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Biomedical subjects

M J Meaney

Publications and source records attributed to M J Meaney.

At least 127 records · Page 7Linked to original sources
PubMed1989

The sexual differentiation of social play.

Sex differences in social play are quantitative and not qualitative, referring to frequency and not the form of the behaviors. Whereas increased perinatal exposure to exogenous testosterone masculinizes social play, experimental manipulations of androgen levels after this period (i.e. following critical periods for neuronal differentiation) apparently have no effect on the expression of social play. This effect appears to involve, at least in part, androgen receptor occupancy in the amygdala. In the rat, there is a prominent sex difference in nuclear-bound androgen receptors in the amygdala during the sensitive period for the masculinization of play-fighting. Moreover, testosterone implants directly into the amygdala during this period masculinize social play in females. Progesterone exposure reduces play-fighting in male rats, as does corticosterone. This latter effect may be mediated by corticosteroid receptors in the limibic brain. Perinatal androgen exposure may also be important in humans, since girls born with congenital adrenal hyperplasia diagnosed and treated at birth still show male-like patterns of play. Theories concerning the function of sex differences in social play emphasize either the social or motor learning functions. Juvenile male primate social rank correlates with number of peer social interactions, which predominantly take the form of play-fighting. Females on the other hand appear to spend less time play-fighting and spend more time waiting and competing for interactions with infants, i.e. play-mothering, whereby they acquire the motor skills necessary for handling infants. Such differences may reflect socio-biological and developmental cascades that are, in some way, initiated by perinatal hormonal events.

Animals↗
PubMed1988

Postnatal development and environmental regulation of hippocampal glucocorticoid and mineralocorticoid receptors.

We report here on developmental changes in [3H]RU 28362 (glucocorticoid receptor) and [3H]aldosterone (mineralocorticoid receptor) binding capacity in soluble fractions prepared from hippocampal tissue. [3H]RU 28362 binding was low on Day 3 of life (less than 30% of that observed in adults) and increased towards adult values during the second and third weeks of life, a pattern virtually identical to that previously reported for dexamethasone binding. In contrast, [3H]aldosterone binding on Day 3 of life was only slightly lower than that observed in adults and reached adult values by Day 7. Postnatal handling of rat pups, which has been shown to increase dexamethasone binding in hippocampus, resulted in a significant increase in [3H]RU 28362 binding capacity in hippocampus, but had no effect on [3H]aldosterone binding.

Adrenalectomy↗
PubMed1988

Postmortem decay in glucocorticoid binding in human and primate brain.

Numerous studies of glucorticoid receptors in the rodent brain suggest that similar studies of normal or diseased human brains might be informative. However, a major confound in quantification of such receptors is their possible decay during the lagtime between death and autopsy. We find evidence for such decay. Assay conditions were optimized in a number of ways to remove endogenous glucocorticoids occupying receptors at the time of death. Despite this, [3H]dexamethasone binding in 3-4.5 h postmortem human hippocampus was approximately half that of fresh human primate tissue, while no binding was detectable in 12-24 h postmortem material. In support of the idea of postmortem decay of these receptors, binding in slices of primate temporal cortex left at room temperature declined approximately 50% by 6 h postmortem.

Animals↗
PubMed1988

Stress-induced occupancy and translocation of hippocampal glucocorticoid receptors.

Using an exchange assay for glucocorticoid receptors, we found that immobilization stress resulted in a approximately 50% translocation of receptors (i.e. receptors assumed to be chromatin bound) from soluble fractions prepared from hippocampal tissue. The increased hormone-receptor signal persisted for about 2-4 h following the termination of the stressor. This time course is consistent with the known temporal pattern for the negative feedback of glucocorticoids on adrenocortical activity.

Adrenalectomy↗
PubMed1988

Glucocorticoid binding sites in human temporal cortex.

This work describes the presence of glucocorticoid binding sites in human temporal cortex obtained following partial lobectomy in two epileptic patients. Using [3H]dexamethasone as radioligand and cold cortisol or RU 28362 as competitor we found an apparent Kd of approximately 2.8 nM with a Bmax of approximately 34 fmol/mg protein. The order of potency of various unlabeled steroids to compete for [3H]dexamethasone binding was as follows: RU 28362 = RU 38486 = cortisol = dexamethasone greater than progesterone greater than spironolactone greater than estradiol. These data provide evidence for an intracellular mechanism by which circulating glucocorticoids might regulate neuronal function in the human cortex.

Adult↗
PubMed1988

Effect of neonatal handling on age-related impairments associated with the hippocampus.

