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Biomedical subjects

M J Meaney

Publications and source records attributed to M J Meaney.

At least 145 records · Page 8Linked to original sources
PubMed1985

[3H]dexamethasone binding in the limbic brain of the fetal rat.

The pituitary-adrenal system in the fetal rat is relatively well-developed and during the later part of fetal life circulating corticosterone levels are comparable to those seen in adults. Shortly after birth the adrenal gland regresses and corticosterone levels decrease dramatically. In this paper we report evidence for a similar developmental pattern for the glucocorticoid receptor system within the limbic brain. Thus, glucocorticoid receptor concentrations are higher during the fetal period than during early postnatal life. Moreover, the specificity and the affinity with which glucocorticoid receptors bind [3H]dexamethasone are, according to our data, indistinguishable from those found in the limbic brain of the adult rat.

Animals↗
PubMed1985

The effects of early postnatal handling on hippocampal glucocorticoid receptor concentrations: temporal parameters.

Glucocorticoid receptor (Gr) concentrations in the rat brain are low at the time of birth and increase towards adult levels during the first two weeks of life. Brief, daily handling of pups for the first 21 days postnatally has been found to permanently increase Gr concentrations within the hippocampus. Thus, the development of this neural receptor system is modifiable by environmental stimulation. The work described in this paper indicates that the handling effect on hippocampal Gr concentrations is apparent as early as Day 7 of life. Moreover, handling on Days 1-7 is as effective in altering Gr concentrations as handling for the first 3 weeks of life; handling on Days 8-14 is somewhat less effective and handling on Days 15-21 is without effect. Thus, the sensitivity of the hippocampal Gr system to this early manipulation wanes through the first 3 weeks of life as Gr concentrations reach adult levels, suggesting that handling may directly alter the number of receptor sites per cell.

Age Factors↗
PubMed1985

The development of the glucocorticoid receptor system in the rat limbic brain. I. Ontogeny and autoregulation.

In order to characterize the development of the glucocorticoid receptor system in the brain, we examined [3H]dexamethasone binding in rat pups at various ages. Using an in vitro, cytosol, receptor assay we found evidence for low levels of glucocorticoid receptors perinatally with a subsequent increase in receptor concentrations that began by about the end of the first week of life. We have also shown that receptors during this period have a ligand specificity similar to that of receptors in adult animals. The postnatal increase in receptor levels parallels an increase in circulating corticosterone titers. Thus, receptor and hormone levels increase coincidentally. In adult animals, however, increasing levels of corticosterone are associated with a decrease in receptor levels and vice versa, such that corticosterone is thought to regulate its own receptor (i.e. autoregulation). This suggested an absence of autoregulation during development. We then determined hippocampal receptor concentrations of rats treated for 5 days with corticosterone, or adrenalectomized (ADX) 5 days prior to assay, examining whether up- or down-regulation occurs throughout development. In adults corticosterone treatment decreased (-45%) and long-term adrenalectomy increased (211%) glucocorticoid receptor concentrations. In contrast, at the youngest age tested (Day 10), the effects of manipulations of corticosterone titers on receptor concentrations were negligible. The potential for autoregulation emerged gradually throughout development. Thus, it appears that corticosterone regulation of its own receptors emerges only by about the time of puberty, and that this permits an increase in receptor levels to occur despite the concurrently increasing levels of circulating corticosterone.

Adrenalectomy↗
PubMed1985

The development of the glucocorticoid receptor system in the rat limbic brain. II. An autoradiographic study.

We report here the results of an autoradiographic analysis of the postnatal development of the hippocampal glucocorticoid receptor system in the rat brain. Quantitative analysis of the autoradiograms revealed a varied pattern of gradual development towards adult receptor concentrations during the second week of life. Receptor concentrations in the dentate gyrus increased dramatically between Days 9 and 15, while the changes during this period in the pyramidal layers of Ammon's horn seemed to reflect both structural changes in these regions as well as increases in receptor concentrations.

Age Factors↗
PubMed1985

The development of the glucocorticoid receptor system in the rat limbic brain. III. Negative-feedback regulation.

