Chronic Early-life Stress Research Articles

Cardiac Remodeling in Aged Rats after Early-life Chronic Stress: Sex-specific Outcomes and Associations with Metabolic Parameters

Cardiovascular disease is the leading cause of death worldwide. Additionally, the incidence of cardiovascular disease varies both across the lifespan and between sexes. While multiple factors influence the development and progression of cardiovascular pathology, prolonged stress is a prominent risk factor for adverse cardiac events. However, the interactions between stress, sex, and aging that impact cardiac susceptibility remain to be determined. To this end, we examined hypertrophy of the aged myocardium in a sex- and stress-specific manner. We hypothesized that sex and stress history would interact to predict cardiac outcomes and that susceptibility/resilience would associate with behavioral, endocrine, and metabolic parameters assessed across the lifespan. In this study, rats were either exposed to chronic variable stress (CVS) in late adolescence (n = 36/sex) or remained as unstressed controls (n = 24/sex). Rats were subsequently challenged with a forced swim test (FST) and glucose tolerance test (GTT) before ageing to 15 months. The FST and GTT were then repeated prior to tissue collection. Cardiac tissue was processed for histological analysis and quantification of ventricular morphology. The data indicated that early-life chronic stress had sex-specific consequences on the aged left ventricle as CVS females had greater concentric hypertrophy. Based on the level of inward remodeling, rats were then classified as susceptible or resilient. Multiple behavioral and endocrine factors in young and aged animals significantly interacted with hypertrophy, including coping behaviors and glucocorticoid responses to hyperglycemia. However, correlations with hypertrophy were only present in males. Male rats that were not exposed to CVS had a positive association between baseline corticosterone and hypertrophy. Alternatively, CVS males had a positive correlation between visceral adiposity and hypertrophy. Thus, sex-specific cardiac susceptibility/resilience relates to endocrine and metabolic measures depending on stress history. This outcome suggests that adverse experiences can have lasting impacts on homeostatic adaptation. Ultimately, these results highlight the importance of sex and prior stress exposure for disparities in cardiovascular risk. NIH R01 HL 150559 (B Myers) NIHH F30 OD032120 (C Dearing) Pilot Translation Research Program grant from the University of Cincinnati (B Myers). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The mineralocorticoid receptor and extra-synaptic NMDA receptor in the lateral habenula involve in the vulnerability to early life stress in the maternal separation model

The lateral habenula (LHb) plays a pivotal role in regulating emotional responses during stress reactions, and its hyperactivity has been associated with depression. Recently it has been demonstrated that chronic early-life stress results in individual differences in stress vulnerability among rodents. However, how synaptic function in the LHb varies between susceptibility and resilience to early life stress remains elusive. In this study, we used a maternal separation model to assign animals with different stress vulnerabilities into groups and investigated the synaptic responses in the LHb. Our findings indicate that synaptic long-term depression (LTD) was impaired and extra-synaptic LTD was enhanced in the LHb of the susceptible group. To mimic the synaptic alteration in stress situations, when administered corticosterone, a stress hormone, the intervention appeared to impair synaptic LTD in the LHb of the control group, through the activation of mineralocorticoid receptors (MR). Indeed, there was an up-regulation of MR mRNA observed in the susceptible group. Following there was an up-regulation of both NR2A and NR2B subunits in the LHb. These results indicated that MR and extra-synaptic NMDA receptors in LHb are critically engaged in the susceptibilities to stress. Furthermore, our findings propose potential therapeutic targets for alleviating stress-related symptoms.