In rats, an environmental manipulation occurring early in life resulted in changes in the adrenocortical axis that persisted throughout the entire life of the animals and attenuated certain deficits associated with aging. Rats handled during infancy had a permanent increase in concentrations of receptors for glucocorticoids in the hippocampus, a critical region in the negative-feedback inhibition of adrenocortical activity. Increased receptor concentrations led to greater hippocampal sensitivity to glucocorticoids and enhanced negative-feedback efficacy in the handled rats. Thus, at all ages tested, rats that were not handled secreted more glucocorticoids in response to stress than did handled rats. At later ages, nonhandled rats also showed elevated basal glucocorticoid levels, with the result that there was a greater cumulative exposure to glucocorticoids in nonhandled rats. Increased exposure to adrenal glucocorticoids can accelerate hippocampal neuron loss and cognitive impairments in aging. Hippocampal cell loss and pronounced spatial memory deficits emerged with age in the nonhandled rats, but were almost absent in the handled rats. Previous work showed that glucocorticoid hypersecretion, hippocampal neuron death, and cognitive impairments form a complex degenerative cascade of aging in the rat. The present study shows that a subtle manipulation early in life can retard the emergence of this cascade.

Aging↗
PubMed1988

The effects of chronic antidepressant treatment in an animal model of anxiety.

We have examined the anxiolytic activity of acute and chronic antidepressant treatment in an animal model of anxiety involving novelty-suppressed feeding. Rats were food deprived for 48 h, placed into a novel environment containing food, and the latency to begin eating was recorded. Chronic (21 days), but not acute injections of desipramine (DMI; 10 mg/kg) and amitriptyline (AMI; 10 mg/kg) significantly reduced the latency to begin eating compared to controls, but the percentage decrease was not as great as that seen with either acute or chronic treatment with diazepam (2 mg/kg) or adinazolam (20 mg/kg). A time course study indicated that at least 2 weeks of treatment was necessary to observe a significant anxiolytic effect of antidepressants. The anxiolytic effect of the antidepressants was specific to the novel environment, as 2 weeks of treatment with either diazepam or DMI did not influence the latency to begin eating in the home cage. Finally, a single dose of the central benzodiazepine receptor antagonist, Ro15-1788 (20 mg/kg), given 15 min prior to testing, did not block the anxiolytic effects of chronic DMI, while it completely eliminated the effect of chronic diazepam treatment. These data suggest that antidepressants acquire anxiolytic properties following chronic administration and that this effect appears to be independent of the benzodiazepine receptor system.

Amitriptyline↗
PubMed1988

The effects of acute and life-long food restriction on basal and stress-induced serum corticosterone levels in young and aged rats.

The effects of short term (1-month) and life-long 60% ad libitum food restriction on the adrenocortical response to restraint stress were compared in young and aged Fischer 344 rats. In rats restricted for 1 month (study 1), the adrenocortical response differed as a function of age. In 8-month-old animals, the initial steep rise in corticosterone in response to stress was of similar magnitude in ad libitum and restricted animals. In 23-month-old animals the corticosterone response was severely blunted in restricted animals. In life-long restricted animals (study 2), the corticosterone response to restraint stress was tested at 8, 16, and 24 months of age. The general pattern of response to stress in these animals was similar to that in study 1. The 16- and 24-month-old animals showed the same blunted response to stress found in the 23-month-old animals restricted for only 1 month, suggesting that the severe restriction per se and not life-long food restriction blunted the response to stress in aged animals. The similarity between the response to stress in study 1 and study 2 was evident even though animals were tested in one case before feeding when corticosterone levels were high, and in the other 4-5 h after feeding when corticosterone levels were lower. In study 3 it was found that in food-restricted young rats, the mean corticosterone level over a 24-h period was significantly elevated above that in ad libitum fed young rats. In aged rats, however, except before daily feeding, corticosterone levels of food-restricted rats remained significantly below those of ad libitum fed animals, whose levels were, in turn, significantly elevated compared to those of ad libitum fed young rats. These findings suggest that in aged animals severe food restriction reduces basal corticosterone levels, adrenal responsiveness to stress, and adrenal size and has the potential to protect against the consequences of high corticosterone levels in aging.

Adrenal Cortex↗
PubMed1987

Postnatal handling reduces novelty-induced fear and increases [3H]flunitrazepam binding in rat brain.

Postnatal handling of rat pups alters their response to novelty. We have now shown that, as adults, rats handled for the first three weeks of life showed a suppression of feeding in a novel environment that was less, and a [3H]flunitrazepam binding in whole brain that was greater than in non-handled animals. These data suggest that variations in benzodiazepam binding capacity could be related to individual differences in the fear response to novelty.

