Long-term Effects Of Early Life Stress Research Articles

Long-term behavioral effects of social separation during early life in a social mammal, Octodon degus

Social separation is thought to induce a strong stress response in social juvenile mammals, but little is known about how this response might vary throughout the development. The present study examines the long-term effects of early-life stress (ELS) induced by social separation on individual behaviors later in life using the social and precocious species Octodon degus. Four experimental groups were established a positive control group of mothers and siblings from six litters comprised the socially housed (SH) group, while pups from seven litters were randomly assigned to three treatments: pups experiencing no separation (NS) treatment while their siblings did; repeated bouts of consecutive separation (CS); intermittent separation (IS). We analyzed the effects of separation treatment on the frequency and duration of freezing, rearing and grooming behaviors. ELS was correlated with higher hyperactivity, and hyperactivity increased with more frequent separation. However, the behavioral trend of the NS group changed to hyperactive in long-term observation. The findings suggest that the NS group was indirectly affected by ELS. In addition, suggesting ELS acts to converge an individual’s behavioral tendencies in a certain direction.

Early-life social stress induces permanent alterations in plasticity and perineuronal nets in the mouse anterior cingulate cortex.

Child maltreatment disrupts trajectories of brain development, but the underlying pathways are unclear. Stressful stimuli in early life interfere with maturation of local inhibitory circuitry and deposition of perineuronal nets (PNNs), specialized extracellular matrix structures involved in the closure of critical periods of development. Alterations in cortical PNN and parvalbumin (PV) following early-life stress (ELS) have been detected in human and animal studies. Aberrations in the anterior cingulate cortex (ACC) are the most consistent neuroimaging findings in maltreated people, but the molecular mechanisms linking ELS with ACC dysfunctions are unknown. Here, we employed a mouse model of early social threat to test whether ELS experienced in a sensitive period for ACC maturation could induce long-term aberrations of PNN and PV development in the ACC, with consequences on plasticity and ACC-dependent behavior. We found that ELS increased PNN but not PV expression in the ACC of young adult mice. This was associated with reduced frequency of inhibitory postsynaptic currents and long-term potentiation impairments and expression of intense object phobia. Our findings provide information on the long-term effects of ELS on ACC functionality and PNN formation and present evidence for a novel neurobiological pathway underlying the impact of early adversity on the brain.

Early life stress-induced neuroinflammation and neurological disorders: a novel perspective for research.

Early life stress-induced neuroinflammation and neurological disorders: a novel perspective for research.

Short and long-term effects of early-life stress on microglia profile: Focus on transcriptome and phagocytic capacity

Short and long-term effects of early-life stress on microglia profile: Focus on transcriptome and phagocytic capacity

Effects of Early Life Stress on the Developing Basolateral Amygdala-Prefrontal Cortex Circuit: The Emerging Role of Local Inhibition and Perineuronal Nets.

The links between early life stress (ELS) and the emergence of psychopathology such as increased anxiety and depression are now well established, although the specific neurobiological and developmental mechanisms that translate ELS into poor health outcomes are still unclear. The consequences of ELS are complex because they depend on the form and severity of early stress, duration, and age of exposure as well as co-occurrence with other forms of physical or psychological trauma. The long term effects of ELS on the corticolimbic circuit underlying emotional and social behavior are particularly salient because ELS occurs during critical developmental periods in the establishment of this circuit, its local balance of inhibition:excitation and its connections with other neuronal pathways. Using examples drawn from the human and rodent literature, we review some of the consequences of ELS on the development of the corticolimbic circuit and how it might impact fear regulation in a sex- and hemispheric-dependent manner in both humans and rodents. We explore the effects of ELS on local inhibitory neurons and the formation of perineuronal nets (PNNs) that terminate critical periods of plasticity and promote the formation of stable local networks. Overall, the bulk of ELS studies report transient and/or long lasting alterations in both glutamatergic circuits and local inhibitory interneurons (INs) and their associated PNNs. Since the activity of INs plays a key role in the maturation of cortical regions and the formation of local field potentials, alterations in these INs triggered by ELS might critically participate in the development of psychiatric disorders in adulthood, including impaired fear extinction and anxiety behavior.

Repeated exposure to challenging environmental conditions influences telomere dynamics across adult life as predicted by changes in mortality risk.

