Long-term behavioral and neuroendocrine adaptations to adverse early experience.
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Adaptation, Physiological↗
Biomedical subjects
M J Meaney
Publications and source records attributed to M J Meaney.
Enhanced nucleus accumbens dopamine and plasma corticosterone stress responses in adult rats with neonatal excitotoxic lesions to the medial prefrontal cortex.
The medial prefrontal cortex modulates the nucleus accumbens dopamine response to stress and has been implicated in feedback regulation of hypothalamic-pituitary-adrenal axis activation by stress. Here we report on the effects of bilateral neonatal (postnatal day 7) ibotenate-induced lesions to the medial prefrontal cortex on nucleus accumbens dopamine and neuroendocrine function in adult rats. Voltammetry was used to monitor the dopamine response to each of five, once-daily exposures to tail-pinch stress whereas alterations in neuroendocrine function were determined from the plasma corticosterone response to a single 20-min episode of restraint stress. Potential lesion-induced deficits in sensory-motor gating were assessed by measuring prepulse inhibition of the acoustic startle response before and after repeated stress. Our data show that each daily stress episode elicited larger and longer-lasting dopamine increases in prefrontal cortex-lesioned animals than in sham-lesioned controls. Furthermore, greater stress-induced elevations in plasma corticosterone were seen in lesioned animals than in their sham-lesioned counterparts. However, while repeated stress potentiated startle responses in animals of both groups, there was no effect of lesion on the amplitude or on prepulse inhibition of the startle response.Together, these findings indicate that neonatal prefrontal cortex damage can lead to changes in mesolimbic dopamine and neuroendocrine function during adulthood. They also add to a growing body of experimental and clinical evidence implicating abnormal prefrontal cortex neuronal development in the pathophysiology of schizophrenia and other disorders linked to central dopamine dysfunction.
Animals↗
The effects of early rearing environment on the development of GABAA and central benzodiazepine receptor levels and novelty-induced fearfulness in the rat.
We compared the effects of handling or maternal separation from the day following birth until postnatal day 14 on behavioral responses to novelty and on GABAA and central benzodiazepine (CBZ) receptor levels in the rat. As adults, handled animals showed reduced startle responsivity, increased exploration in a novel open field, and decreased novelty-induced suppression of feeding relative to the handled (H) and/or maternal separation (MS) groups. As compared with handled animals, both nonhandled (NH) and MS animals displayed: (1) reduced GABAA receptor levels in the locus coeruleus (LC) and the n. tractus solitarius (NTS); (2) reduced CBZ receptor sites in the central and lateral n. of the amygdala, the frontal cortex, and in the LC and NTS; and (3) reduced levels of the mRNA for the gamma 2 subunit of the GABAA receptor complex, which confers high affinity BZ binding, in the amygdaloid nuclei as well as in the LC and NTS. Both the amygdala and the ascending noradrenergic systems have been considered as critical sites for the anxiolytic effects of benzodiazepines. These data suggest that early life events influence the development of the GABAA receptor system, thus altering the expression of fearfulness in adulthood.
Acoustic Stimulation↗
Maternal care, hippocampal synaptogenesis and cognitive development in rats.
We report that variations in maternal care in the rat promote hippocampal synaptogenesis and spatial learning and memory through systems known to mediate experience-dependent neural development. Thus, the offspring of mothers that show high levels of pup licking and grooming and arched-back nursing showed increased expression of NMDA receptor subunit and brain-derived neurotrophic factor (BDNF) mRNA, increased cholinergic innervation of the hippocampus and enhanced spatial learning and memory. A cross-fostering study provided evidence for a direct relationship between maternal behavior and hippocampal development, although not all neonates were equally sensitive to variations in maternal care.
Animals↗
Influence of neonatal rearing conditions on stress-induced adrenocorticotropin responses and norepinepherine release in the hypothalamic paraventricular nucleus.
