Search PubMed⌕ Search

Biomedical subjects

M J Meaney

Publications and source records attributed to M J Meaney.

At least 91 records · Page 5Linked to original sources
PubMed1994

Postnatal handling alters glucocorticoid, but not mineralocorticoid messenger RNA expression in the hippocampus of adult rats.

Postnatal handling alters hypothalamic-pituitary-adrenal (HPA) responses to stress in the rat. Handling also increases hippocampal glucocorticoid receptor density, and this effect appears to form, in part at least, the basis for the effect of handling on HPA responsiveness to stress. In the present study we have used in situ hybridization techniques to examine the effect of postnatal handling on the expression of glucocorticoid and mineralocorticoid receptor mRNAs in various cell fields of the dorsal hippocampus in adult rats. Grain counting analysis over individual cells showed that postnatal handling significantly increased (40-50%) glucocorticoid receptor mRNA in all hippocampal cell fields. In contrast, handling had no effect on mineralocorticoid receptor mRNA expression. These findings are consistent with the results of receptor binding studies showing that handling increases hippocampal glucocorticoid receptor, but not mineralocorticoid receptor density. Thus, the increase in glucocorticoid receptor binding in handled animals is likely associated with altered rates of receptor biosynthesis. Moreover, the handling effect is quite specific, altering glucocorticoid receptor, but not mineralocorticoid receptor mRNA expression. The mechanism(s) whereby glucocorticoid receptor gene expression is permanently increased by postnatal handling remains to be determined.

Aging↗
PubMed1994

Hypothalamic-pituitary-adrenal activation following endotoxin administration in the developing rat: a CRH-mediated effect.

The present studies assessed hypothalamic-pituitary-adrenal (HPA) responses following immune activation with endotoxin (i.p.) in three-day old Long Evans rats. Marked plasma corticosterone (B), adrenocorticotrophic hormone (ACTH) responses and biphasic fluctuations in plasma glucose were maximal at a dose of 0.05 mg/kg. HPA responses peaked between 3-5 h following immune challenge and plasma ACTH and B responses were greater in female than in male rat pups. Plasma levels of corticosterone binding globulin (CBG) were reduced in males and substantially increased in females during the peak HPA response. Changes in plasma glucose were biphasic with slight increases when ACTH and B levels were maximal, but hypoglycemia was evident once plasma B levels returned to resting values. Endotoxin challenge reduced median eminence corticotropin-releasing hormone (CRH) levels at times corresponding with elevated HPA activity, and prior i.c.v. injection of the CRH antagonist, alpha-helical CRH, significantly attenuated elevations in plasma ACTH and B. In addition, alpha-helical CRH pretreatment completely blocked endotoxin-induced changes in plasma CBG in both males and females. These findings support the view that endotoxin-induced HPA activation in the neonate may occur via CRH.

Adrenal Glands↗
PubMed1994

Regulation of the adrenomedullary catecholaminergic system after mild, acute stress.

The time course of regulation of rat adrenomedullary phenylethanolamine N-methyltransferase (PNMT) and tyrosine hydroxylase (TH) activity was studied after a single episode of 20-min restraint stress. Significant increases in PNMT and TH activity were observed 18 h after the beginning of the stress. The time course of acute stress-induced regulation of PNMT and TH was examined for the influence of neural and hormonal input. Unilateral denervation was performed, and the animals were exposed to a single episode of restraint. PNMT activity increased similarly in both the innervated and denervated adrenals, with a significant increase observed at 36 h after the stress. TH activity was similar in both denervated and innervated adrenals, with a significant increase observed at 24 and 36 h after stress. Finally, suppression of endogenous corticosterone with dexamethasone delayed the stress-induced increase in activity of PNMT but not TH. The present study indicates that increases in catecholamine biosynthetic enzymes can be observed after a single episode of mild, acute stress. In addition, glucocorticoids appear to be important in the time course of the stress-induced increase in PNMT but not TH activity, whereas neural input does not seem to affect the time course of these increases.

Acute Disease↗
PubMed1994

Hypothalamic-pituitary-adrenal activity during chronic central administration of interleukin-2.