The effects of stress exposure are likely to vary depending on life-stage and stressor. While it has been postulated that mild stress exposure may have beneficial effects, the duration of such effects and the underlying mechanisms are unclear. While the long-term effects of early-life stress are relatively well studied, we know much less about the effects of exposure in adulthood since the early- and adult-life environments are often similar. We previously reported that repeated experimental exposure to a relatively mild stressor in female zebra finches, first experienced in young adulthood, initially had no effect on mortality risk, reduced mortality in middle age, but the apparently beneficial effects disappeared in old age. We show here that this is underpinned by differences between the control and stress-exposed group in the pattern of telomere change, with stress-exposed birds showing reduced telomere loss in middle adulthood. We thereby provide novel experimental evidence that telomere dynamics play a key role linking stress resilience and aging.

Early Life Stress Increases Brain Glutamate and Induces Neurobehavioral Manifestations in Rats.

Early life stress (ELS) is associated with an increased risk of developing depression and anxiety disorders. Disturbances of the neurobiological glutamatergic system are implicated in depression; however, the long-term effects of ELS on glutamate (Glu) metabolites remain unclear. Our study used 7T proton magnetic resonance spectroscopy (7T 1H MRS) to detect metabolic Glu in a rat model to investigate maternal deprivation (MD)-induced ELS. MD was established in Sprague-Dawley rats by periodic separation from mothers and peers. Changes in the hippocampal volume and Glu metabolism were detected by 7T 1H MRS after testing for depression-like behavior via open field, sucrose preference, and Morris water maze tests. Adult MD offspring exhibited depression-like behavior. Compared to the control, the MD group exhibited reduced ratio of central activity time to total time and decreased sucrose consumption (p < 0.05). MD rats spent less time in the fourth quadrant, where the platform was originally placed, in the Morris water maze test. According to 7T 1H MRS, hippocampus of MD rats had elevated Glu and glutamate + glutamine (Glu+Gln) levels compared with the control group hippocampi, but Gln, γ-aminobutyric acid (GABA), and glutamate + glutamine (Glu+Gln) in the prefrontal cortex of MD rats showed a downward trend. Depression-like behavior and cognition deficits related to ELS may induce region-specific changes in Glu metabolism in the prefrontal cortex and hippocampus. The novel, noninvasive 7T 1H MRS-identified associations between Glu levels and ELS may guide future clinical studies.

Antidepressant-like effects of URB597 and JZL184 in male and female rats exposed to early life stress

Early life stress (ELS) may increase predisposition to depression. Despite extensive research, there is still a lack of knowledge of how to optimally treat depression. We aimed to establish a role for the endocannabinoid (ECB) system within the hippocampal-nucleus accumbens (NAc) network as a possible effective target in combating the pathophysiological development of depression-like behavior and neuronal alterations that are precipitated by ELS.Male and female rats were exposed to ELS during post-natal days (P) 7–14, injected with the fatty acid amide hydrolase (FAAH) inhibitor URB597 or the monoacylglycerol lipase (MAGL) inhibitor JZL184 for 2 weeks during late-adolescence (P45–60). Rats were tested starting at P90 for depressive- and anxiety-like behaviors as well as social preference and recognition; alterations in FAAH and MAGL activity; the expression of brain-derived neurotrophic factor (BDNF); and plasticity in the hippocampal-NAc pathway.FAAH and MAGL inhibitors during late-adolescence prevented: (i) the long-term effects of ELS on depression- and anxiety-like behavior and the impairment in social behavior and neuronal plasticity in males and females; (ii) ELS-induced alterations in MAGL activity in males' hippocampus and females' hippocampus and NAc; and (iii) ELS-induced alterations in BDNF in males' hippocampus and NAc and females' hippocampus. Significant correlations were observed between alterations in MAGL and BDNF levels and the behavioral phenotype.The findings suggest that alterations in MAGL activity and BDNF expression in the hippocampal-NAc network contribute to the depressive-like behavioral phenotype in ELS males and females. Moreover, the study suggests FAAH and MAGL inhibitors as potential intervention drugs for depression.

Long-Term Impact of Early-Life Stress on Hippocampal Plasticity: Spotlight on Astrocytes.