Animals↗
PubMed1987

The beta-endorphin response to stress during postnatal development in the rat.

The plasma beta-endorphin and adrenocortical responses to ether and handling stress were examined in animals of various ages. At each age studied there was a significant, stress-induced elevation of plasma beta-endorphin-like immunoreactivity levels. Moreover, basal beta-endorphin-like immunoreactivity levels were higher in animals 3, 7, and 14 days of age than in adults. In contrast, plasma corticosterone levels in the Day 7 pups were not elevated by stress; a finding consistent with several previous reports on the absence of increased release of adrenocorticotropin and corticosterone during stress in the neonate. These data suggest that the release of adrenocorticotropin and beta-endorphin in response to stress differ in the developing animal.

Animals↗
PubMed1987

Thyroid hormones influence the development of hippocampal glucocorticoid receptors in the rat: a mechanism for the effects of postnatal handling on the development of the adrenocortical stress response.

The role of thyroid hormones on the development of intracellular glucocorticoid receptor concentrations was examined in the hippocampus, hypothalamus, and pituitary of the rat. Adult animals, administered triiodothyronine (T3; 1.0 micrograms/g body weight) on days 1, 2, and 4 of life or thyroxine (T4; 2.5 micrograms/g body weight) on days 1 and 2 of life, had significantly elevated glucocorticoid receptor concentrations in the hippocampus, but not in hypothalamus or pituitary. Adult animals treated with propylthiouracil (PTU; 0.2% in the mother's food), a thyroid hormone synthesis inhibitor, for the first 2 weeks of life showed decreased glucocorticoid receptor concentrations in hippocampus, but not in hypothalamus or pituitary. We then examined whether thyroid hormones might mediate the effects of early stimulation on the development of hippocampal glucocorticoid receptor concentrations. Animals that were handled for 15 min daily (Ha) for the first 2 weeks of life showed increased hippocampal glucocorticoid receptor concentrations as adults compared to nonhandled (NHa) controls. PTU administration blocked the effects of handling, such that Ha/PTU animals showed hippocampal glucocorticoid receptor concentrations that were indistinguishable from those of NHa animals. In contrast, corticosterone administration over the first 2 weeks of life had no effect on adult hippocampal glucocorticoid receptor concentrations. These data suggest that thyroid hormones mediate, in part at least, the development of glucocorticoid receptor concentrations in the hippocampus and that this effect occurs independently of their effects on corticosterone titers.

Animals↗
PubMed1986

Testosterone implants into the amygdala during the neonatal period masculinize the social play of juvenile female rats.

The masculinization of social play behavior in the rat is dependent upon the actions of androgens during the neonatal period. The amygdala, a major androgen-target region in the rat limbic brain, appears to be a critical site for this androgenic effect. We tested this hypothesis by implanting testosterone-bearing cannulae into the amygdala of female rat pups on Day 1 of life; the implants were removed on Day 8 of life. The animals were then observed daily between Days 26 and 40 of life and the frequency of play-fighting was recorded. Testosterone-implanted females, like normal males, engaged in significantly more play-fighting than did control females (implanted with cholesterol-bearing cannulae). We have also presented data indicating that the testosterone diffusion from the cannulae was, for the most part, restricted to the amygdala. Thus, testosterone implanted into the amygdala mimicked the effects previously reported for systemic testosterone injections, supporting the idea that the amygdala is a critical region for the actions of androgens on the sexual differentiation of social play behavior in the rat.

Amygdala↗
PubMed1986

Molybdate stabilizes soluble [3H]dexamethasone binding sites in rat brain tissue in incubations at room temperature (22 degrees C).

We have described an in vitro procedure for the measurement of glucocorticoid receptor concentrations in soluble fractions prepared from rat brain tissue using a relatively short incubation period of 1 h at room temperature (22 degrees C). Using [3H]dexamethasone as ligand we found that, with the addition of sodium molybdate (Na2MoO4) to the buffer, estimates of receptor-binding parameters derived from Scatchard analysis (Kd and Bmax) did not differ significantly between assays using 4-5 h incubations at 0-4 degrees C and those using a 1 h incubation performed at room temperature (22 degrees C). The use of molybdate was critical; 1 h incubations at 22 degrees C in the absence of molybdate resulted in a substantial (approximately 65%) loss of [3H]dexamethasone binding.

Animals↗
PubMed1986

Maturation of the adrenocortical stress response: neuroendocrine control mechanisms and the stress hyporesponsive period.