Chronic early life stress alters the neuroimmune profile and functioning of the developing zebrafish gut

Chronic early life stress (ELS) potently impacts the developing central nervous and immune systems and is associated with the onset of gastrointestinal disease in humans. Though the gut-brain axis is appreciated to be a major target of the stress response, the underlying mechanisms linking ELS to gut dysfunction later in life is incompletely understood. Zebrafish are a powerful model validated for stress research and have emerged as an important tool in delineating neuroimmune mechanisms in the developing gut. Here, we developed a novel model of ELS and utilized a comparative transcriptomics approach to assess how chronic ELS modulated expression of neuroimmune genes in the developing gut and brain. Zebrafish exposed to ELS throughout larval development exhibited anxiety-like behavior and altered expression of neuroimmune genes in a time- and tissue-dependent manner. Further, the altered gut neuroimmune profile, which included increased expression of genes associated with neuronal modulation, correlated with a reduction in enteric neuronal density and delayed gut transit. Together, these findings provide insights into the mechanisms linking ELS with gastrointestinal dysfunction and highlight the zebrafish model organism as a valuable tool in uncovering how “the body keeps the score.”

Chronic early-life stress increases cognitive impulsivity and D2 immunoreactivity in the nucleus accumbens of adult rats.

Chronic early life stress (ECS) induced by limited bedding and nesting (LBN) material in rodents is a naturalistic stress model that mimics many of the behavioral and neural consequences of child abuse and neglect; however, the effect of ECS on adult impulsivity has never been studied. The aim of our work was to determine the effects of ECS on cognitive impulsivity and its relation to D2 immunoreactivity in the nucleus accumbens (NAc) and prefrontal cortex (PFC) of adult male rats. Sprague-Dawley rats were exposed to LBN from postnatal day 2 to 9. We evaluated dams' maternal behavior and offspring corticosterone levels. The rats' impulsive cognitive behavior was evaluated by a delay-discounting task (transitional bridge) on P70, and we evaluated D2 receptors by immunostaining. Our results indicated that ECS affected maternal behavior in the dams and increased pups' corticosterone levels at P9, but not in adults. ECS rats showed lower frequencies of choosing the delayed reinforcer and shorter latencies to cross on the delay-discounting task. In addition, ECS rats showed increased D2 immunoreactivity in the NAc when compared with controls. Our data suggest that ECS can cause impulsive behaviors in adult rats characterized by less convenient choices, likely related to an increase in D2 receptors in the NAc. These findings could contribute to our understanding of the effects of child abuse and neglect on impulsive behavior.

Clinical translational neuroimaging of the antioxidant effect of N-acetylcysteine on neural microstructure.

Oxidative stress and downstream effectors have emerged as important pathological processes that drive psychiatric illness, suggesting that antioxidants may have a therapeutic role in psychiatric disease. However, no imaging biomarkers are currently available to track therapeutic response. The purpose of this study was to examine whether advanced DWI techniques are able to sensitively detect the potential therapeutic effects of the antioxidant N-acetylcysteine (NAC) in a Disc1 svΔ2 preclinical rat model of psychiatric illness. Male and female Disc1 svΔ2 rats and age-matched, sex-matched Sprague-Dawley wild-type controls were treated with a saline vehicle or NAC before ex vivo MRI acquisition at P50. Imaging data were fit to DTI and neurite orientation dispersion and density imaging models and analyzed for region-specific changes in quantitative diffusion metrics. Brains were further processed for cellular quantification of microglial density and morphology. All experiments were repeated for Disc1 svΔ2 rats exposed to chronic early-life stress to test how gene-environment interactions might alter effectiveness of NAC therapy. The DTI and neurite orientation dispersion and density imaging analyses demonstrated amelioration of early-life, sex-specific neural microstructural deficits with concomitant differences in microglial morphology across multiple brain regions relevant to neuropsychiatric illness with NAC treatment, but only in male Disc1 svΔ2 rats. Addition of chronic early-life stress reduced the ability of NAC to restore microstructural deficits. These findings provide evidence for a treatment pathway targeting endogenous antioxidant capacity, and the clinical translational utility of neurite orientation dispersion and density imaging microstructural imaging to sensitively detect microstructural alterations resulting from antioxidant treatment.