The cytokine interleukin-2 (IL-2) exerts numerous effects within the immune as well as the central nervous system and is thought to serve as a humoral signal in their communication. Brain-derived or blood-borne IL-2 may also control the activity of the hypothalamic-pituitary-adrenal (HPA) axis at various levels of regulation. In this study we investigated whether persistently elevated levels of central IL-2, which are associated with several diseases or induced during immunotherapeutic use of this cytokine, could induce long term activation of the HPA axis. Adult male Sprague-Dawley rats received an intracerebroventricular infusion of the recombinant cytokine at a rate of 5 U/h (equivalent to 2.5 ng/h or 162 fmol/h) by means of osmotic minipumps. Control animals received heat-inactivated IL-2. After 7 days of continuous infusion, blood samples were taken at intervals of 4 h over a period of 24 h, and plasma levels of ACTH and corticosterone (CORT) were determined. IL-2 caused a significant increase in ACTH levels during the later portion of the dark phase of the cycle. Plasma CORT concentrations were significantly elevated over almost the whole diurnal cycle. Measurements of CORT-binding globulin concentrations revealed IL-2-induced decreases during the dark phase, resulting in a marked increase in free CORT. Additionally, after 11 days of chronic infusion, both groups of animals underwent a 20-min restraint stress. IL-2-treated animals showed stress-induced increases in plasma ACTH and CORT that were not significantly different from those of animals treated with heat-inactivated IL-2. Along with the alteration of HPA activity seen in the IL-2-treated animals, chronic delivery of the cytokine caused periventricular tissue damage and gliosis. Taken together, the data reflect the capacity of IL-2 to modulate neuroendocrine activity over an extended period of treatment. Moreover, the IL-2-induced effects on HPA activity seen here may help to explain some of the endocrine disturbances seen in patients undergoing IL-2 immunotherapy.

Adrenocorticotropic Hormone↗
PubMed1994

Basal cortisol levels and cognitive deficits in human aging.

A group of 19 healthy elderly subjects previously shown to differ in terms of their cortisol levels over a 4 year period were administered a neuropsychological test battery assessing memory, attention, and language. Correlational analyses performed on various corticosteroid measures showed that the slope of the change in cortisol levels over time predicted cognitive deficits in this elderly population. Aged subjects showing a significant increase in cortisol levels with years and with high current basal cortisol levels were impaired on tasks measuring explicit memory and selective attention when compared to aged subjects presenting either decreasing cortisol levels with years or increasing cortisol levels with moderate current basal cortisol levels. We further showed that subjects presenting a decrease in cortisol levels with years performed as well as young healthy subjects with regard to cognitive performance. Thus, impaired cognitive performance was associated with recent evidence of hypothalamic-pituitary-adrenal (HPA) dysregulation and elevated basal cortisol levels. These results are consistent with recent animal studies showing the existence of subpopulations of aged rats that differ in HPA activity and cognitive performance. Finally, the pattern of cognitive results related to the cortisol history of subjects is in agreement with a role played by the hippocampus in age-related HPA dysfunction and cognitive performance.

Aged↗
PubMed1993

The effects of prostaglandin E2 injected into the paraventricular nucleus of the hypothalamus on brown adipose tissue thermogenesis in spontaneously hypertensive rats.

We examined brown adipose tissue (BAT) thermogenic responses to prostaglandin E2 (PGE2) injected into the paraventricular nucleus of the hypothalamus in the spontaneously hypertensive rat (SHR). 250 ng of PGE2 produced smaller increases in BAT and core temperatures in SHRs compared to their normotensive controls, the WKYs. The results of the present study suggest that the ability of SHRs to mount a febrile response may be compromised.

Adipose Tissue, Brown↗
PubMed1993

Central and feedback regulation of hypothalamic corticotropin-releasing factor secretion.

Physical, emotional and metabolic stressors activate the hypothalamo-pituitary-adrenal (HPA) axis via multiple neural pathways. Final hypothalamic coding of stressor-induced adrenocorticotropic hormone (ACTH) secretion is mediated by differential release of ACTH secretagogues. These include, but may not be limited to, corticotropin-releasing factor (CRF), arginine vasopressin, oxytocin and, possibly, adrenaline. Among these substances, CRF serves as the predominant regulatory factor of this axis because its presence is obligatory for the action of intrinsically weaker secretagogues. Because neural input-encoding qualities of individual stressors utilize, in part, stimulus-specific pathways, the effectiveness of glucocorticoid negative feedback in modulating ongoing and subsequent activity of the HPA axis is dependent upon the type of stressor and the nature of the neural pathways mediating the initial activity. Studies suggest that responses to physical stressors (for example, haemorrhage) are resistant to classical intermediate feedback, whereas those to emotional/cognitive stressors (such as a novel environment) are strongly susceptible to feedback. Overall functional characteristics of the HPA axis in adult organisms are at least partially a result of neonatal experience. In the adult differences in hypothalamic CRF mRNA levels, median eminence peptide content and pituitary responsiveness to stressors can be correlated with aspects of neonatal experience.