During the first two weeks of life rat pups show a markedly reduced adrenocortical response to stress, and this period of adrenocortical quiescence has been termed the 'stress non-responsive period' (SNRP). The adaptive value of the SNRP can be understood in terms of the effects of glucocorticoids on CNS development: excessively high or low corticoid levels are associated with abnormal neural and behavioral development. We have attempted to explain adrenocortical activity during this period in terms of the unique pattern of glucocorticoid-receptor concentrations that exist in the brain and pituitary of the neonatal rat. This pattern of receptor concentrations results in a negative-feedback condition at the level of the brain and pituitary that ensures the low, stable corticoid levels that appear to be optimal for neuronal development in glucocorticoid-sensitive brain regions.

Adaptation, Physiological↗
PubMed1986

Increased pituitary sensitivity to glucocorticoid feedback during the stress nonresponsive period in the neonatal rat.

Neonatal rats show a diminished response to stress [the stress-nonresponsive period (SNRP)] from day 2-3 until day 14 of age; the physiological bases for the SNRP are unknown. We examined whether enhanced sensitivity of the brain or pituitary to the inhibitory feedback effects of circulating glucocorticoids (GC) contributes to the SNRP. Age-related changes in the ability of corticosterone (CORT) and dexamethasone (DEX) to inhibit the ACTH secretion induced by urethane or CRF were studied. We also examined the ACTH response to ether stress or CRF in intact or 24 h-adrenalectomized 5-day-old rats. Plasma ACTH did not increase in intact rats after ether stress (basal: 64.6 +/- 9.1 pg/ml vs. stressed: 66.8 +/- 8.9 pg/ml; P greater than 0.05), whereas small elevations occurred after CRF challenge (184.6 +/- 40 pg/ml; P less than or equal to 0.01). Five-day-old adrenalectomized rats, which had elevated basal ACTH concentrations, increased ACTH secretion after exposure to ether or CRF. Thus, negative feedback appears to mediate critically the SNRP. Furthermore, sensitivity to such feedback was enhanced during the SNRP since the capacity of CORT to inhibit urethane-induced ACTH secretion in vivo declined with age; 1 mg/kg BW was the minimal dose that inhibited ACTH secretion at day 10, whereas at day 18, the threshold for a similar inhibition was 5 mg/kg BW. In contrast, at both ages, a dose of 10 micrograms/kg BW DEX inhibited ACTH release. In vitro dose response studies in whole pituitaries further demonstrated the enhanced pituitary sensitivity to GC feedback during the SNRP since the IC50 for CORT inhibition of CRF-induced ACTH release increased from days 3-5 to days 22-23. A similar, although not statistically significant trend was observed for DEX inhibition. Thus, neonatal rats exhibit an enhanced pituitary sensitivity to GC during the SNRP and removal of this inhibition allows ACTH secretion in response to ether stress.

Adrenalectomy↗
PubMed1985

[3H]Dexamethasone binding in rat frontal cortex.

The work described in this paper presents evidence for the existence of specific glucocorticoid receptors in the rat frontal cortex. Using [3H]dexamethasone we found a Kd approximately 6 nM and a Bmax approximately 270 fmol/mg protein, concentrations that were about 75% of those found in hippocampus. [3H]dexamethasone binding in the frontal cortex, like that in hippocampus, was regulated by the corticosterone: thus, one-week treatment with corticosterone results in a decrease and long-term adrenalectomy results in an increase in [3H]dexamethasone binding. Developmentally, as reported for other brain regions, [3H]dexamethasone binding in frontal cortex was low during the first week of life and then rose during the following 10 days to approximate adult levels. These results are discussed in terms of providing a possible mechanism for the influence of corticoids on catecholamine activity in the frontal cortex.

Adrenalectomy↗
PubMed1985

Nuclear and cytosolic androgen receptor levels in the limbic brain of neonatal male and female rats.

Nuclear and cytosolic androgen receptors in the limbic brain were measured in neonatal male and female rat pups. There were no sex differences in cytosolic receptor concentrations during the neonatal period in any of the regions studied (hypothalamus, amygdala, preoptic area and septum). Receptor concentrations in all 4 regions increase gradually over the first 10 days of life, with no change in the affinity for 5-alpha-dihydrotestosterone. Nuclear receptor levels in intact pups, measured using an exchange assay, are highest between days 4 and 8 of life. In general, nuclear receptor levels are higher in males than in females; however, this sex difference is most consistently seen in the amygdala. These results are discussed in relation to sex differences in circulating testosterone levels and with respect to the contribution of androgens to the sexual differentiation of behavior.

Amygdala↗