Chronic Early-Life Stress Increases Cognitive Impulsivity and D2 Immunoreactivity in the Nucleus Accumbens of Adult Rats

Chronic Early-Life Stress Increases Cognitive Impulsivity and D2 Immunoreactivity in the Nucleus Accumbens of Adult Rats

Early life stress facilitates synapse premature unsilencing to enhance AMPA receptor function in the developing hippocampus.

Chronic early life stress (ELS) increases vulnerability to psychopathologies and cognitive deficits in adulthood by disrupting the function of related neural circuits. However, whether this disruption emerges early in the developing brain remains largely unexplored. In the current study, using an established limited-bedding and nesting model of ELS in postnatal day (P)2-10 mice, we provide direct evidence that ELS caused early modification of hippocampal glutamatergic synapses in the developing brain. We demonstrated that ELS induced rapid enhancement of AMPA receptor function in hippocampal CA1 pyramidal neurons through a postsynaptic mechanism, and importantly, this was associated with premature unsilencing of NMDA receptor-only silent hippocampal synapses. These results suggest that potentiation of AMPAR function may represent an early mediator of ELS-induced alterations of neural networks in the developing brain and may potentially contribute to subsequent cognitive impairments later in life.NEW & NOTEWORTHY Early life stress (ELS) is known to increase the risk of later life cognitive deficits by disrupting neural circuit function. However, whether this disruption emerges early in the developing brain remains largely unexplored. The current study presents direct evidence that ELS prematurely unsilences hippocampal synapses to enhance AMPA receptor functions in a limited-bedding and nesting model, revealing an early mediator of ELS-induced neural circuit reorganizations.

Early-life stress and inflammation: A systematic review of a key experimental approach in rodents.

Repeated maternal separation is the most widely used pre-clinical approach to investigate the relationship between early-life chronic stress and its neuropsychiatric and physical consequences. In this systematic review, we identified 46 studies that conducted repeated maternal separation or single-episode maternal separation and reported measurements of interleukin-1b, interleukin-6, interleukin-10, tumour necrosis factor-alpha, or microglia activation and density. We report that in the short-term and in the context of later-life stress, repeated maternal separation has pro-inflammatory immune consequences in diverse tissues. Repeated maternal separation animals exhibit greater microglial activation and elevated pro-inflammatory cytokine signalling in key brain regions implicated in human psychiatric disorders. Notably, repeated maternal separation generally has no long-term effect on cytokine expression in any tissue in the absence of later-life stress. These observations suggest that the elevated inflammatory signalling that has been reported in humans with a history of early-life stress may be the joint consequence of ongoing stressor exposure together with potentiated neural and/or immune responsiveness to stressors. Finally, our findings provide detailed guidance for future studies interrogating the causal roles of early-life stress and inflammation in disorders such as major depression.

Maternal separation blunted spatial memory formation independent of peripheral and hippocampal insulin content in young adult male rats.

