippocampus due to ELS were not sustained in adults. Mitochondrial adaptations to ELS were also exhibited peripherally by liver. Overall, the temporal distinctions in mitochondrial responses to ELS show that ELS-generated adaptations and outcomes are complex over the lifespan. This may contribute to differences in the timing of appearance of mental and physical disturbances, as well as potential sex differences that influence only select outcomes.

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Genetic predisposition for high stress reactivity amplifies effects of early-life adversity

Cited by 37 publications

References 91 publications

Late-Onset Cognitive Impairments after Early-Life Stress Are Shaped by Inherited Differences in Stress Reactivity

Late-Onset Cognitive Impairments after Early-Life Stress Are Shaped by Inherited Differences in Stress Reactivity

Innate Obesity, Revealed by Selection Markers, Confers Significant Imprint of Hypothalamic Genes Controlling Energy Expenditure

Proteomic and mitochondrial adaptations to early-life stress are distinct in juveniles and adults

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