Biomedical subjects

Michael J Meaney

Publications and source records attributed to Michael J Meaney.

At least 19 recordsLinked to original sources

PubMed2004

Epigenetic programming by maternal behavior.

Here we report that increased pup licking and grooming (LG) and arched-back nursing (ABN) by rat mothers altered the offspring epigenome at a glucocorticoid receptor (GR) gene promoter in the hippocampus. Offspring of mothers that showed high levels of LG and ABN were found to have differences in DNA methylation, as compared to offspring of 'low-LG-ABN' mothers. These differences emerged over the first week of life, were reversed with cross-fostering, persisted into adulthood and were associated with altered histone acetylation and transcription factor (NGFI-A) binding to the GR promoter. Central infusion of a histone deacetylase inhibitor removed the group differences in histone acetylation, DNA methylation, NGFI-A binding, GR expression and hypothalamic-pituitary-adrenal (HPA) responses to stress, suggesting a causal relation among epigenomic state, GR expression and the maternal effect on stress responses in the offspring. Thus we show that an epigenomic state of a gene can be established through behavioral programming, and it is potentially reversible.

Acetylation↗

PubMed2004

Variations in nucleus accumbens dopamine associated with individual differences in maternal behavior in the rat.

Lactating rats exhibit stable individual differences in pup licking/grooming. We used in vivo voltammetry to monitor changes in extracellular dopamine (DA) in the nucleus accumbens (n. Acc) shell of lactating rats interacting with pups and found that (1) the DA signal increased significantly with pup licking/grooming; (2) the onset of such increases preceded pup licking/grooming; and (3) the magnitude and duration of the increase in the DA signal were significantly correlated with the duration of the licking/grooming bout. In females characterized on the basis of behavioral observations as high-licking/grooming mothers, the magnitude of the increase in the DA signal associated with licking/grooming was significantly greater than in low-licking/grooming dams. Dopamine transporter binding in the n. Acc was increased in low-compared with high-licking/grooming mothers. Injection of the selective DA uptake inhibitor GBR 12909 [1-(2-(Bis-(4-fluorophenyl)methoxy)ethyl)-4-(3 phenypropyl)piperazine dihydrochloride] (5 mg/kg, s.c.) increased the DA signal in the n. Acc and pup licking/grooming in low-licking/grooming mothers to levels comparable with those observed in high-licking/grooming dams. Receptor autoradiographic studies showed elevated levels of D1 and D3 receptors in the n. Acc shell region in high-licking/grooming dams. These results suggest that high- and low-licking/grooming dams differ in mesolimbic dopaminergic activity associated with mother-pup interactions. Such differences may serve as neural substrates for individual differences in the motivational component of maternal behavior.

Animals↗

PubMed2004

Dopamine release in response to a psychological stress in humans and its relationship to early life maternal care: a positron emission tomography study using [11C]raclopride.

Mesolimbic dopamine is thought to play a role in the processing of rewards. However, animal studies also demonstrate dopamine release in response to aversive stressful stimuli. Also, in animal studies, disruptions of the mother-infant relationship have been shown to have long-lasting effects on the mesolimbic dopamine system and the hypothalamic-pituitary adrenal axis. We therefore investigated dopamine release in response to stress in human subjects, considering the relationship to early life parental care. We screened 120 healthy young college students for parental care in early life using a combination of telephone interviews and questionnaires. Five students from the top end and five students from the bottom end of the parental care distribution were then invited for a positron emission tomography study using [11C]raclopride and a psychosocial stress task. The psychosocial stressor caused a significant release of dopamine in the ventral striatum as indicated by a reduction in [11C]raclopride binding potential in the stress versus resting condition in subjects reporting low parental care. Moreover, the magnitude of the salivary cortisol response to stress was significantly correlated with the reduction in [11C]raclopride binding in the ventral striatum (r = 0.78), consistent with a facilitating effect of cortisol on dopamine neuron firing. These data suggest that aversive stressful events can be associated with mesolimbic dopamine release in humans, and that the method presented here may be useful to study the effects of early life events on neurobiological stress systems.