Animals↗
PubMed1993

Molecular basis for the development of individual differences in the hypothalamic-pituitary-adrenal stress response.

1. Several years ago, investigators described the effects of infantile handling on the development of hypothalamic-pituitary-adrenal (HPA) responses to stress in the rat. Rat pups exposed to brief periods of innocuous handling early in life showed reduced HPA responses to a wide variety of stressors, and the effect persists throughout the life of the animal. These effects are robust and provide an excellent model for understanding how early environmental stimuli, which are external to the organism, alter neural differentiation and, thus, neuroendocrine responsivity to stress. 2. This paper reviews the endocrine mechanisms affected by early handling and our current understanding of the neural transduction of environmental events and their effects at the level of the target neurons (in the hippocampus and frontal cortex). 3. In brief, handling serves to increase glucocorticoid receptor gene transcription, increasing sensitivity to glucocorticoid negative feedback regulation and, thus, altering the activity within hypothalamic corticotropin-releasing factor/vasopressin neurons. Together these changes serve to determine neuroendocrine responsivity to stress.

Adrenal Cortex↗
PubMed1993

Early, postnatal experience alters hypothalamic corticotropin-releasing factor (CRF) mRNA, median eminence CRF content and stress-induced release in adult rats.

Rat pups 2-14 days of age were exposed daily to handling (15 min of separation from mother and home cage), maternal separation (MS; 180 min of comparable separation), or were left entirely undisturbed (non-handled; NH). As adults, MS rats showed increased hypothalamic corticotropin-releasing factor (CRF) mRNA levels compared with NH rats, while CRF mRNA levels in H rats were significantly lower than either MS or NH animals. Hypothalamic CRF content under basal conditions followed exactly the same pattern. A 20-min period of restraint stress produced significant CRF depletion in all groups, although the percentage of depletion was significantly lower in H animals compared with either MS or NH animals. Restraint stress produced significantly higher increases in plasma corticosterone in MS and NH animals than in H animals. These data reflect the importance of early environmental factors in regulating the development of the hypothalamic CRF system and the responsiveness of the hypothalamic-pituitary-adrenal axis to stress.

Actins↗
PubMed1993

Glucocorticoid receptor gene expression is unaltered in hippocampal neurons in Alzheimer's disease.

Excessive glucocorticoid levels increase the metabolic vulnerability of hippocampal neurons to a wide variety of insults. Since glucocorticoid hypersecretion occurs in Alzheimer's-type dementia it has been proposed that a primary reduction in hippocampal glucocorticoid receptor expression leads to failure of feedback, hypercortisolemia and hence further neuronal loss. However, we have recently found that lesions of the cholinergic innervation of the hippocampus--known to be severely affected in Alzheimer's disease--increase corticosteroid receptor gene expression in the rat hippocampus. We have now examined both glucocorticoid (GR) and mineralocorticoid (MR) receptor gene expression in individual neurons in human postmortem hippocampus, using in situ hybridization histochemistry in 5 patients with Alzheimer's disease (81 +/- 3 years) and 7 controls (81 +/- 7 years) without neurological disease. The distribution and intensity of MR and GR mRNA expression in the hippocampus of Alzheimer's disease were similar to that in control tissue, with high expression in dentate gyrus and CA2-4, but significantly lower expression in CA1. In a separate group of patients with Alzheimer's disease we found significantly increased 24 h integrated plasma cortisol levels (59% greater than age-matched controls) and reduced cortisol-binding globulin (21% lower). These data do not suggest a primary deficiency of biosynthesis of hippocampal corticosteroid receptors in Alzheimer's disease. The maintenance of hippocampal GR and MR gene expression, in the face of an increased glucocorticoid feedback signal, may reflect loss of the cholinergic innervation.

Aged↗
PubMed1993

Glucocorticoid receptors in bovine adrenal medullary cells in culture: regulation by cyclic nucleotides.