This study explores the effects of maternal separation as a chronic early life stress (ELS) on pancreatic islets insulin content and secretion, and their potential relationship with the hippocampus insulin content and spatial memory in young adulthood.Male rat offspring were divided into two groups: stress (STR) and non-stress (non-STR) groups. The animals of the STR group were separated from their mothers during postnatal days (PND) 1 to 21. During the weaning time, that is, PND-0 to PND-21, the body weight and length of the pups were measured. Blood samples were collected on PND-1, 21, 29 and 34 and during young adulthood (53±2 days) to determine plasma corticosterone and insulin levels. The young adult animals were also tested for spatial memory. One day after the memory test, the animals were decapitated and their pancreases were removed to measure the islets insulin content and secretion. Finally, the animals’ hippocampi were isolated to determine their insulin content and insulin receptor protein amounts.During the period of weaning, the body weight and length of pups belonging to the STR group were significantly lower as compared to those in the non-STR group. Maternal separation did not change the plasma levels of insulin but increased plasma corticosterone levels from PND-21 to young adulthood and also reduced the islets insulin content but did not affect insulin secretion and the hippocampus insulin content and insulin receptor protein amount. Although, at the end of the memory tests, rats of the STR group reached the escape box at almost the same time and distance and with the same errors as rats of the non-STR group, the distance traveled to reach the escape box showed a steep reduction in the non-STR group as compared to the STR group after the first trial. Moreover, as compared to the STR group, the non-STR group showed an increasing trend for direct strategy to find the escape box. The islets insulin content and secretion, and the plasma insulin concentration were not significantly correlated with the hippocampus insulin content.From the results of the present study, it appears that the main behavioral effect of the maternal separation stress in the spatial memory task was to impair the strategy used by the animals to reach the escape box. This may indicate that maternal separation stress affects brain regions other than the hippocampus. Moreover, due to the reduction of the body weight and length of offspring belonging to the STR group, it should be further considered that both maternal separation and early life malnutrition are directly (and mechanistically) linked to cognitive alterations later in life in ways that are not dependent on peripheral and hippocampal insulin content.

Reduced resting-state functional connectivity of the basolateral amygdala to the medial prefrontal cortex in preweaning rats exposed to chronic early-life stress.

Early-life stress (ELS) exposure has long-term consequences for both brain structure and function and impacts cognitive and emotional behavior. The basolateral amygdala (BLA) plays an important role in anxiety and fear conditioning through its extensive anatomical and functional connections, in particular to the medial prefrontal cortex (mPFC). However, how ELS affects amygdala function and connectivity in developing rats is unknown. We used the naturalistic limited bedding/nesting (LB) paradigm to induce chronic stress in the pups between postnatal day (PND) 1-10. Male normal bedding (NB, control) or LB offspring underwent structural and resting-state functional MRI (rs-fMRI) on PND18 and in adulthood (PND74-76). Adult male rats were tested for fear conditioning and extinction behavior prior to scanning. Seed-based functional connectivity maps were generated based on four BLA seeds (left, right, anterior and posterior). At both ages, LB induced different effects on anterior and posterior BLA networks, with significant reductions in rs-fMRI connectivity between the anterior BLA and mPFC in LB compared to NB offspring. BLA connectivity was lateralized by preweaning age, with the right hemisphere displaying more connectivity changes than the left. Weak negative volumetric correlations between the BLA and mPFC were also present, mostly in preweaning LB animals. rs-fMRI connectivity and volumetric changes were associated with enhanced fear behaviors in adult LB offspring. Activation of the LB-exposed neonatal amygdala described previously might accelerate the maturation of BLA-mPFC projections and/or modify the activity of reciprocal connections between these structures, leading to a net reduction in rs-fMRI connectivity and increased fear behavior.

Early-Life Stress Does Not Aggravate Spatial Memory or the Process of Hippocampal Neurogenesis in Adult and Middle-Aged APP/PS1 Mice.