In the neonatal rat, there are parallel increases with age in the concentrations of glucocorticoid receptors in the limbic system, and in the sensitivity of the hypothalamic-pituitary-adrenal (HPA) axis to negative-feedback inhibition by circulating glucocorticoids. We speculated that the increasing receptor concentrations may mediate this increasing sensitivity of the HPA axis to the suppressive effects of glucocorticoids. To examine this idea we treated rats with exogenous corticosterone from days 29 to 34, resulting in a down-regulation of glucocorticoid receptors in the brain at Day 35 to levels similar to those of younger animals. Subjects whose maturational increase in receptors was reversed in this manner were less sensitive to feedback inhibition of glucocorticoids. Specifically, compared to controls they continued to secrete corticosterone after the end of stress, and were relatively insensitive to the suppressive effects of the synthetic glucocorticoid, dexamethasone, on corticosterone titers. Our data specifically implicate the hippocampus in modulating feedback sensitivity, as down-regulation was extensive in this structure, and did not occur in the septum, amygdala, hypothalamus or pituitary.

Animals↗
PubMed1985

The effects of postnatal handling on the development of the glucocorticoid receptor systems and stress recovery in the rat.

We have examined the effects of postnatal handling of rat pups from Days 1 to 21 on the development of the intracellular, glucocorticoid receptor in the hippocampus, and pituitary transcortin, and corticoid binding globulin in plasma. All animals were sacrificed 10-14h following adrenalectomy and the in vitro receptor assays were performed using 3H dexamethasone (intracellular receptors) or [3H] corticosterone (transcortin and corticoid binding globulin). Early handling resulted in a 30-40% increase in 3H dexamethasone binding (increase in Bmax with no change in Kd) in the hippocampus. In the pituitary handling was associated with a decrease in transcortin binding. There was no effect on plasma corticoid binding globulin. When tested as adults, nonhandled animals hypersecreted corticosterone following the termination of a stressor. This suggests a more efficient adrenocortical negative-feedback system in the handled animals and these data are consistent with previous work on the relationship between hippocampal glucocorticoid receptors and adrenocortical stress recovery.

Adrenal Cortex↗
PubMed1985

Early postnatal handling alters glucocorticoid receptor concentrations in selected brain regions.

Norway rat pups were either handled (H) or undisturbed (nonhandled, NH) in the period between birth and weaning on Day 21. Following weaning, half of the animals in each group were housed socially (Soc), and half were housed in isolation (Isol). At 120-150 days of age, all animals were sacrificed, and the following regions were dissected and frozen at -70 degrees C until the time of assay: frontal cortex, hippocampus, hypothalamus, amygdala, septum, and pituitary. [3H]Dexamethasone (3H Dex) binding in each region was examined by an in vitro, cytosol, receptor assay. 3H Dex binding was significantly higher in the hippocampus of both H-Soc and H-Isol than in NH groups. In the frontal cortex, 3H Dex binding was higher in the H-Soc animals than in the H-Isol and NH-Isol animals. There were no significant handling or housing effects found in the amygdala, hypothalamus, septum, or pituitary. Thus, early postnatal handling appears to influence the development of the glucocorticoid receptor system in the hippocampus and frontal cortex. These results are discussed as providing a possible mechanism for some of the previously reported effects of early handling on the development of the pituitary-adrenal response to stress.

Amygdala↗
PubMed1983

In vitro measurement of cytosol and cell nuclear androgen receptors in male rat brain and pituitary.

An in vitro assay procedure is described for measuring androgen receptor binding in cytosol and cell nuclei of brain and pituitary tissue using [3H]R1881 as ligand. The cell nuclear assay uses the exchange method, which permits assessment of endogenous occupancy of androgen receptors in brain and pituitary. Competition and saturation analysis indicated that [3H]R1881 binding has the specificity and nanomolar affinity expected of an androgen receptor. Moreover, we demonstrated that androgen receptor binding predominated in cytosol from castrated rats and in cell nuclei of male rats treated in vivo with testosterone. Furthermore, as expected, testicular feminized male rats showed low levels of putative androgen receptors in both cytosol and cell nuclei.

Animals↗
PubMedDate not supplied

Temporally graded, age-related impairments in spatial memory in the rat.

We report here on the analysis of data from 6-, 12-, and 24-month-old Long-Evans rats tested in the Morris water maze. The animals were given 18 trials over a 5-day period with the platform submerged (spatial condition); 3 trials on the first day, 4 trials on each of the subsequent 3 days, followed by 3 trials on the fifth day. On the sixth day, the animals were given five trials in which the platform was elevated above the water level (cued condition). Over the 18 trials in the spatial condition, the 24-month-old animals took significantly longer to find the platform than did the 6-month-old animals; the performance of the 12-month-day animals lay between the older and younger groups. We then analyzed the latency data depending on the position of the trial in that day of testing: The first trial of each day followed the preceding trial by 20-22 hours, whereas the last trial of each day followed the preceding trial by only 20 minutes. The performance of the 12-month-old animals on the first trial of the second, third, and fourth days of testing was indistinguishable from that of the 24-month-old animals. Whereas, the performance of the 12-month-old animals on the last trial of the second, third, and fourth days of testing was indistinguishable from that of the 6-month-old animals. An analysis of the distance data (distance covered before locating the platform) revealed the same pattern of results.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗
PubMedDate not supplied

Postnatal handling attenuates certain neuroendocrine, anatomical, and cognitive dysfunctions associated with aging in female rats.