Adverse experiences during childhood are among the most prominent risk factors for developing mood and anxiety disorders later in life. Early-life stress interventions have been established as suitable models to study the neurobiological basis of childhood adversity in rodents. Different models such as maternal separation, impaired maternal care and juvenile stress during the postweaning/prepubertal life phase are utilized. Especially within the limbic system, they induce lasting alterations in neuronal circuits, neurotransmitter systems, neuronal architecture and plasticity that are further associated with emotional and cognitive information processing. Recent studies found that astrocytes, a special group of glial cells, have altered functions following early-life stress as well. As part of the tripartite synapse, astrocytes interact with neurons in multiple ways by affecting neurotransmitter uptake and metabolism, by providing gliotransmitters and by providing energy to neurons within local circuits. Thus, astrocytes comprise powerful modulators of neuronal plasticity and are well suited to mediate the long-term effects of early-life stress on neuronal circuits. In this review, we will summarize current findings on altered astrocyte function and hippocampal plasticity following early-life stress. Highlighting studies for astrocyte-related plasticity modulation as well as open questions, we will elucidate the potential of astrocytes as new targets for interventions against stress-induced neuropsychiatric disorders.

Post-natal corticosterone exposure downregulates the HPA axis through adulthood in a common passerine.

The hypothalamic-pituitaryadrenal (HPA) axis is one of the most important physiological mechanisms for mediating life-history trade-offs by reallocating resources to immediate survival from other life-history components during a perturbation. Early-life stressor experience and associated upregulation of glucocorticoids can induce short- and long-term changes to the HPA axis in ways that may optimize survival and/or reproduction for the expected adult environment. Although short-term changes to the HPA axis following perinatal stress are well documented, we know less about the long-term effects of early-life stress especially for non-mammalian wild species. Here, we determined long-term effects of experimental post-natal increases in a circulating glucocorticoid on the HPA axis in a common passerine bird, the house sparrow (Passer domesticus). We manipulated circulating corticosterone in wild, free-living nestlings, transferred fledglings to captivity and assessed corticosterone response to a standardized capture-restraint protocol at the pre-fledging, juvenile, and adult stages. Early-life corticosterone manipulation was associated with depressed baseline and stress-induced concentrations of corticosterone at all stages of life, through adulthood. These results provide rare evidence for the effects of early-life stressor experiences through adulthood, with important implications for understanding developmental programming of an endocrine mediator of life history trade-offs.

The enduring effects of early‐life stress on the microbiota–gut–brain axis are buffered by dietary supplementation with milk fat globule membrane and a prebiotic blend

Nutritional interventions targeting the microbiota-gut-brain axis are proposed to modulate stress-induced dysfunction of physiological processes and brain development. Maternal separation (MS) in rats induces long-term alterations to behaviour, pain responses, gut microbiome and brain neurochemistry. In this study, the effects of dietary interventions (milk fat globule membrane [MFGM] and a polydextrose/galacto-oligosaccharide prebiotic blend) were evaluated. Diets were provided from postnatal day 21 to both non-separated and MS offspring. Spatial memory, visceral sensitivity and stress reactivity were assessed in adulthood. Gene transcripts associated with cognition and stress and the caecal microbiota composition were analysed. MS-induced visceral hypersensitivity was ameliorated by MFGM and to greater extent with the combination of MFGM and prebiotic blend. Furthermore, spatial learning and memory were improved by prebiotics and MFGM alone and with the combination. The prebiotic blend and the combination of the prebiotics and MFGM appeared to facilitate return to baseline with regard to HPA axis response to the restraint stress, which can be beneficial in times where coping mechanisms to stressful events are required. Interestingly, the combination of MFGM and prebiotic reduced the long-term impact of MS on a marker of myelination in the prefrontal cortex. MS affected the microbiota at family level only, while MFGM, the prebiotic blend and the combination influenced abundance at family and genus level as well as influencing beta-diversity levels. In conclusion, intervention with MFGM and prebiotic blend significantly impacted the composition of the microbiota as well as ameliorating some of the long-term effects of early-life stress.

"Comfort-foods" chronic intake has different behavioral and neurobiological effects in male rats exposed or not to early-life stress.