Adult↗

PubMed2004

Effect of neonatal handling and paternal care on offspring cognitive development in the monogamous California mouse (Peromyscus californicus).

In the laboratory rat and mouse, neonatal handling enhances hippocampal-dependent learning in adulthood, an effect mediated by changes in maternal behavior toward the handled young. In the present study, we examined the interaction between neonatal handling and biparental care during the early postnatal period and its effect on cognitive function in adult California mice (Peromyscus californicus). We characterized the parental behavior of handled and nonhandled father-present and father-absent families over the first 15 days of life. We then assessed cognitive performance of male and female offspring in the Barnes maze and object recognition test after they were 60 days of age. We found that the amount of licking and grooming received by pups was decreased in father-absent families. By postnatal days 12-15, licking and grooming in handled, father-absent families were equivalent to that of nonhandled, father-present families. Handling enhanced novel object recognition in father-present male mice with no effect in females. In the nonhandled group, the presence of the father had no effect on object recognition learning in male or female mice. Handling also enhanced spatial learning in the Barnes maze. In nonhandled families, the presence of the father appeared to have no effect on spatial learning in the male offspring. Interestingly, spatial learning in nonhandled, father-absent, female offspring was similar to that of handled animals. The average amount of licking and grooming received by pups was negatively correlated with the average number of errors made on the first day of reversal training in the Barnes maze. These data support previous findings that neonatal handling facilitates learning and memory in adulthood, suggest that under certain environmental conditions, there is a sex difference in the response of pups to paternal care, and further demonstrate the importance of active parental investment for offspring cognitive development.

Animals↗

PubMed2004

Maternal behavior regulates benzodiazepine/GABAA receptor subunit expression in brain regions associated with fear in BALB/c and C57BL/6 mice.

Inbred strains of mice, such as BALB/cByJ and C57BL/6ByJ, have been used repeatedly to study genotype-phenotype relations. These strains differ on behavioral measures of fear. In novel environments, for example, BALB/c mice are substantially more neophobic than C57BL/6 animals. The benzodiazepine (BZ)/GABAA receptor system has been proposed as a regulator of behavioral responses to stress, and BALB/c and C57BL/6 mice differ in BZ/GABAA receptor binding. In the present study, we found increased BZ receptor levels in C57BL/6 mice in the central and basolateral nuclei of the amygdala as well as the locus coeruleus using either flunitrazepam (nonselective) or zolpidem (alpha1 subtype selective) as radioligands. Differences in receptor binding were most pronounced in the amygdala and locus coeruleus using [3H]zolpidem. C57BL/6 mice showed increased alpha1 mRNA levels in the locus coeuruleus compared to BALB/c mice. In addition, gamma2 mRNA expression in BALB/c mice was decreased in the central nucleus of the amygdala to levels that were 2-2.5-fold lower than those of C57BL/6 mice. The results of an adoption study revealed that the biological offspring of C57BL/6 mothers fostered after birth to BALB/c dams showed decreased levels of gamma2 mRNA expression in the central nucleus of the amygdala in comparison to peers fostered to other C57BL/6 mothers (the reverse was found for the biological offspring of BALB/c mothers). In a step-down exploration paradigm, BALB/cByJ mice crossfostered onto a C57BL/6ByJ dam expressed reduced anxiety responses. However, among C57BL/6ByJ mice, the relatively low levels of anxiety ordinarily evident were not increased when mice of this strain were reared by a BALB/cByJ dam. These preliminary findings suggest that the strain differences in the BZ/GABAA receptor system occur, at least in part, as a function of parental care. Such findings may reflect a mammalian example of an indirect genetic effect mediated by maternal care.

Adoption↗

PubMed2004

Influence of early postnatal rearing conditions on mesocorticolimbic dopamine and behavioural responses to psychostimulants and stressors in adult rats.