Glucocorticoid receptor levels within a given cell determine the glucocorticoid effect in the target tissue. Glucocorticoid receptors are present in adrenal medullary cells in culture where they are involved in the regulation of catecholamine biosynthesis. Modulation of glucocorticoid receptor protein and/or messenger RNA levels in response to cyclic nucleotides has been found in various cell types. In this study, we have investigated the effects of cyclic AMP and cyclic GMP on glucocorticoid receptor binding and glucocorticoid receptor-mediated function in Percoll-isolated bovine adrenal medullary cells in culture. Four-day treatment of cells with 8-bromo-cyclic AMP (10(-3) M) an analogue of cAMP, or forskolin (10(-5) M), an activator of adenylate cyclase, decreased soluble [3H]dexamethasone binding by 55 and 54%, respectively. 8-Bromo-cyclic GMP treatment decreased [3H]dexamethasone binding by 31 and 34% at 10(-5) and 10(-4) M, respectively. Treatment with 8-bromo-cyclic AMP or forskolin, but not 8-bromo-cyclic GMP, elevated cortisol levels in the medium of treated cells, presumably by elevating steroidogenesis in contaminating cortical cells. Cultures further purified to produce chromaffin-enriched cell cultures, also showed a loss (41%) in soluble [3H]dexamethasone binding when treated with 8-bromo-cyclic AMP (10(-3) M). Four-day treatment of standard Percoll-isolated cells with low concentrations of cortisol (10(-9) to 2 x 10(-7) M) similar to that found in the medium of 8-bromo-cyclic AMP-treated cells, did not decrease soluble [3H]dexamethasone binding, whereas higher cortisol concentrations (10(-6) M) produced a 62% loss in soluble binding. Adsorption of cortisol with bovine serum albumin (5 mg/ml) prevented a cortisol (10(-6) M)-induced loss in soluble [3H]dexamethasone binding with no effect on the 8-bromo-cyclic AMP-induced loss in binding, suggesting that the decrease in binding observed following 8-bromo-cyclic AMP treatment is not due to the release of cortisol from contaminating cortical cells. Finally, we report a loss in the ability of 8-bromo-cyclic AMP- or 8-bromo-cyclic GMP-treated cells to fully induce the activity of phenylethanolamine N-methyltransferase in response to cortisol, indicating that decreases in soluble [3H]dexamethasone binding translate into a decrease in the functional consequence of glucocorticoid receptor binding in adrenal medullary cells. In conclusion, these results indicate that long-term increases in cyclic nucleotide second messengers are able to decrease glucocorticoid receptor binding in bovine adrenal medullary cells, via a mechanism independent of released cortisol.(ABSTRACT TRUNCATED AT 400 WORDS)

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1993

Blockade of the hypothalamic-pituitary-adrenal response to stress by intraventricular injection of dexamethasone: a method for studying the stress-induced peripheral effects of glucocorticoids.

Interest in the mechanisms whereby stressors can influence behavior and physiological functioning has involved the use of a variety of methods to prevent the stress-induced release of glucocorticoids, an important and commonly studied stress hormone. We examined the effect of intracerebral ventricular dexamethasone (ICV DEX) on the stress-induced release of adrenocorticotropic hormone (ACTH), corticosterone, plasma epinephrine (E), and plasma norepinephrine (NE). Male Sprague-Dawley rats were stereotaxically implanted with third ventricle ICV cannulae, administered DEX or vehicle, and exposed to 100 1.6-mA tail shocks. Stress hormones were assessed from blood taken during and after the cessation the shock. We report an ICV DEX injection protocol (10 microgram given four times) that results in blocking the stress-induced release of ACTH and corticosterone, and attenuating the stress-induced release of plasma E and NE. We hypothesize that ICV DEX reduces hypothalamic corticotropin releasing hormone (CRH) synthesis and/or release. This method would be especially useful for those studying the effect of pituitary-adrenal hormones on steroid sensitive peripheral targets, such as the immune system.

Adrenocorticotropic Hormone↗
PubMed1993

Entorhinal cortex lesions transiently alter glucocorticoid but not mineralocorticoid receptor gene expression in the rat hippocampus.