Life-time experiences are thought to influence the risk to develop the neurodegenerative disorder Alzheimer’s disease (AD). In particular, early-life stress (ES) may modulate the onset and progression of AD. There is recent evidence by our group and others that AD-related neuropathological progression and the associated neuroimmune responses are modulated by ES in the classic APPswe/PS1dE9 mouse model for AD. We here extend our previous study on ES mediated modulation of neuropathology and neuroinflammation and address in the same cohort of mice whether ES accelerates and/or aggravates AD-induced cognitive decline and alterations in the process of adult hippocampal neurogenesis (AHN), a form of brain plasticity. Chronic ES was induced by limiting bedding and nesting material during the first postnatal week and is known to induce cognitive deficits by 4 months in wild type (WT) mice. The onset of cognitive decline in APP/PS1 mice generally starts around 6 months of age. We here tested mice at ages 2–4 months to study acceleration and at ages 8–10 months for aggravation of the APP/PS1 phenotype. ES-exposed WT and APP/PS1 mice were able to perform the object recognition (ORT) and location tasks (OLT) at 2 months of age. Interestingly, at 3 months, ES induced impairments in the performance of the OLT in WT, but not in APP/PS1 mice. APP/PS1 mice exhibited alterations in hippocampal cell proliferation and differentiation, but ES exposure did not further change this. At 9 months, APP/PS1 mice exhibited impaired performance in the Morris Water Maze (MWM) task, as well as reductions in markers of the AHN process, which were not further modulated by ES exposure. In addition, we observed a so far unreported hyperactivity in ES-exposed mice at 8 months of age, which hampered assessment of cognitive functions in the ORT and OLT. In conclusion, while ES has been reported to modulate AD neuropathology and neuroinflammation before, it failed to accelerate or aggravate the decline in cognition or the process of AHN in APP/PS1 mice at ages 2–4 and 8–10 months. Future studies are needed to unravel how ES might affect the vulnerability to develop AD.

Targeting glucocorticoid receptors prevents the effects of early life stress on amyloid pathology and cognitive performance in APP/PS1 mice

Exposure to chronic stress or elevated glucocorticoid hormone levels in adult life has been associated with cognitive deficits and an increased risk for Alzheimer’s disease (AD). Since exposure to stress during early life enhances stress-responsiveness and lastingly affects cognition in adult life, we here investigated; (i) whether chronic early life stress (ELS) affects AD pathology and cognition in middle-aged APPswe/PS1dE9 mice, and (ii) whether it is still possible to rescue these late effects by briefly blocking glucocorticoid receptors (GRs) at a translationally relevant, middle age. Transgenic APPswe/PS1dE9 mice were subjected to ELS by housing dams and pups with limited nesting and bedding material from postnatal days 2–9 only. In 6- and 12-month-old offspring, this resulted in enhanced hippocampal amyloid-β (Aβ)-40 and -42 levels, and in reduced cognitive flexibility, that correlated well with the Aβ42 levels. In parallel, CORT levels and BACE1 levels were significantly elevated. Surprisingly, blocking GRs for only 3 days at 12 months of age reduced CORT levels, reduced hippocampal Aβ40 and -42, and β-site APP-cleaving enzyme 1 (BACE1) levels, and notably rescued the cognitive deficits in 12-month-old APPswe/PS1dE9 mice. These mouse data demonstrate that exposure to stress during the sensitive period early in life influences later amyloid pathology and cognition in genetically predisposed, mutant mice, and as such, may increase AD vulnerability. The fact that a short treatment with a GR antagonist at middle age lastingly reduced Aβ levels and rescued the cognitive deficits after ELS, highlights the therapeutic potential of this drug for reducing amyloid pathology.

Early Life Stress: Consequences for the Development of the Brain

This literature review demonstrates the importance and consequences of early life stress for the development of the brain and its role in the formation of neurological and mental illnesses (particularly depression). The most dangerous is chronic early life stress during the neonatal period of development in the first days after birth, when the effects on the development of the brain, neuro-, synapto-, and glio-, and angiogenesis are the most stable. Among all the neuropsychological effects of early life stress, the most common are apparent as depressive disorders in humans and animals, and this constitutes a widely used model of experimental depression in rodents.

Tissue-Specific Expression of DNA Methyltransferases Involved in Early-Life Nutritional Stress of Chicken, Gallus gallus.