While many experiment with drugs, relatively few individuals develop a true addiction. We hypothesized that, in rats, such individual differences in the actions of addictive drugs might be determined by postnatal rearing conditions. To test this idea, we investigated whether stimulant- and stress-induced activation of nucleus accumbens dopamine transmission and dopamine-dependent behaviours might differ among adults rats that had been either repeatedly subjected to prolonged maternal separation or a brief handling procedure or left undisturbed (non-handled) during the first 14 days of life. We found that, in comparison with their handled counterparts, maternally separated and non-handled animals are hyperactive when placed in a novel setting, display a dose-dependent higher sensitivity to cocaine-induced locomotor activity and respond to a mild stressor (tail-pinch) with significantly greater increases in nucleus accumbens dopamine levels. In addition, maternally separated animals were found to sensitize to the locomotor stimulant action of amphetamine when repeatedly stressed under conditions that failed to sensitize handled and non-handled animals. Finally, quantitative receptor autoradiography revealed a lower density of nucleus accumbens-core and striatal dopamine transporter sites in maternally separated animals. Interestingly, we also found greatly reduced D(3) dopamine receptor binding and mRNA levels in the nucleus accumbens-shell of handled animals. Together, these findings provide compelling evidence that disruptions in early postnatal rearing conditions can lead to profound and lasting changes in the responsiveness of mesocorticolimbic dopamine neurons to stress and psychostimulants, and suggest a neurobiological basis for individual differences in vulnerability to compulsive drug taking.

Amphetamine↗

PubMed2004

Peripubertal environmental enrichment reverses the effects of maternal care on hippocampal development and glutamate receptor subunit expression.

Maternal care in the rat influences the development of cognitive function in the offspring through neural systems known to mediate activity-dependent synaptic plasticity. The offspring of mothers that exhibit increased levels of pup licking/grooming (high-LG mothers) show increased hippocampal N-methyl-D-aspartate (NMDA) subunit mRNA expression, enhanced synaptogenesis and improved hippocampal-dependent spatial learning in comparison with animals reared by low-LG mothers. The effects of reduced maternal care on cognitive function are reversed with peripubertal environmental enrichment; however, the neural mechanisms mediating this effect are not known. In these studies we exposed the offspring of high- and low-LG mothers to environmental enrichment from days 22 to 70 of life, and measured the expression of genes encoding for glutamate receptor subunits and synaptophysin expression as a measure of synaptic density. Environmental enrichment reversed the effects of maternal care on synaptic density and this effect was, in turn, associated with a reversal of the effect of maternal care on the NR2A and NR2B subunits of the NMDA receptor, as well as effects on (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits. Finally, direct infusion of an NR2B-specific NMDA receptor antagonist into the hippocampus eliminated the effects of maternal care on spatial learning/memory in the Morris water maze. These findings suggest that: (1) the effects of maternal care are mediated by changes in NR2B gene expression; and (2) that environmental enrichment reverses the effects of reduced maternal care through the same genomic target, the NR2B gene, and possibly effects on other subunits of the NMDA and AMPA receptors.

Age Factors↗

PubMed2004

Glucocorticoid programming.

Epidemiological evidence suggests that an adverse fetal environment permanently programs physiology, leading to increased risks of cardiovascular, metabolic, and neuroendocrine disorders in adulthood. Prenatal glucocorticoid excess or stress might link fetal maturation and adult pathophysiology. In a variety of animal models, prenatal glucocorticoid exposure or inhibition of 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), the fetoplacental "barrier" to maternal glucocorticoids, reduces birth weight and causes permanent hypertension, hyperglycemia, and increased hypothalamic-pituitary-adrenal axis (HPA) activity and behavior resembling anxiety. In humans, 11beta-HSD2 gene mutations cause low birth weight and reduced placental 11beta-HSD2 activity associated with intrauterine growth retardation. Low birth weight babies have higher plasma cortisol levels throughout adult life, indicating HPA programming. The molecular mechanisms may reflect permanent changes in the expression of specific transcription factors; key is the glucocorticoid receptor itself. Differential programming of the glucocorticoid receptor in different tissues reflects effects upon one or more of the multiple tissue-specific alternate first exons/promoters of the glucocorticoid receptor gene. Overall, the data suggest that either pharmacological or physiological exposure to excess glucocorticoids prenatally programs pathologies in adult life.