Postnatal rearing conditions influence the development of hypothalamic-pituitary-adrenal (HPA) responses to stress in the rat. Thus, postnatal handling dampens HPA responsivity to stress, while prolonged periods of maternal separation have the opposite effect. HPA responses to stress are initiated by the release of corticotropin-releasing factor and/or arginine vasopressin from the neurones of the paraventricular nucleus of the hypothalamus (PVNh). A major source of input to the PVNh arises from brainstem noradrenergic neurones with signalling occurring via alpha1 adrenoreceptors. We examined the noradrenergic response to stress in the PVNh in adult animals exposed to daily periods of handling or maternal separation over the first 2 weeks of life using microdialysis in conscious animals. Maternal separation increased, while handling greatly decreased and norepinepherine responses to restraint stress in the PVNh as compared to non-handled controls; the same pattern was observed for plasma adrenocorticotropic hormone (ACTH) responses to stress. Rearing condition did not affect either alpha1 or alpha2 receptor levels in the PVNh. However, alpha2 receptor binding levels in the noradrenergic cell body regions of the locus coeruleus and the n. tractus solitarius were significantly increased in handled animals. These alpha2 receptors are principally located on noradrenergic neurones (i.e. autoreceptors) and inhibit noradrenaline release at terminal sites. The effects on alpha2 receptor levels could serve as a mechanism for the differences in stress-induced noradrenaline levels in the PVNh and in HPA activity among handled vs non-handled and maternal separation animals. Thus, early life events may serve to influence the differentiation of noradrenergic neurones and thus alter HPA responses stress in adulthood.
Adrenocorticotropic Hormone↗
Variations in maternal behaviour are associated with differences in oxytocin receptor levels in the rat.
Female Long-Evans rats exhibit stable individual differences in maternal behaviours such as pup licking/grooming and arched-back nursing posture (LG-ABN). These variations in maternal behaviour are accompanied by differences in lactation-induced increases in oxytocin receptor levels in brain regions known to mediate the expression of maternal care in this species (i.e. the bed nucleus of the stria terminalis, the medial preoptic area and the lateral septum). Oxytocin receptor levels in the central nucleus of the amygdala were significantly higher in high compared to low LG-ABN females regardless of reproductive status. These findings suggest that individual differences in maternal behaviour may be directly related to variations in oxytocin receptor expression.
Amygdala↗
5'-heterogeneity of glucocorticoid receptor messenger RNA is tissue specific: differential regulation of variant transcripts by early-life events.
Glucocorticoid receptor (GR) gene expression is regulated in a complex tissue-specific manner, notably by early-life environmental events that program tissue GR levels. We have identified and characterized several new rat GR mRNAs. All encode a common protein, but differ in their 5'-leader sequences as a consequence of alternate splicing of, potentially, 11 different exon 1 sequences. Most are located in a 3-kb CpG island, upstream of exon 2, that exhibits substantial promoter activity in transfected cells. Ribonuclease (RNase) protection analysis demonstrated significant levels of six alternate exons 1 in vivo in rat, with differences between liver, hippocampus, and thymus reflecting tissue-specific differences in promoter activity. Two of the alternate exons 1 (exons 1(6) and 1(10)) were expressed in all tissues examined, together present in 77-87% of total GR mRNA. The remaining GR transcripts contained tissue-specific alternate first exons. Importantly, tissue-specific first exon usage was altered by perinatal environmental manipulations. Postnatal handling, which permanently increases GR in the hippocampus, causing attenuation of stress responses, selectively elevated GR mRNA containing the hippocampus-specific exon 1(7). Prenatal glucocorticoid exposure, which increases hepatic GR expression and produces adult hyperglycemia, decreased the proportion of hepatic GR mRNA containing the predominant exon 1(10), suggesting an increase in a minor exon 1 variant. Such tissue specificity of promoter usage allows differential GR regulation and programming.
Alternative Splicing↗
Neonatal handling permanently alters hypothalamic-pituitary- adrenal axis function, behaviour, and body weight in boars.
