Biomedical subjects

M J Meaney

Publications and source records attributed to M J Meaney.

150 records · Page 9Linked to original sources

PubMedDate not supplied

Longitudinal study of basal cortisol levels in healthy elderly subjects: evidence for subgroups.

A group of 51 healthy elderly volunteer subjects participated in a 3- to 6-year longitudinal study of basal cortisol levels. Once per year basal cortisol levels were examined using hourly sampling over a 24-h period. Analyses of three cortisol measures (last measure obtained, mean cortisol levels across years, and the cortisol slope) revealed that the slope of the regression line measuring cortisol levels at each year was the most predictive measure of cortisol secretion over the years in this elderly population. Cortisol levels were shown to increase with years in one subgroup, to decrease in another, and to remain stable in a third. The age of the subjects was not related to either cortisol levels or to the pattern of change in cortisol secretion over years. Free and total cortisol levels were highly correlated and the groups did not differ with regard to plasma corticosteroid binding globulin. No group differences were observed for weight, height, body mass index, pulse, blood pressure and glucose. However, significant group differences were reported for plasma triglycerides levels as well as high density lipoproteins levels. Positive correlations were reported between the obsession/compulsion subscale of the SCL-90 questionnaire and the cortisol slope of subjects. Finally, previously reported group differences in neuropsychological performance are summarized. Thus, there exists considerable variation in hypothalamo-pituitary-adrenal function amongst aged humans. These results are consistent with recent animal studies showing the existence of subpopulations of aged rats which differ in hypothalamo-pituitary-adrenal activity and cognitive efficiency.

Adrenal Glands↗

PubMedDate not supplied

Estrogen-induced hypothalamic beta-endorphin neuron loss: a possible model of hypothalamic aging.

Over the course of normal aging, all female mammals with regular cycles display an irreversible arrest of cyclicity at mid-life. Males, in contrast, exhibit gametogenesis until death. Although it is widely accepted that exposure to estradiol throughout life contributes to reproductive aging, a unified hypothesis of the role of estradiol in reproductive senescence has yet to emerge. Recent evidence derived from a rodent model of chronic estradiol-mediated accelerated reproductive senescence now suggests such a hypothesis. It has been shown that chronic estradiol exposure results in the destruction of greater than 60% of all beta-endorphin neurons in the arcuate nucleus while leaving other neuronal populations spared. This loss of opioid neurons is prevented by treatment with antioxidants indicating that it results from estradiol-induced formation of free radicals. Furthermore, we have shown that this beta-endorphin cell loss is followed by a compensatory upregulation of mu opioid receptors in the vicinity of LHRH cell bodies. The increment in mu opioid receptors presumably renders the opioid target cells supersensitive to either residual beta-endorphin or other endogenous mu ligands, such as met-enkephalin, thus resulting in chronic opioid suppression of the pattern of LHRH release, and subsequently that of LH. Indeed, prevention of the neuroendocrine effects of estradiol by antioxidant treatment also prevents the cascade of neuroendocrine aberrations resulting in anovulatory acyclicity. The loss of beta-endorphin neurons along with the paradoxical opioid supersensitivity which ensues, provides a unifying framework in which to interpret the diverse features that characterize the reproductively senescent female.

Aging↗

PubMedDate not supplied

Individual differences in hypothalamic-pituitary-adrenal activity in later life and hippocampal aging.

Variation in magnitude of cognitive decline in later life is a central feature of human aging. The more severe forms of dementias, such as Alzheimer's disease, clearly define one end of the spectrum. However, among those showing no obvious signs of clinical dementia there are considerable individual differences. Thus, although evidence for learning, memory, and language loss appears in some individuals as early as 50-55 years of age, many people continue to function alertly well into their 90s. These individuals exemplify what Rowe and Kahn (1987) have termed "successful" aging. The wide variability in CNS aging, often a nuisance factor in studies, are becoming a major focus for brain aging research (e.g., Gage et al., 1984;Gallager and Pelleymounter, 1988; Aitken and Meaney, 1990; Issa et al., 1990). Our studies over the past few years have added support to the idea that individual differences in hypothalamic-pituitary-adrenal (HPA) activity can account for part of the variation seen in neurological function among the elderly. In this article we discuss the evidence for the idea that adrenal glucocorticoids can compromise hippocampal function and, thus, produce cognitive impairments, as well as the potential mechanisms for these effects.

Aged↗

PubMedDate not supplied

Neurotrophin receptor and tyrosine hydroxylase gene expression in aged sympathetic neurons.