The ability of "comfort-food" (CF) diet to revert long-term effects of early-life stress (ELS) is less well known. The objective of this study was to verify if the chronic exposure to CF diet in animals submitted to ELS could relief the stress response at behavioral, neuroendocrine, and neurobiochemical levels, via differences in glucocorticoid receptors expression in brain areas involved in the stress response. From the second day of life, litters of Wistar rats and their mothers were submitted to the reduced nesting material protocol (ELS). In adult life, ELS and a control group were exposed chronically to two diet schemes: standard rat chow only or both "CF" diet, containing fat (34%) and sugar (20%) and a diet similar to the standard diet. Anxiety-like behavior, neuroendocrine response stress, leptin, GR, SOCS-3, pSTAT3, and the abdominal fat were evaluated. The anxiety-like behavior results showed that ELS group when exposed to comfort food were not different from the others groups. Chronic exposure to CF diet induced an anxiety-like behavior in the control group. Groups chronically exposed to CF diet had lower levels of corticosterone over time independent of the neonatal group. The ELS group exposed to the "CF" diet had higher levels of hippocampal GR, lower levels of hypothalamic SOCS-3 and greater accumulation of abdominal fat. Chronic CF diet consumption is able to reduce corticosterone levels independent of the neonatal history, but is associated with anxiety-like behavior in animals without previous history of trauma. Metabolic disturbances like increased adiposity and altered SOCS-3 seem to be a result of multiple insults (neonatal trauma followed by chronic CF diet). We highlight that the Control-chow and ELS-chow data were previously published, and are included in this study for comparative analysis.

Pharmacological restoration of gut barrier function in stressed neonates partially reverses long-term alterations associated with maternal separation.

Intestinal permeability plays an important role in gut-brain axis communication. Recent studies indicate that intestinal permeability increases in neonate pups during maternal separation (MS). The present study aims to determine whether pharmacological inhibition of myosin light chain kinase (MLCK), which regulates tight junction contraction and controls intestinal permeability, in stressed neonates, protects against the long-term effects of MS. Male Wistar rats were exposed to MS (3h per day from post-natal day (PND)2 to PND14) or left undisturbed and received daily intraperitoneal injection of a MLCK inhibitor (ML-7, 5mg/kg) or vehicle during the same period. At adulthood, emotional behaviors, corticosterone response to stress, and gut microbiota composition were analyzed. ML-7 restored gut barrier function in MS rats specifically during the neonatal period. Remarkably, ML-7 prevented MS-induced sexual reward-seeking impairment and reversed the alteration of corticosterone response to stress at adulthood. The effects of ML-7 were accompanied by the normalization of the abundance of members of Lachnospiraceae, Clostridiales, Desulfovibrio, Bacteroidales, Enterorhabdus, and Bifidobacterium in the feces of MS rats at adulthood. Altogether, our work suggests that improvement of intestinal barrier defects during development may alleviate some of the long-term effects of early-life stress and provides new insight on brain-gut axis communication in a context of stress.

P.1.h.041 - Pharmacological inhibition of gut leakiness prevents the long-term effects of early-life stress in rats

P.1.h.041 - Pharmacological inhibition of gut leakiness prevents the long-term effects of early-life stress in rats

Pathophysiological trajectories and biological consequences of early life trauma

ABSTRACTExperience of early life stress (ELS) (childhood trauma, maltreatment, neglect, separation, physical and sexual abuse, parental loss and other severe anxiety/stress symptoms) is highly prevalent in the general population and constitutes a major public health problem (Gilbert et al., 2009). The objective of this paper is to review evidence on epidemiological risk factors, pathophysiological trajectories and neurobiological pathways exerting the enduring adverse effects of ELS and leading to compromised overall health in adulthood.Prolonged neuropsychobiological alterations as sequelae of early trauma could mediate the risk of disease in adulthood, and lead to cumulative disadvantages and increased physical and mental morbidity in later life. In particular, a higher risk of psychiatric disorders (e.g. depression, post-traumatic stress disorder and other anxiety disorders) and their unfavourable outcomes (e.g. treatment resistance, suicide) has been associated with a history of ELS in several retrospective but also prospective studies, while the moderating interaction of ELS and pre-existing genetic vulnerability in these disorders has been extensively discussed in recent literature. Nevertheless, the chronic physical health consequences of childhood adversities may be as substantial as mental health consequences. Prior research suggests an association of ELS with cardiovascular, pulmonary and metabolic diseases, chronic inflammatory and pain syndromes, frequency of medical consultations and number of medical diagnoses. In addition, risk behaviour patterns such as substance use, and especially tobacco and alcohol consumption, are considered significantly increased in individuals with experience of ELS. Consequently, many studies have reported a negative impact of ELS on adult general mental and physical health-related quality of life, while recognizing the additive effect of the number or different types of childhood adversities is important for understanding their cumulative effect on later life adjustment (Agorastos, Pittman et al., 2014).The distinct impact of ELS may lie in enhanced plasticity mechanisms during this period that lead to persistent functional and epigenetic alterations and to higher allostatic load over time. Experience of ELS has been shown to lead to an increased neuroendocrine stress response and vulnerability to stress, hypothalamic–pituitary–adrenal axis dysregulation, long-lasting alterations in emotional and psychophysiological reactivity, impaired adaptive functioning, malfunction of fear response circuits and structural changes in the central nervous system. ELS can also lead to epigenetic modifications in response to environmental influences through stress-related gene expression and, thus, play a central role in the long-term biological trajectories leading to stress-related disease, and may explain interindividual variation. In addition, ELS represents an independent risk factor for neuroendocrine–immunological abnormalities with the development, to some level, of a proinflammatory phenotype in adulthood. Finally, recent literature has focused on the potentially fundamental role of sleep and circadian rhythms in the development of ELS-related disorders. Central and peripheral circadian disruption after severe stress in childhood could engrave pathophysiological trajectories of ELS through impaired homeostatic balance, with overall neuroendocrine, immune, metabolic and autonomic dysregulation (Agorastos, Kellner et al., 2014).Taken together, persistent structural, functional and epigenetic changes in neural circuits after ELS could foster chronic chronodisruption and thus mediate the risk of disease and resilience in adults, following a distinct dose–response relationship. The long-term effects of ELS may be conceptualized as a common developmental risk factor triggering a health-related risk cascade with high public health impact. Future studies should focus on prospective investigation of potential predictors and mediators, their temporal sequence and combined effects at epidemiological, biological and epigenetic levels, while taking into account the potentially delayed time-frame for the expression of their effects. Screening strategies for ELS need to be improved, as they would help to identify an individual’s risk level for disease development and predict the response to treatment, towards a better understanding of the relationship between gene and environmental exposures that impacts resilience.