Neonatal handling permanently alters hypothalamic- pituitary-adrenal axis (HPA) function in rats. In the rat, this treatment increases hippocampal glucocorticoid receptors (GR) and dampens plasma ACTH and corticosterone responses to stressors. The objectives of this study were to determine whether neonatal handling of pigs would effect permanent changes in plasma corticosteroid binding capacity (CBG), basal or stressor-induced plasma cortisol and ACTH concentrations, brain or pituitary GR levels, dexamethasone suppression of plasma cortisol and ACTH concentrations, behaviour in an open field-test pen, and body weights. Twelve litters of pigs were randomly assigned to either neonatal handling or no disturbance. Handled litters were removed from the farrowing crate for 10 min per day for the first 14 days of life. Male pigs were kept for the study and the boars were weighed monthly. At 7 months of age, boars were tested for locomotory behaviour in an open field-test pen. The boars were implanted with indwelling ear-vein catheters and blood samples were obtained basally, during and after application of a nose snare, and after 0.04 mg/kg dexamethasone. Boars were killed and blood samples were obtained and the brain and pituitary glands collected. Handled boars had greater (P<0.05) plasma CBG binding and lower basal total (P<0.05) and calculated free (P<0.03) plasma cortisol concentrations. No significant differences between treatments were found in plasma ACTH or cortisol responses to a nose-snare stressor; however, when killed, handled boars had greater (P<0.02) plasma ACTH concentrations. Handled and non-handled boars did not differ in plasma ACTH or cortisol responses to dexamethasone. There was no treatment effect on GR expression in the pituitary gland, frontal cortex, hippocampus, or hypothalamus. Behaviourally, the handled boars had higher (P<0.03) locomotor scores over inner squares and a lower (P<0.05) ratio of outer:inner squares entered in open field-tests. During the first 7 months of life, body weights were lower (P<0.004) for handled boars. In conclusion, neonatal handling permanently altered HPA function in pigs, but in a manner dissimilar to that found in the rat. These changes induced in the pig were not beneficial for commercial production with respect to body weight.
Adrenocorticotropic Hormone↗
Nongenomic transmission across generations of maternal behavior and stress responses in the rat.
In the rat, variations in maternal care appear to influence the development of behavioral and endocrine responses to stress in the offspring. The results of cross-fostering studies reported here provide evidence for (i) a causal relationship between maternal behavior and stress reactivity in the offspring and (ii) the transmission of such individual differences in maternal behavior from one generation of females to the next. Moreover, an environmental manipulation imposed during early development that alters maternal behavior can then affect the pattern of transmission in subsequent generations. Taken together, these findings indicate that variations in maternal care can serve as the basis for a nongenomic behavioral transmission of individual differences in stress reactivity across generations.
Amygdala↗
The role of corticotropin-releasing factor--norepinephrine systems in mediating the effects of early experience on the development of behavioral and endocrine responses to stress.
Naturally occurring variations in maternal care in early postnatal life are associated with the development of individual differences in behavioral and hypothalamic-pituitary-adrenal responses to stress in the rat. These effects appear to be mediated by the influence of maternal licking and grooming on the development of central corticotropin-releasing factor (CRF) systems, which regulate the expression of behavioral, endocrine, and autonomic responses to stress through activation of forebrain noradrenergic systems. These findings provide a neurobiologic basis for the observed relationship between early life events and health in adulthood. In more recent studies, we explored the behavioral transmission of individual differences in stress reactivity, and thus, vulnerability to stress-induced illness, across generations.
Animals↗
Effect of amygdala kindling on emotional behavior and benzodiazepine receptor binding in rats.
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Amygdala↗
Maternal care and the development of stress responses.
Studies dating from the 1950s have documented the impact of early life events on the development of behavioral and endocrine responses to stress. Recent findings suggest that these effects are mediated through changes in mother-offspring interactions and have identified central corticotropin-releasing factor systems as a critical target for the effects of variations in maternal care.
Animals↗
Maternal care, gene expression, and the development of individual differences in stress reactivity.
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Adaptation, Psychological↗
Increased cortisol levels and impaired cognition in human aging: implication for depression and dementia in later life.
Perhaps the most prominent feature of human aging is the variability in decline of intellectual processes. Although many research avenues have been used to study the origin of such an increased variability with aging, new studies show that some biological factors may be associated with normal and pathological cognitive aging. One biological parameter that came under scrutiny in the past few years is the hypothalamic-pituitary-adrenal (HPA) axis, an endocrine closed-loop system controlling the secretion of stress hormones (glucocorticoids). In this review, we summarize data obtained in both animals and humans suggesting that cumulative exposure to high levels of glucocorticoids can be particularly detrimental for the aged hippocampus, a brain structure involved in learning and memory in both animals and humans. We then analyze the implication of these data for the study of dementia and depression in later life, two disorders characterized by increased glucocorticoid secretion in a significant proportion of patients. Finally, we suggest various factors that could explain the development of glucocorticoid hypersecretion in later life.