Ribonuclease protection measurements revealed decreases of 26% in p75 neurotrophin receptor mRNA and 30% in trkA mRNA in superior cervical ganglia (SCG) of aged Long-Evans rats. These declines were not related to the presence of a spatial memory impairment, whose presence is known to strongly predict increased hypothalamic-pituitary-adrenal axis activity in these aged animals. A similar decrease with age was observed in p75, but not cyclophilin mRNA levels in SCG from F-344 inbred rats. In situ hybridization with paired sections from mature and aged F-344 rats revealed a 25% decline in the mean neuronal labeling index (LI) for p75 mRNA. In other paired sections, mean trkA LI decreased 16%, tyrosine hydroxylase (TH) LI increased 74% and cyclophilin LI did not change. Neuronal hypertrophy, p75 decreases and TH increases all occurred to a greatest extent in intermediate-sized neurons, resembling those innervating the pineal and cerebral vessels. In contrast to other SCG targets, this innervation is known to decline nearly 50% with aging. Retrograde tracer/in situ hybridization studies will be required to establish whether decreased p75 represents a marker for selective axonal regression and also to determine the significance of increased TH and neuronal hypertrophy.

Adrenocorticotropic Hormone↗

PubMedDate not supplied

Antidepressants restore hypothalamic-pituitary-adrenal feedback function in aged, cognitively-impaired rats.

Aged, cognitively-impaired rats (and humans) show hypothalamic-pituitary-adrenal (HPA) hyperactivity that correlates with hippocampal damage. The resultant increase in plasma glucocorticoid exposure is thought to contribute to impaired hippocampal function and to potentiate hippocampal neuron death. In young, adult rats antidepressant drugs increase corticosteroid receptor expression in brain regions known to regulate the HPA axis, leading to increased negative-feedback control and decreased HPA activity. In the present study we examined basal levels of plasma adrenocorticotropin hormone (ACTH) and corticosterone in aged, cognitively-impaired (AI), aged, cognitively-unimpaired (AU) and young, adult (Yg) rats. Plasma ACTH and corticosterone levels were significantly elevated in the AI rats, but only in samples obtained during the diurnal peak. Five weeks of treatment with desipramine (15 mg/kg) significantly reduced evening levels of both ACTH and corticosterone in all groups, and eliminated the group differences. We then examined delayed, glucocorticoid negative feedback in these animals. Among vehicle-treated animals, a bolus injection of corticosterone (10 mg/kg), administered 3 hours prior to testing, completely inhibited the plasma ACTH response to restraint in AU and Yg, but not AI animals. In contrast, plasma ACTH responses to restraint were completely inhibited in AI rats following chronic treatment with desipramine. These findings indicate that the antidepressant, desipramine, decreases HPA activity and increases glucocorticoid negative-feedback sensitivity in AI rats, suggesting that antidepressant drugs may form a useful therapeutic approach to HPA dysfunction in elderly human populations.

Adrenocorticotropic Hormone↗

PubMedDate not supplied

Do early-life events permanently alter behavioral and hormonal responses to stressors?

Early-life stimulation (e.g., brief handling) attenuates the behavioral and neuroendocrine responses to stressors encountered in adulthood, particularly with respect to activation of hypothalamic-pituitary-adrenal (HPA) activity. In contrast, if neonates were subjected to a more severe stressor, such as protracted separation from the dam or exposure to an endotoxin, then the adult response to a stressor was exaggerated. These early-life experiences program HPA functioning, including negative feedback derived from stimulation of hippocampal glucocorticoid receptors, and corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) coexpression in PVN neurons, to modify the response to subsequent stressor experiences. The persistent variations of HPA activity observed in handled/stimulated animals may stem from alterations in dam-pup interactions (e.g. increased arched-back feeding, licking, grooming). In addition genetic makeup is critical in determining stress reactivity. For instance, BALB/cByJ mice are more reactive to stressors than C57BL/6ByJ mice, exhibiting greater HPA hormonal alterations and behavioral disturbances. BALB/cByJ also fail to acquire a spatial learning response in a Morris water-maze paradigm, which has been shown to be correlated with hippocampal cell loss associated with aging. Early-life handling of BALB/cByJ mice prevented these performance deficits and attenuated the hypersecretion of ACTH and corticosterone elicited by stressors. The stressor reactivity may have been related to maternal and genetic factors. When BALB/cByJ mice were raised by a C57BL/6ByJ dam, the excessive stress-elicited HPA activity was reduced, as were the behavioral impairments. However, cross-fostering the more resilient C57BL/6ByJ mice to a BALB/cByJ dam failed to elicit the behavioral disturbances. It is suggested that genetic factors may influence dam-pup interactive styles and may thus proactively influence the response to subsequent stressors among vulnerable animals. In contrast, in relatively hardy animals the early-life manipulations may have less obvious effects.

Aging↗