Delayed effect of early-life corticosterone treatment on adult anti-predator behavior in a common passerine

Acute, short-term effects of early-life stress and associated glucocorticoid upregulation on behavior are widely documented across vertebrates. However, the persistence and severity of these effects are largely unknown, especially through the adult stage and in wild species. Here, we investigate long-term effects of experimental post-natal increases in a circulating glucocorticoid on antipredator behavior in wild house sparrows (Passer domesticus) tested in captivity. We manipulate circulating corticosterone concentration in wild, free-living nestlings, transfer fledglings to captivity, and test juveniles and adults for two measures of antipredator behavior: evasiveness during a direct human encounter, and propensity to escape from a risky environment. We find no effect of early-life stress hormone manipulation on escape behavior, but a delayed effect on evasive behavior: evasive behavior was depressed in adults but not juveniles, and influenced by current body condition. These results highlight the importance of state-behavior interactions and life stage in assessing long-term effects of early-life stress, and provide rare evidence for delayed effects of early-life stress to adults of a wild avian species.

Prenatal loss of father during World War One is predictive of a reduced lifespan in adulthood

Although early-life stress is known to alter health, its long-term consequences on mortality remain largely unknown. Thanks to unique French legislation established in 1917 for war orphans and children of disabled soldiers, we were able to study the adult mortality of individuals born in 1914-1916 whose fathers were killed during World War 1. Vital information and socio-demographic characteristics were extracted manually from historical civil registers for 5,671 children born between 1 August 1914 and 31 December 1916 who were granted the status of "pupille de la Nation" (orphan of the Nation). We used a database comprising 1.4 million deceased soldiers to identify war orphans and collect information on their fathers and then paired each orphan with a nonorphan from the same birth register matched for date of birth, sex, and mother's age at the infant's birth. Mortality between ages 31 and 99 y was analyzed for 2,365 orphan/nonorphan pairs. The mean loss of adult lifespan of orphans who had lost their father before birth was 2.4 y (95% CI: 0.7, 3.9 y) and was the result of increased mortality before age 65 y. Adult lifespan was not reduced when the father's death occurred after the infant's birth. These results support the notion that intrauterine exposure to a major psychological maternal stress can affect human longevity.