11-beta-Hydroxysteroid Dehydrogenase Type 2↗

PubMed2004

Maternal programming of individual differences in defensive responses in the rat.

This paper describes the results of a series of studies showing that variations in mother-pup interactions program the development of individual differences in behavioral and endocrine stress responses in the rat. These effects are associated with altered expression of genes in brain regions, such as the amygdala, hippocampus, and hypothalamus, that regulate the expression of stress responses. Studies from evolutionary biology suggest that such "maternal effects" are common and often associated with variations in the quality of the maternal environment. Together these findings suggest an epigenetic process whereby the experience of the mother alters the nature of the parent-offspring interactions and thus the phenotype of the offspring.

Adaptation, Biological↗

PubMed2004

Preliminary evidence of altered sensitivity to benzodiazepines as a function of maternal care in the rat.

Variations in maternal care over the first week of life alter the expression of genes encoding for various subunits of the GABA(A)/benzodiazepine (BZ) receptor in the amygdala, a brain region associated with fear behavior. Increased maternal licking/grooming and arched-back nursing are associated with decreased fearfulness and enhanced expression of the subunits that confer BZ sensitivity. In these studies we found that the offspring of high licking/grooming-arched-back nursing mothers also showed increased behavioral sensitivity to acute BZ treatment, suggesting a functional relation between the effect on gene expression and fear behavior.

Animals↗

PubMed2004

Early environmental regulation of hippocampal glucocorticoid receptor gene expression: characterization of intracellular mediators and potential genomic target sites.

Environmental conditions in early life permanently alter the development of glucocorticoid receptor gene expression in the hippocampus and hypothalamic-pituitary-adrenal responses to acute or chronic stress. In part, these effects can involve an activation of ascending serotonergic pathways and subsequent changes in the expression of transcription factors that might drive glucocorticoid receptor expression in the hippocampus. This paper summarizes the evidence in favor of these pathways as well as recent studies describing regulatory targets within the chromatin structure of the promoter region of the rat hippocampal glucocorticoid receptor gene.

Animals↗

PubMed2004

Testosterone-dependent variations in plasma and intrapituitary corticosteroid binding globulin and stress hypothalamic-pituitary-adrenal activity in the male rat.

Hypothalamic-pituitary-adrenal (HPA) activity is governed by glucocorticoid negative feedback and the magnitude of this signal is determined, in part, by variations in plasma corticosteroid-binding globulin (CBG) capacity. Here, in gonadectomized male rats we examine the extent to which different testosterone replacement levels impact on CBG and HPA function. Compared with gonadectomized rats with low testosterone replacement ( approximately 2 ng/ml), plasma adrenocorticotropin and beta-endorphin/beta-lipotropin responses to restraint stress were reduced in gonadectomized rats with high testosterone replacement ( approximately 5 ng/ml). Plasma CBG levels also varied negatively as a function of testosterone concentration. Moreover, glucocorticoid receptor binding in the liver was elevated by higher testosterone replacement, suggesting that testosterone acts to enhance glucocorticoid suppression of CBG synthesis. Since pituitary intracellular CBG (or transcortin) is derived from plasma, this prompted us to examine whether transcortin binding was similarly responsive to different testosterone replacement levels. Transcortin binding was lower in gonadectomized rats with high plasma testosterone replacement ( approximately 7 ng/ml) than in gonadectomized rats with low testosterone replacement ( approximately 2 ng/ml). This testosterone-dependent decrease in pituitary transcortin was associated, in vitro, with an enhanced nuclear uptake of corticosterone. These findings indicate that the inhibitory effects of testosterone on corticotrope responses to stress may be linked to decrements in plasma and intrapituitary CBG. This could permit greater access of corticosterone to its receptors and enhance glucocorticoid feedback regulation of ACTH release and/or proopiomelanocortin processing.

