Programming HPA-axis by early life experience: Mechanisms of stress susceptibility and adaptation

Editors

Nikolaos P Daskalakis

Harvard Medical School

Rachel Yehuda

Icahn School of Medicine at Mount Sinai

Impact

ACTH [(A); picogram/milliliter], corticosterone [(B); CORT in nanogram/milliliter] blood plasma levels, and their ratio [(C); ACTH/CORT] of non-deprived (NON-DEP) and 24 h deprived (DEP) pups measured at basal conditions (basal; white bars) or after 30 min of novelty exposure (novelty; black bars) at postnatal day (pnd) 5. Data represent mean ± SEM. * vs. basal, # vs. NON-DEP, $ vs. CD1. Significance level was set at p = 0.05.

Original Research

05 November 2014

Immediate Effects of Maternal Deprivation on the (Re)Activity of the HPA-Axis Differ in CD1 and C57Bl/6J Mouse Pups

Nikolaos P. Daskalakis

, 3 more and

Melly S. Oitzl

5,688 views

17 citations

Long-term outcome of post-natal dexamethasone. (A) All groups except dexamethasone non-handled (DEX NH) spent significantly more time in the new compared to the familiar arm during re-exposure to T-maze. Data represent mean ± SEM, *p < 0.05, **p < 0.01. (B) Cortcosterone (CORT) levels before, during, and following exposure to 10 min restraint stress. Both handling and DEX treatment result in enhanced negative feedback of the HPA-axis at t = 120 min. Data represent mean ± SEM. Time × drug treatment × handling interaction p = 0.01, *p < 0.05 (from Ref. (93)).

Review

09 July 2014

Context Modulates Outcome of Perinatal Glucocorticoid Action in the Brain

E. Ronald de Kloet

, 1 more and

Jiska Kentrop

6,679 views

28 citations

Twenty-four-hour urinary cortisol excretion based on maternal age at Holocaust exposure in control subjects and Holocaust offspring. Estimated marginal means ± SEM for urinary cortisol levels (microgram per day) are presented for comparison subjects (white bar) and Holocaust survivor offspring grouped according to whether offspring’s mother was a child (age 0–11; solid blue bar), adolescent (age 12–18; speckled gold bar), or adult (diagonally striped red bar) at Holocaust exposure (age 18 or older). Statistical significance was set at p < 0.05.

Original Research

04 July 2014

Maternal Age at Holocaust Exposure and Maternal PTSD Independently Influence Urinary Cortisol Levels in Adult Offspring

Heather N. Bader

, 4 more and

Rachel Yehuda

6,355 views

30 citations

How does ELS increase the risk for insulin resistance and hyperglycemia? Early-life stress (ELS) induced by three different paradigms including maternal deprivation, maternal separation, and limited nesting material are known to dysregulate HPA axis activity, with limited data on the effects of ELS on hypothalamic feeding neuropeptides and inflammation. It is proposed that ELS disturbs circulating glucocorticoids (GC) through a combined action of HPA axis activity, hypothalamic feeding neuropeptides, and inflammatory changes. The effects of ELS on liver 11β-HSD1, an enzyme that converts inactive GC to active GC, and 5α-reductase, an enzyme involved in GC metabolism, is less known. It is proposed that during the maladaptation period, ELS affects tissue levels of these enzymes, thus increasing exposure of peripheral tissues to GC. Excess GC availability can alter insulin signaling, leading to hyperinsulinemia and insulin resistance over time. Thus, increases in circulating and tissue GC induced by ELS act synergistically to exacerbate insulin resistance in peripheral tissues and alter energy expenditure and utilization. ELS, early-life stress; MD, maternal deprivation; MS, maternal separation; LN, limited nesting material; GC, glucocorticoids; TNF-α, tumor necrosis factor alpha; IL-6, interleukin 6; IL-1β, interleukin-1 beta; 11β-HSD1, 11-beta hydroxysteroid dehydrogenase.

Review

13 May 2014

Early-Life Stress, HPA Axis Adaptation, and Mechanisms Contributing to Later Health Outcomes

Jayanthi Maniam

, 1 more and

Margaret J. Morris

Stress activates the hypothalamic–pituitary–adrenal (HPA) axis, which then modulates the degree of adaptation and response to a later stressor. It is known that early-life stress can impact on later health but less is known about how early-life stress impairs HPA axis activity, contributing to maladaptation of the stress–response system. Early-life stress exposure (either prenatally or in the early postnatal period) can impact developmental pathways resulting in lasting structural and regulatory changes that predispose to adulthood disease. Epidemiological, clinical, and experimental studies have demonstrated that early-life stress produces long term hyper-responsiveness to stress with exaggerated circulating glucocorticoids, and enhanced anxiety and depression-like behaviors. Recently, evidence has emerged on early-life stress-induced metabolic derangements, for example hyperinsulinemia and altered insulin sensitivity on exposure to a high energy diet later in life. This draws our attention to the contribution of later environment to disease vulnerability. Early-life stress can alter the expression of genes in peripheral tissues, such as the glucocorticoid receptor and 11-beta hydroxysteroid dehydrogenase (11β-HSD1). We propose that interactions between altered HPA axis activity and liver 11β-HSD1 modulates both tissue and circulating glucocorticoid availability, with adverse metabolic consequences. This review discusses the potential mechanisms underlying early-life stress-induced maladaptation of the HPA axis, and its subsequent effects on energy utilization and expenditure. The effects of positive later environments as a means of ameliorating early-life stress-induced health deficits, and proposed mechanisms underpinning the interaction between early-life stress and subsequent detrimental environmental exposures on metabolic risk will be outlined. Limitations in current methodology linking early-life stress and later health outcomes will also be addressed.