DNA methylation was reported as a possible stress-adaptation mechanism involved in the transcriptional regulation of stress responsive genes. Limited data are available on effects of psychological stress and early-life nutritional stress on DNA methylation regulators [DNMTs: DNA (cytosine-5)-methyltransferase 1 (DNMT1), DNMT1 associated protein (DMAP1), DNMT 3 alpha (DNMT3A) and beta (DNMT3B)] in avian species. The objectives of this study were to: (1) investigate changes in expression of DNMT1, DMAP1, DNMT3A, and DNMT3B following acute (AS) or chronic immobilization stress (CS); (2) test immediate effect of early-life nutritional stress [food deprivation (FD) for 12 h (12hFD) or 36 h (36hFD) at the post-hatching period] on expression of DNA methylation regulators and glucocorticoid receptor (GR), and the long-term effect of early-life nutritional stress at 6 weeks of age. Expression of DNMTs and plasma corticosterone (CORT) concentration decreased by CS compared to AS (p < 0.05), indicating differential roles of DNA methylation regulators in the stress response. Plasma CORT at 12hFD and 36hFD birds increased compared to control birds (12hF and 36hF), but there were no significant differences in plasma CORT of 12hFD and 36hFD birds at 6 weeks of age compared to 6 week controls. DNMT1, DMAP1, and DNMT3B expression in the anterior pituitary increased by 12hFD, but decreased at 36hFD compared to their controls (P < 0.05). In liver, DNMT1, DNMT3A, and DNMT3B expression decreased by 12hFD, however, no significant changes occurred at 36hFD. Expression of DMAP1, DNMT3A, and DNMT3B in anterior pituitary and DMAP1 and DNMT3A expression in liver at 6 weeks of age were higher in 36hFD stressed birds compared to controls as well as 12hFD stressed birds. Hepatic GR expression decreased by 12hFD and increased by 36hFD (p < 0.05). Expression patterns of GR in the liver of FD stress-induced birds persisted until 6 weeks of age, suggesting the possible lifelong involvement of liver GR in early-life nutritional stress response of birds. Taken together, results suggest that DNA methylation regulator genes are tissue-specifically responsive to acute and chronic stress, and hepatic GR may play a critical role in regulating the early-life nutritional stress response of birds. In addition, the downregulation of DNMT1 and DMAP1 may be one of the adaptive mechanisms to chronic early-life nutritional stress via passive demethylation.

Morphological and functional changes in the preweaning basolateral amygdala induced by early chronic stress associate with anxiety and fear behavior in adult male, but not female rats

Suboptimal maternal care is a form of chronic early-life stress (ELS) and a risk factor for mental illness and behavioral impairments throughout the life span. The amygdala, particularly the basolateral amygdala (BLA), exhibits exquisite sensitivity to ELS and could promote dysregulation of stress reactivity and anxiety-related disorders. While ELS has profound impacts on the adult or adolescent amygdala, less is known regarding the sensitivity of the preweaning BLA to ELS. We employed a naturalistic rodent model of chronic ELS that limits the amount of bedding/nesting material (LB) available to the mother between postnatal day (PND) 1–9 and examined the morphological and functional effects in the preweaning BLA on PND10 and 18–22. BLA neurons displayed dendritic hypertrophy and increased spine numbers in male, but not female, LB pups already by PND10 and BLA volume tended to increase after LB exposure in preweaning rats, suggesting an accelerated and long-lasting recruitment of the amygdala. Morphological changes seen in male LB pups were paralleled with increased evoked synaptic responses recorded from BLA neurons in vitro, suggesting enhanced excitatory inputs to these neurons. Interestingly, morphological and functional changes in the preweaning BLA were not associated with basal hypercorticosteronemia or enhanced stress responsiveness in LB pups, perhaps due to a differential sensitivity of the neuroendocrine stress axis to the effects of LB exposure. Early changes in the synaptic organization and excitability of the neonatal amygdala might contribute to the increased anxiety-like and fear behavior observed in adulthood, specifically in male offspring.