Adrenocorticotropic Hormone↗

PubMed2003

Natural variations in maternal care are associated with estrogen receptor alpha expression and estrogen sensitivity in the medial preoptic area.

Lactating rats exhibit stable individual differences in pup licking/grooming (LG) over the first week postpartum. Such naturally occurring variations in maternal behavior are associated with differences in estrogen-inducible oxytocin receptors in the medial preoptic area (MPOA) of the hypothalamus. We compared levels of ER alpha and ER beta mRNA in the MPOA of lactating High or Low LG mothers as well as in their nonlactating, female offspring, which inherit the maternal phenotype of their mothers. Among lactating females, High LG females exhibited significantly elevated levels of ER alpha mRNA compared with Low LG females. Likewise, the adult, virgin female offspring of High LG mothers showed higher levels of ER alpha mRNA in the MPOA compared with those of Low LG mothers. There were no group differences in levels of ER beta mRNA. Differences in ER alpha protein expression in the MPOA were confirmed using Western blot analysis. To further characterize the effects of estrogen in the MPOA, cFos immunoreactivity was compared in ovariectomized, adult offspring of High and Low LG dams treated with estradiol or oil. Increased cFos activity in the anterior ventral nucleus of the MPOA was observed in estradiol-treated High LG, but not Low LG females. These findings suggest that natural variations in maternal care are associated with differences in ER alpha expression in the MPOA and that such differences are transmitted from the mother to her female offspring.

Animals↗

PubMed2003

Amygdala kindling increases fear responses and decreases glucocorticoid receptor mRNA expression in hippocampal regions.

Amygdala kindling dramatically increases fearful behavior in rats. Because kindling-induced fear increases in magnitude as rats receive more stimulations, kindling provides an excellent model for studying the nature and neural mechanisms of fear sensitization. In the present experiment, we studied whether the development of kindling-induced fear is related to changes in glucocorticoid receptor (GR) mRNA expression in various brain regions. Rats received 20, 60 or 100 amygdala kindling stimulations or 100 sham stimulations. One day after the final stimulation, their fearful behavior was assessed in an unfamiliar open field. Then, the rats were sacrificed and their brains were processed for in situ hybridization of GR mRNA expression. We found that compared with the sham-stimulated rats, the rats that received 60 or 100 kindling stimulations were significantly more fearful in the open field and also had significantly less GR mRNA expression in the dentate gyrus and CA1 subfield of the hippocampus. Importantly, the changes in fearful behavior were significantly correlated with the changes in GR mRNA expression. These results suggest that alterations in GR mRNA expression in hippocampal regions may play a role in the development of kindling-induced fear.

Amygdala↗

PubMed2003

Variations in maternal care in the rat as a mediating influence for the effects of environment on development.

Variations in maternal care have been widely considered as a critical influence in development. In the rat, variations in maternal behavior, particularly in licking/grooming, regulate the development of endocrine, emotional and cognitive responses to stress. These studies form the basis of a potentially useful model for the study of maternal effects in mammals. In this paper we provide a detailed methodological investigation into this model of maternal behavior, providing an analysis of the frequency, temporal dynamics, and transmission of maternal licking/grooming in several large cohorts. Frequency data indicate that licking/grooming is normally distributed across dams. The peak in licking/grooming occurs in the first few days postpartum and gradually declines. Dams designated as High or Low LG mothers differ in this behavior only during the first week postpartum. Observations over Days 2 to 5 postpartum are essential for the reliable assessments of individual differences in maternal behavior. Individual differences in licking/grooming behavior are stable across multiple litters, and are not associated with differences in litter size, weaning weight of pups, or gender ratio of the litter. We also observed no significant differences in the amount of licking/grooming received by individual pups within a litter, though variation does exist. Finally, maternal licking/grooming is transmitted to female offspring, though there is considerable within-litter variation in the expression of this behavior. Overall, these findings indicate considerable, normal variations in licking/grooming in the rat that are a stable, individual characteristic of rat dams.