31,654 views

249 citations

Review

21 March 2014

Early Life Trauma and Attachment: Immediate and Enduring Effects on Neurobehavioral and Stress Axis Development

Millie Rincón-Cortés

and

Regina M. Sullivan

Over half a century of converging clinical and animal research indicates that early life experiences induce enduring neuroplasticity of the HPA-axis and the developing brain. This experience-induced neuroplasticity is due to alterations in the frequency and intensity of stimulation of pups’ sensory systems (i.e., olfactory, somatosensory, gustatory) embedded in mother–infant interactions. This stimulation provides “hidden regulators” of pups’ behavioral, physiological, and neural responses that have both immediate and enduring consequences, including those involving the stress response. While variation in stimulation can produce individual differences and adaptive behaviors, pathological early life experiences can induce maladaptive behaviors, initiate a pathway to pathology, and increase risk for later-life psychopathologies, such as mood and affective disorders, suggesting that infant-attachment relationships program later-life neurobehavioral function. Recent evidence suggests that the effects of maternal presence or absence during this sensory stimulation provide a major modulatory role in neural and endocrine system responses, which have minimal impact on pups’ immediate neurobehavior but a robust impact on neurobehavioral development. This concept is reviewed here using two complementary rodent models of infant trauma within attachment: infant paired-odor-shock conditioning (mimicking maternal odor attachment learning) and rearing with an abusive mother that converge in producing a similar behavioral phenotype in later-life including depressive-like behavior as well as disrupted HPA-axis and amygdala function. The importance of maternal social presence on pups’ immediate and enduring brain and behavior suggests unique processing of sensory stimuli in early life that could provide insight into the development of novel strategies for prevention and therapeutic interventions for trauma experienced with the abusive caregiver.

21,026 views

131 citations

Effects of social isolation on hippocampal cell proliferation. (A) Representative images of BrdU-positive cell labeling in dentate gyrus subgranular area in rostral region for each group in a wider view (upper panel) and in detail of the indicated area as showed in the lower panel; arrow heads indicate cells included in the counting; scale bar for upper panel = 200 μm; scale bar for lower panel = 150 μm. (B) graphical representation of the total number of BrdU-positive cells per section at three different rostral-caudal levels of the hippocampus for animals that were socially isolated for 1 week, 3 weeks, and non-isolated age matched controls (CTR). (C) Orthogonal Z-section of confocal microscope image of BrdU-DCX double-labeled cell in hippocampal dentate gyrus used to estimate the number of new cells undergoing a neuronal fate per section, showed in graph (D). Figure (E) represents DCX-immunorreactivity density in dentate gyrus for each marmoset under control or 1 weeks or 3 weeks isolation periods. BrdU labels in green and DCX labels in red; scale bar: 50 μm. Data represented as mean ± standard error. * Indicates statistical significance between CTR and the respective group.

Original Research

27 March 2014

Social isolation disrupts hippocampal neurogenesis in young non-human primates

Simone M. Cinini

, 6 more and

Luiz E. Mello

13,669 views

62 citations

Review

20 February 2014

Age- and Sex-Dependent Effects of Early Life Stress on Hippocampal Neurogenesis

Manila Loi

, 2 more and

Marian Joëls

Meta-analysis of age- and sex-dependent effects of early life adversity on neurogenesis. The graphs show the percentage change in number of Ki-67 and Doublecortin (DCX)-positive cells after perinatal stress (y-axis; 100% is control), as a function of the age at which the change in neurogenesis was determined (x-axis, in weeks). (A) Both in males (top) and females (bottom), the change in number of Ki-67 positive cells due to prenatal (triangle), maternal separation (diamond) or maternal deprivation (square) was negatively correlated to the age at which the effect was determined. (B) In male rodents (top), the number of DCX-positive cells was found to be enhanced by perinatal stress when examined at a very young age. When studied at time-points >2 months of age, generally a decrease in the number of DCX-positive cells was observed. Overall, this resulted in a negative correlation between the effect of early life stress on neurogenesis and the age at which these effects were apparent. In female rats (bottom), we observed a correlation in the opposite direction. The data points are based on the references summarized in Table 1. The one data-point depicted by the filled symbol in the graphs of the females represents the percentage change found in the pilot study described in Figure 4 (not incorporated in Table 1).The striped horizontal line in the graphs indicates the control condition (i.e., the non-stressed groups mentioned in the same publications) against which the number of cells in the stress groups was expressed. The drawn line indicates the best fit for the linear correlation.

Early life stress is a well-documented risk factor for the development of psychopathology in genetically predisposed individuals. As it is hard to study how early life stress impacts human brain structure and function, various animal models have been developed to address this issue. The models discussed here reveal that perinatal stress in rodents exerts lasting effects on the stress system as well as on the structure and function of the brain. One of the structural parameters strongly affected by perinatal stress is adult hippocampal neurogenesis. Based on compiled literature data, we report that postnatal stress slightly enhances neurogenesis until the onset of puberty in male rats; when animals reach adulthood, neurogenesis is reduced as a consequence of perinatal stress. By contrast, female rats show a prominent reduction in neurogenesis prior to the onset of puberty, but this effect subsides when animals reach young adulthood. We further present preliminary data that transient treatment with a glucocorticoid receptor antagonist can normalize cell proliferation in maternally deprived female rats, while the compound had no effect in non-deprived rats. Taken together, the data show that neurogenesis is affected by early life stress in an age- and sex-dependent manner and that normalization may be possible during critical stages of brain development.

9,672 views

113 citations

Mini Review

26 February 2014

Mother–Pup Interactions: Rodents and Humans

Aldo B. Lucion

and

Maria Cátira Bortolini

5,468 views

25 citations

Review

17 February 2014