Aging↗
Maternal care during infancy regulates the development of neural systems mediating the expression of fearfulness in the rat.
The mothers of infant rats show individual differences in the frequency of licking/grooming and arched-back nursing (LG-ABN) of pups that contribute to the development of individual differences in behavioral responses to stress. As adults, the offspring of mothers that exhibited high levels of LG-ABN showed substantially reduced behavioral fearfulness in response to novelty compared with the offspring of low LG-ABN mothers. In addition, the adult offspring of the high LG-ABN mothers showed significantly (i) increased central benzodiazepine receptor density in the central, lateral, and basolateral nuclei of the amygdala as well as in the locus ceruleus, (ii) increased alpha2 adrenoreceptor density in the locus ceruleus, and (iii) decreased corticotropin-releasing hormone (CRH) receptor density in the locus ceruleus. The expression of fear and anxiety is regulated by a neural circuitry that includes the activation of ascending noradrenergic projections from the locus ceruleus to the forebrain structures. Considering the importance of the amygdala, notably the anxiogenic influence of CRH projections from the amygdala to the locus ceruleus, as well as the anxiolytic actions of benzodiazepines, for the expression of behavioral responses to stress, these findings suggest that maternal care during infancy serves to "program" behavioral responses to stress in the offspring by altering the development of the neural systems that mediate fearfulness.
Amygdala↗
Reactivity to novelty in cognitively-impaired and cognitively-unimpaired aged rats and young rats.
Two distinct populations of aged, Long-Evans rats can be identified on the basis of performance in the Morris water maze task. Aged (24 month) unimpaired rats perform similarly to young (six month) animals. Aged, impaired rats display latencies to find the submerged platform greater than two standard deviations from the mean of the young animals. A hallmark of efficient cognitive processing is the ability to cope with environmental change. Consequently, the present studies were conducted to assess if aged, impaired animals display differential reactivity to repeated exposure to novel stimuli. Reactivity was assessed by examining the degree of (i) consumption of a novel gustatory/olfactory stimulus (sweetened milk), (ii) pain inhibition induced by exposure to a novel hot-plate (48.5 degrees C) apparatus and (iii) exploratory behaviour in an elevated plus maze and a novel open field. Aged, impaired rats exhibited lower milk consumption on day one and protracted reactivity (lower consumption over days two to eight) in comparison to aged, unimpaired and young animals. Aged, impaired rats were more reactive to novelty on the hot plate test (as indicated by longer paw lick latencies); this novelty-induced pain inhibition did not habituate in aged, impaired rats following repeated plate exposures. The degree of exploratory behaviour in both the plus maze and the open field was reduced in aged, impaired rats. This effect was not entirely a consequence of deficient affective mechanisms, as measures of anxiety (e.g., time in open arms, time in inner squares) were not different among aged impaired, aged unimpaired and young animals. These results are the first to demonstrate that behavioural deficits observed in aged, impaired animals extend beyond the impairments observed in the water maze. This behavioural profile is attributed, in part, to heightened anxiety. In addition, the impairments observed in aged, impaired animals may also reflect a reduced sensitivity to the positive incentive properties of novel stimuli.
Aging↗
Cortisol levels during human aging predict hippocampal atrophy and memory deficits.
Elevated glucocorticoid levels produce hippocampal dysfunction and correlate with individual deficits in spatial learning in aged rats. Previously we related persistent cortisol increases to memory impairments in elderly humans studied over five years. Here we demonstrate that aged humans with significant prolonged cortisol elevations showed reduced hippocampal volume and deficits in hippocampus-dependent memory tasks compared to normal-cortisol controls. Moreover, the degree of hippocampal atrophy correlated strongly with both the degree of cortisol elevation over time and current basal cortisol levels. Therefore, basal cortisol elevation may cause hippocampal damage and impair hippocampus-dependent learning and memory in humans.
Aged↗
Tissue-specific differences in rat glucocorticoid receptor gene transcriptional regulation.
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Animals↗