Adaptation, Physiological↗

PubMed2003

Variations in maternal care alter GABA(A) receptor subunit expression in brain regions associated with fear.

Maternal care influences the development of stress reactivity in the offspring. These effects are accompanied by changes in corticotropin-releasing factor (CRF) expression in brain regions that regulate responses to stress. However, such effects appear secondary to those involving systems that normally serve to inhibit CRF expression and release. Thus, maternal care over the first week of life alters GABA(A) (gamma-aminobutyric acid)(A) receptor mRNA subunit expression. The adult offspring of mothers that exhibit increased levels of pup licking/grooming and arched back-nursing (high LG-ABN mothers) show increased alpha1 mRNA levels in the medial prefrontal cortex, the hippocampus as well as the basolateral and central regions, of the amygdala and increased gamma2 mRNA in the amygdala. Western blot analyses confirm these effects at the level of protein. In contrast, the offspring of low LG-ABN mothers showed increased levels of alpha3 and alpha4 subunit mRNAs. The results of an adoption study showed that the biological offspring of low LG-ABN mothers fostered shortly after birth to high LG-ABN dams showed the increased levels of both alpha1 and gamma2 mRNA expression in the amygdala in comparison to peers fostered to other low LG-ABN mothers (the reverse was true for the biological offspring of high LG-ABN mothers). These findings are consistent with earlier reports of the effects of maternal care on GABA(A)/benzodiazepine receptor binding and suggest that maternal care can permanently alter the subunit composition of the GABA(A) receptor complex in brain regions that regulate responses to stress.

Animals↗

PubMed2003

Maternal care influences neuronal survival in the hippocampus of the rat.

Maternal care during the first week of postnatal life influences hippocampal development and function (Liu et al., 2000; Nature Neurosci., 3, 799-806). Offspring reared by mothers who exhibit increased levels of pup licking/grooming (LG) show increased hippocampal synaptic density and enhanced spatial learning and memory. Using 5-bromo-2'-deoxyuridine (BrdU), a thymidine analogue incorporated into cells during DNA synthesis, we examined the effects of early maternal care on hippocampal cell proliferation and neuronal survival in the rat. Twenty-four hours following injection on day 7 of life (P7) there were no differences in BrdU labelling in the offspring of high- compared with low-LG mothers, suggesting no maternal effect on the rate of proliferation at this age. However, 14 and 83 days following injection (P21 and P90), the offspring of high-LG mothers had significantly more surviving BrdU-labelled cells and BrdU-NeuN+-colabelled neurons in the dentate gyrus subgranular zone and granule cell layer. At P21, the offspring of high-LG mothers showed increased protein expression of basic fibroblast growth factor and significantly decreased levels of pyknosis. These findings suggest an influence of maternal care on neuronal survival in the hippocampus. Conversely, at the same time point there was a significantly higher level of hippocampal glial fibrillary acidic protein expression in the offspring of low-LG mothers. These findings emphasize the importance of early maternal care for hippocampal development.

Animals↗

PubMed2002

Serotonin regulates hippocampal glucocorticoid receptor expression via a 5-HT7 receptor.

Glucocorticoid receptor expression in primary hippocampal cell cultures was significantly increased with either 10 mM 8-bromo cAMP, 50 nM 5-carboxamidotryptamine (5-CT), a potent 5-HT7 receptor agonist, or 100 nM 5-HT. The effect of 5-HT or 5-CT was blocked with methiothepin or by a protein kinase A inhibitor, but not pindolol. These results suggest that the effects of 5-HT on hippocampal GR expression is mediated by a 5-HT7 receptor.

8-Bromo Cyclic Adenosine Monophosphate↗