Ghrelin and hypothalamic NPY/AgRP expression in mice are affected by chronic early-life stress exposure in a sex-specific manner

Early-life stress (ES) is a risk factor for metabolic disorders (e.g. obesity) with a notoriously higher prevalence in women compared to men. However, mechanisms underlying these effects remain elusive. The development of the hypothalamic feeding and metabolic regulatory circuits occurs mostly in the early sensitive postnatal phase in rodents and is tightly regulated by the metabolic hormones leptin and ghrelin. We have previously demonstrated that chronic ES reduces circulating leptin and alters adipose tissue metabolism early and later in life similarly in both sexes. However, it is unknown whether chronic ES might also affect developmental ghrelin and insulin levels, and if it induces changes in hypothalamic feeding circuits, possibly in a sex-dependent manner. We here show that chronic ES, in the form of exposure to limited nesting and bedding material from postnatal day (P)2 to P9 in mice, affects ghrelin levels differently, depending on the form of ghrelin (acylated vs desacylated), on age (P9 vs P14) and on sex, while insulin levels were similarly increased in both sexes after ES at P9. Even though ghrelin levels were more strongly affected in ES-exposed females, hypothalamic neuropeptide Y (NPY) and agouti-related peptide (AgRP) fiber density at P14 were similarly altered in both sexes by ES. In the paraventricular nucleus of the hypothalamus, both NPY and AgRP fiber density were increased, while in the arcuate nucleus of the hypothalamus, NPY was increased and AgRP unaltered. Additionally, the hypothalamic mRNA expression of ghrelin’s receptor (i.e. growth hormone secretagogue receptor) was not affected by ES. Taken together, the specific alterations found in these important regulatory circuits after ES might contribute to an altered energy balance and feeding behavior in adulthood and thereby to an increased vulnerability to develop metabolic disorders.

EARLY LIFE STRESS ACCELERATES AMYLOID PATHOLOGY AND COGNITIVE DECLINE IN APPSWE/PS1DE9 MICE, BUT CAN BE RESCUED BY BRIEFLY BLOCKING GLUCOCORTICOID RECEPTORS AT MIDDLE AGE

Exposure to stress or elevated glucocorticoid hormone levels in adult life has been associated with cognitive deficits and an increased risk for Alzheimer's disease (AD). Since exposure to stress during early life enhances stress-responsiveness and lastingly affects cognition in adult life, we here investigated; i) whether early life stress (ELS) affects AD pathology and cognition in adult and middle-aged APPswe/PS1dE9 mice, and ii) whether it is still possible to later rescue these effects by blocking glucocorticoid receptors (GR) at middle age. Transgenic APPswe/PS1dE9 mice were subjected to ELS by housing the dams with limited nesting and bedding material only from postnatal days 2–9 (1,2). At 6 and 12 months of age, different amyloid species, MR/GR, corticosterone and BACE1 levels, and learning and memory performance were determined. The same measures were determined after GRs were blocked at 12 months of age by giving mifepristone for 3 days (3). In 6 and 12 months old offspring, enhanced amyloid-b (Aβ)-40 and -42 levels, enhanced BACE1 levels and cognitive deficits were found, that correlated well with the Aβ42 levels. Surprisingly, blocking GRs for only 3 days at 12 months of age reduced corticosterone levels, reduced hippocampal Ab40/42 and BACE1 levels, and notably, rescued the cognitive deficits in 12 months old APPswe/PS1dE9 mice. This demonstrates that exposure to stress during the sensitive period of early life can modify the emergence of later amyloid pathology, and as such, may increase the vulnerability to AD. The fact that a short treatment with a GR blocker at middle age lastingly reduced Aβ levels and rescued the cognitive deficits after ELS, highlights the therapeutic potential of this drug for reducing amyloid pathology. References 1) Naninck EFG et al., Chronic early life stress alters developmental and adult neurogenesis and impairs cognitive function in mice. Hippocampus 2015. 2) Lesuis SL et al., Positive and negative early life experiences differentially modulate long term survival and amyloid protein levels in a mouse model of Alzheimer's disease. Oncotarget 2016. 3) Krugers HJ et al., Blockade of glucocorticoid receptors rapidly restores hippocampal CA1 synaptic plasticity after exposure to chronic stress. Eur J Neurosci 2006.