Hippocampal degeneration with aging is associated with increased hypothalamic-pituitary-adrenal (HPA) activity and, in male rats, both are attenuated by postnatal handling. Considering the important sex differences in the effects of handling and in HPA responses to stress in older rats, we have examined the effects of postnatal handling on aging in females. Female, Long-Evans rats were handled (H) during the first 3 weeks of life and later compared with nonhandled (NH) controls at various ages. Handling resulted in permanently increased hippocampal type II, glucocorticoid receptor binding. Relative to H females, NH females showed increased basal corticosterone levels in later life and hypersecreted corticosterone following stress at all ages examined. Both effects are similar to those reported in males. However, unlike males, H and NH females did not differ in corticosterone levels achieved during stress, a finding that may be related to sex-dependent effects of handling on pituitary transcortin receptors. There were no differences in hippocampal neuron density in 6-month-old animals. However, the older NH animals showed considerable neuron loss in the CA1 and CA3 hippocampal cellfields. There was little or no neuron loss in the H animals. Finally, the NH animals exhibited age-related spatial memory impairments, such that by 24 months of age the performance of the NH females was profoundly worse than that of the younger NHs and same-aged H animals. These data suggest that early handling permanently alters CNS systems that regulate hypothalamic-pituitary-adrenal (HPA) function, although the effect may depend on the gender of the animal. In both males and females, however, handling appears to prevent (or minimize) increased adrenal secretion in later life and to attenuate hippocampal cell loss and spatial memory impairments.

Aging↗
PubMedDate not supplied

Age-related changes in glucocorticoid receptor binding and mRNA levels in the rat brain and pituitary.

Hypothalamic-pituitary-adrenal (HPA) activity under both basal and poststress conditions is often increased in the aged rat. This change has been associated with the loss of corticosteroid receptors in specific regions that mediate glucocorticoid negative feedback. In order to study the cellular basis for the loss of receptors, we measured glucocorticoid (type II corticosteroid) receptor binding and mRNA levels in pituitary and selected brain regions in rats at 6, 12, and 24 months of age. Receptor binding, measured using [3H]RU 28362, was stable in all regions (pituitary, hypothalamus, amygdala, and frontal cortex) except the hippocampus, where there was about a 40% decrease in binding capacity, with no change in the affinity of the receptor for RU 28362. The loss of receptors in the hippocampus was apparent in animals at 12 months of age, and binding was further decreased at 24 months. Glucocorticoid receptor mRNA levels were significantly higher in all regions at 12 months of age than at 6 months. By 24 months, however, receptor mRNA levels in most regions had returned to levels that were similar to those at 6 months of age. In contrast, glucocorticoid receptor mRNA levels in the hippocampus were significantly decreased at 24 months of age compared to levels at both 6 and 12 months of age. Thus, in general, variations in receptor mRNA levels parallel those in receptor binding in animals 6 and 24 months of age, with the hippocampus as the only region showing a significant loss of receptors and a decrease in mRNA levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMedDate not supplied

Peripheral benzodiazepine binding sites in Alzheimer's disease frontal and temporal cortex.

Much evidence has accumulated to suggest that the peripheral type benzodiazepine (PBZ) binding site has a predominantly glial localization. Elevated PBZ binding densities have been reported in various models of brain damage, apparently reflecting glial proliferation in response to neurodegeneration. In the present study, PBZ receptor densities were examined in frontal and temporal cortex of Alzheimer's disease (AD) patients using the ligand [3H]PK 11195. There was a highly significant (p less than 0.01) increase in PBZ binding sites in the temporal cortex from AD patients. In the frontal cortex, a moderate increase was observed that approached statistical significance (p = 0.07). Decreased choline acetyltransferase activity was observed in both regions. These findings offer support for the potential use of the PBZ binding site as a marker for gliosis associated with neuronal cell death.

Aged↗