The impact of psychological distress during pregnancy on the developing fetus: biological mechanisms and the potential benefits of mindfulness interventions

The in utero environment plays an essential role in shaping future growth and development. Psychological distress during pregnancy has been shown to perturb the delicate physiological milieu of pregnancy, and has been associated with negative repercussions in the offspring, including adverse birth outcomes, long-term defects in cognitive development, behavioral problems during childhood and high baseline levels of stress-related hormones. Fetal epigenetic programming, involving epigenetic processes, may help explain the link between maternal prenatal stress and its negative effects on the child. Given the potential long-term effects of early-life stress on a child's health, it is crucial to minimize maternal distress during pregnancy. A number of recent studies have examined the usefulness of mindfulness-based programs to reduce prenatal psychological stress and improve maternal psychological health, and these are reviewed here. Overall, the findings are promising, but more research is needed with large studies using randomized controlled study designs. It remains unclear whether or not such interventions could also improve child health outcomes, and whether these changes are modulated at the epigenetic level during fetal development. Further studies in this area are needed.

Unraveling the Longstanding Scars of Early Neurodevelopmental Stress

Early neurodevelopment, both in utero and in the postnatal phase, is a time when stressors can produce long-lasting changes that significantly increase the risk of mental health problems in adulthood (1). Pregnancy complications such as depression in the mother and childhood trauma can impact on neurodevelopment and increase the likelihood of psychiatric illnesses, such as major depression together with anxiety and personality disorders. Large-scale prospective studies indicate that the increased risk of these disorders following early adversity persists into old age. It is equally clear that not everyone who experiences early stressors develops psychiatric illness in adulthood and neither is there a relationship between any specific stress and a particular psychiatric disorder. If we are to ameliorate the impact of early stress, it is important that we gain an increased understanding of the manner in which such stress impacts on biological development and the psychosocial and genetic factors that help decrease the toxic effects of stress. In this regard, two articles in this issue of Biological Psychiatry focus on the underlying persistent neuronal alterations in subjects who have been exposed to, albeit qualitatively different and potent, early-life stressors (2,3). Interestingly, both articles highlight an important role for the amygdala in these effects. Olsavsky et al. (2) provide evidence in a functional magnetic resonance imaging experiment that altered activation of the amygdala plays a role in long-term behavioral problems in maternally deprived children that had been subsequently adopted (children were aged between 6 and 15 years at the time of scanning). Behaviorally, they found that this cohort had indiscriminate friendliness, which can be defined as an uncharacteristic reduced reticence and atypical approach behaviors towards adults, including strangers, being unable to distinguish adopted mothers from strangers and that this was also demonstrable in terms of amygdala discrimination to both types of stimuli. Interestingly, there was a positive correlation between age at adoption and hence duration of maternal deprivation and extent of the amygdala discrimination and behavioral response in terms of indiscriminate friendliness. On the other hand, Rifkin-Graboi et al. (3) takes a different approach, but once again, this study highlights the role of the amygdala in the long-term effects of early-life stress. They show that microstructural changes in the right amygdala (as assessed within the first 2 weeks of life) can be induced as a result of depression in the mother. The study adds further to our understanding of the toxic effect of maternal depression on the developing fetus. It is also worth noting that recent studies are pointing to a link between maternal childhood maltreatment and maternal antenatal depression (4), thus continuing the cycle of stress-induced effects across the generations with the cooccurrence of both insults significantly increasing the risk of offspring adversity. The mechanism for both of these associations is unclear and may include genomic and environmental influences both during fetal development and postnatally. Experimental studies in animals involving gestation stress or in early life are proving invaluable in uncovering key changes in the neurodevelopment of limbic structures, including alteration in amygdala size, neuronal activity, and expression of key stress-related genes (5). Moreover, starting with the work of Levine et al. (6) in Stanford and Meaney et al. (7) in McGill, a growing body of preclinical data in both rodents and nonhuman primates has been focused on understanding the consequences of alterations in maternal care in early life to both the susceptibility and resilience to psychopathology [see (1) for review].

Long-term, progressive hippocampal cell loss and dysfunction induced by early-life administration of corticotropin-releasing hormone reproduce the effects of early-life stress.

Stress early in postnatal life may result in long-term memory deficits and selective loss of hippocampal neurons. The mechanisms involved are poorly understood, but they may involve molecules and processes in the immature limbic system that are activated by stressful challenges. We report that administration of corticotropin-releasing hormone (CRH), the key limbic stress modulator, to the brains of immature rats reproduced the consequences of early-life stress, reducing memory functions throughout life. These deficits were associated with progressive loss of hippocampal CA3 neurons and chronic up-regulation of hippocampal CRH expression. Importantly, they did not require the presence of stress levels of glucocorticoids. These findings indicate a critical role for CRH in the mechanisms underlying the long-term effects of early-life stress on hippocampal integrity and function.