Overexpression of Mineralocorticoid Receptors in the Mouse Forebrain Partly Alleviates the Effects of Chronic Early Life Stress on Spatial Memory, Neurogenesis and Synaptic Function in the Dentate Gyrus.

Evidence from human studies suggests that high expression of brain mineralocorticoid receptors (MR) may promote resilience against negative consequences of stress exposure, including childhood trauma. We examined, in mice, whether brain MR overexpression can alleviate the effects of chronic early life stress (ELS) on contextual memory formation under low and high stress conditions, and neurogenesis and synaptic function of dentate gyrus granular cells. Male mice were exposed to ELS by housing the dam with limited nesting and bedding material from postnatal day (PND) 2 to 9. We investigated the moderating role of MRs by using forebrain-specific transgenic MR overexpression (MR-tg) mice. Low-stress contextual (i.e., object relocation) memory formation was hampered by ELS in wildtype but not MR-tg mice. Anxiety like behavior and high-stress contextual (i.e., fear) memory formation were unaffected by ELS and/or MR expression level. At the cellular level, an interaction effect was observed between ELS and MR overexpression on the number of doublecortin-positive cells, with a significant difference between the wildtype ELS and MR-tg ELS groups. No interaction was found regarding Ki-67 and BrdU staining. A significant interaction between ELS and MR expression was further observed with regard to mEPSCs and mIPSC frequency. The ratio of evoked EPSC/IPSC or NMDA/AMPA responses was unaffected. Overall, these results suggest that ELS affects contextual memory formation under low stress conditions as well as neurogenesis and synaptic transmission in dentate granule cells, an effect that can be alleviated by MR-overexpression.

Early Social Isolation Stress and Perinatal NMDA Receptor Antagonist Treatment Induce Changes in the Structure and Neurochemistry of Inhibitory Neurons of the Adult Amygdala and Prefrontal Cortex.

The exposure to aversive experiences during early life influences brain development and leads to altered behavior. Moreover, the combination of these experiences with subtle alterations in neurodevelopment may contribute to the emergence of psychiatric disorders, such as schizophrenia. Recent hypotheses suggest that imbalances between excitatory and inhibitory (E/I) neurotransmission, especially in the prefrontal cortex and the amygdala, may underlie their etiopathology. In order to understand better the neurobiological bases of these alterations, we studied the impact of altered neurodevelopment and chronic early-life stress on these two brain regions. Transgenic mice displaying fluorescent excitatory and inhibitory neurons, received a single injection of MK801 (NMDAR antagonist) or vehicle solution at postnatal day 7 and/or were socially isolated from the age of weaning until adulthood (3 months old). We found that anxiety-related behavior, brain volume, neuronal structure, and the expression of molecules related to plasticity and E/I neurotransmission in adult mice were importantly affected by early-life stress. Interestingly, many of these effects were potentiated when the stress paradigm was applied to mice perinatally injected with MK801 ("double-hit" model). These results clearly show the impact of early-life stress on the adult brain, especially on the structure and plasticity of inhibitory networks, and highlight the double-hit model as a valuable tool to study the contribution of early-life stress in the emergence of neurodevelopmental psychiatric disorders, such as schizophrenia.

Impact of stress in childhood: Psychobiological alterations

An extremely high percentage of children worldwide are exposed to stress from the first months of life.&nbsp; The aim of this review is to bring together the experimental results related to chronic early-life stress in both human and experimental models. &nbsp;Methods: We aimed to achieve our objective via a thorough review of the literature. Early-life stress is a challenge for the developing organism and leads to negative effects in the medium and long term. The emotional, cognitive, and behavioral domains are compromised due to alterations produced in the nervous system, with some of the most important being related to the main neurotransmission systems. By using experimental models, it is possible to address the study of the structural and functional changes resulting from early-life stress and, thus, plan intervention and prevention alternatives.&nbsp.