Entorhinal cortex lesions destroy an important hippocampal input and lead to axonal sprouting in the dentate gyrus. Glucocorticoids are known to inhibit this reinnervation process. In the present study, we examined changes in hippocampal glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) mRNA expression using in situ hybridization following unilateral entorhinal cortex lesioning (ECL) in the rat. As early as 1 day postlesioning, a 33% bilateral decrease in GR mRNA expression was observed in the dentate gyrus. By contrast, a 36% bilateral increase in GR mRNA expression was detected in the CA1 cell field. GR mRNA levels in both regions returned to those of control animals 2 days postlesioning, indicating that these effects were transient. Adjacent sections hybridized with probes to MR mRNA revealed no changes in hippocampal MR gene expression as a result of ECL. The selective decrease in GR mRNA expression observed in the dentate gyrus following ECL is specific to the hippocampal subregion targeted for reactive synaptogenesis and thus may serve to attenuate the inhibitory actions of circulating glucocorticoids.

Animals↗
PubMed1993

Increased plasma ACTH responses to stress in nonhandled compared with handled rats require basal levels of corticosterone and are associated with increased levels of ACTH secretagogues in the median eminence.

Postnatal handling of rat pups is known to alter permanently hypothalamic-pituitary-adrenal (HPA) responses to a wide variety of stressors. As adults, handled (H) and nonhandled (NH) animals also differ in sensitivity to the delayed negative-feedback effects of glucocorticoids on stress-induced HPA activity. However, it is not understood how handling alters neuroendocrine responses to stressful stimuli, and how differences in feedback sensitivity might account for changes in HPA activity both during and following stress. In the present studies, plasma ACTH responses to both restraint and ether stress were significantly greater in NH compared with H animals. Administration of 100 micrograms/kg corticosterone (B) immediately prior to restraint stress significantly decreased subsequent plasma ACTH responses to restraint to the same extent in H and NH animals, suggesting that H and NH animals do not differ in glucocorticoid fast feedback. H and NH animals adrenalectomized (ADX) 5 d prior to testing did not differ in plasma ACTH responses to restraint stress, demonstrating that the differences between the groups are dependent upon the presence of circulating B. However, the handling effect was apparent in ADX animals provided with a low level of B replacement (approximately 5-6 micrograms/dl). B replacement significantly decreased plasma ACTH levels under both basal conditions and in response to restraint stress in H/ADX rats. In contrast, although B replacement also decreased basal ACTH levels in ADX/NH rats, there were no differences in plasma ACTH responses to restraint between NH/ADX and NH/ADX+B animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenalectomy↗
PubMed1993

The role of the medial prefrontal cortex (cingulate gyrus) in the regulation of hypothalamic-pituitary-adrenal responses to stress.

In the studies reported here we have examined the role of the medial prefrontal cortex (MpFC) in regulating hypothalamic-pituitary-adrenal (HPA) activity under basal and stressful conditions. In preliminary studies we characterized corticosteroid receptor binding in the rat MpFC. The results revealed high-affinity (Kd approximately 1 nM) binding with a moderate capacity (42.9 +/- 3 fmol/mg) for 3H-aldosterone (with a 50-fold excess of cold RU28362; mineralocorticoid receptor) and high-affinity (Kd approximately 0.5-1.0 nM) binding with higher capacity (183.2 +/- 22 fmol/mg) for 3H-RU 28362 (glucocorticoid receptor). Lesions of the MpFC (cingulate gyrus) significantly increased plasma levels of both adrenocorticotropin (ACTH) and corticosterone (CORT) in response to a 20 min restraint stress. The same lesions had no effect on hormone levels following a 2.5 min exposure to ether. Implants of crystalline CORT into the same region of the MpFC produced a significant decrease in plasma levels of both ACTH and CORT with restraint stress, but again, there was no effect with ether stress. Neither MpFC lesions nor CORT implants had any consistent effect on A.M. or P.M. levels of plasma ACTH or CORT. Manipulations of MpFC function were not associated with changes in the clearance rate for CORT or in corticosteroid receptor densities in the pituitary, hypothalamus, hippocampus, or amygdala. Taken together, these findings suggest that MpFC is a target site for the negative-feedback effects of glucocorticoids on stress-induced HPA activity, and that this effect is dependent upon the nature of the stress.

Adrenalectomy↗
PubMed1993

Relationship of social support to [3H]imipramine binding during and after examination stress.

The relationship between social support, depressive symptoms and the maximal binding capacity of [3H]imipramine (Bmax) in platelets was examined in medical students during and after a period of examination stress. There was a positive correlation between the students' perception of their social support and [3H]imipramine Bmax values during examinations, and their perception of social support contributed significantly to the prediction of Bmax by depressive symptomatology. The results suggest that psychosocial factors may be associated with alterations in serotonergic neurotransmission, rendering an individual more physiologically vulnerable to psychological disturbances.

Adult↗