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Biomedical subjects

M J Meaney

Publications and source records attributed to M J Meaney.

At least 55 records · Page 3Linked to original sources
PubMed1997

Maternal care, hippocampal glucocorticoid receptors, and hypothalamic-pituitary-adrenal responses to stress.

Variations in maternal care affect the development of individual differences in neuroendocrine responses to stress in rats. As adults, the offspring of mothers that exhibited more licking and grooming of pups during the first 10 days of life showed reduced plasma adrenocorticotropic hormone and corticosterone responses to acute stress, increased hippocampal glucocorticoid receptor messenger RNA expression, enhanced glucocorticoid feedback sensitivity, and decreased levels of hypothalamic corticotropin-releasing hormone messenger RNA. Each measure was significantly correlated with the frequency of maternal licking and grooming (all r's > -0.6). These findings suggest that maternal behavior serves to "program" hypothalamic-pituitary-adrenal responses to stress in the offspring.

Adrenocorticotropic Hormone↗
PubMed1997

Spatial memory in transgenic mice with impaired glucocorticoid receptor function.

Spatial learning and memory function of transgenic mice with impaired glucocorticoid receptor function was assessed in the Morris water maze and the radial arm maze. Transgenic mice took longer to find a submerged and a visual platform in the water maze task than did mice from the parent strain (B6C/3F1), although performance was improved in the visible platform condition relative to the submerged platform task. In the radial arm maze, transgenic mice made significantly more errors than B6C/3F1 mice. In both tasks, the behavioural strategies adopted by transgenic mice were non-optimal for correct performance. It is suggested that the impaired performance displayed by transgenic mice in both tests is largely attributable to these altered behavioural strategies.

Animals↗
PubMed1997

Dynamic variations in plasma corticosteroid-binding globulin and basal HPA activity following acute stress in adult rats.

We report on dynamic changes in plasma corticosteroid-binding globulin (CBG) binding and basal hypothalamic-pituitary-adrenal (HPA) activity following acute stress in adult rats. Plasma CBG binding was significantly reduced at 24 and 48 h following a single 60 min period of restraint. Basal levels of plasma ACTH and total corticosterone (B) during the light phase of the cycle were elevated at 24 h following restraint. These effects occurred only when animals were stressed in the light phase of the cycle; animals exposed to restraint stress during the dark phase of the cycle showed no change in plasma CBG binding or in basal HPA activity. Pituitary intracellular transcortin, which is derived from circulating CBG, was also decreased by restraint stress. The decrease in CBG binding was also associated with a significant increase in resting-state free B levels. Together, these effects produced a substantially (i.e. approximately 10-fold) increased 'basal' glucocorticoid signal 24 h following acute stress. These data suggest that the increase in the circulating glucocorticoid signal associated with acute stress endures well beyond the period of increased total B levels.

Adrenal Glands↗
PubMed1997

High-fat feeding alters both basal and stress-induced hypothalamic-pituitary-adrenal activity in the rat.

High-fat feeding induces insulin resistance and increases the risk for the development of diabetes and coronary artery disease. Glucocorticoids exacerbate this hyperinsulinemic state, rendering an individual at further risk for chronic disease. The present studies were undertaken to determine whether dietary fat-induced increases in corticosterone (B) reflect alterations in the regulatory components of the hypothalamic-pituitary-adrenal (HPA) axis. Adult male rats were maintained on a high-fat (20%) or control (4%) diet for varying periods of time. Marked elevations in light-phase spontaneous basal B levels were evident as early as 7 days after fat diet onset, and B concentrations remained significantly elevated up to 21 days after fat diet onset compared with controls. In contrast, there were no significant effects on any parameters of spontaneous growth hormone secretory profiles, thus providing support for the specificity of the effects on the HPA axis. In a second study, all groups of rats fed the high-fat diet for 1, 9, or 12 wk exhibited significantly elevated levels of plasma adrenocorticotropic hormone, B, fatty acid, and glucose before, during, and/or at 20, 60, and/or 120 min after the termination of a restraint stress. Furthermore 12-wk fat-fed animals showed a significant resistance to insulin compared with normally fed controls. There were no differences in negative feedback efficacy in high-fat-fed rats vs. controls. Taken together, these results suggest that dietary fat intake acts as a background form of chronic stress, elevating basal B levels and enhancing HPA responses to stress.

Adrenalectomy↗
PubMed1997

Central administration of the neurotensin receptor antagonist, SR48692, modulates diurnal and stress-related hypothalamic-pituitary-adrenal activity.

Previous studies in our laboratory suggest that neurotensin (NT) acts centrally to modulate adrenocorticotropin hormone (ACTH) and corticosterone release. In the present studies, we examined hypothalamic-pituitary-adrenal (HPA) function under basal conditions and during restraint stress following central administration of the highly specific NT receptor antagonist, SR48692. Chronic delivery of SR48692 to the paraventricular nucleus (PVN) of the hypothalamus via indwelling central cannulae attenuated both the diurnal- and stress-induced elevations in HPA activity. Thus, SR48692 decreased the diurnal increase in plasma ACTH and corticosterone during the evening phase of the cycle, but did not affect morning levels. Restraint-induced increases in plasma ACTH and corticosterone levels were also significantly reduced in the SR48692-implanted animals. This suggests that the inhibitory effects of SR48692 were restricted to periods of stimulated HPA activity. A decrease in corticotropin-releasing hormone (CRH)-like immunoreactivity was observed within the PVN following chronic SR48692, and parallel decreases in CRH-like immunoreactivity were observed within the external zone of the median eminence. These findings suggest that endogenous NT serves to increase HPA activity during periods of enhanced stimulation.

Animals↗
PubMed1997

Stress-induced declarative memory impairment in healthy elderly subjects: relationship to cortisol reactivity.

A group of 14 healthy elderly subjects was submitted to a nonstressful (attentional task) and a stressful (public speaking task) condition. Declarative (conscious recollection of learned information) and nondeclarative (retrieved information without conscious or explicit access) memory as well as salivary cortisol levels were measured before and after each condition. The results showed that the stressful condition significantly decreased declarative memory performance, whereas the nonstressful condition did not. Nondeclarative memory performance was not affected by either condition. Further analyses separating the subjects into responders and nonresponders in terms of stress-induced cortisol changes revealed a very different pattern of cortisol secretion and declarative memory performance in both populations. We showed that the responders presented increased cortisol levels 60 min before the actual stressor, whereas the nonresponders presented increased cortisol levels 25 min before the actual stressor. Although the responders did not differ from the nonresponders in declarative memory performance before and after the nonstressful condition, they presented a lower declarative memory performance when measured before and after the stressful condition. The early increase in cortisol levels observed in the responder group suggests that the anticipation of the stress, rather than the actual stressor per se, may have played a more significant role in the stress-induced declarative memory deficits observed in this subgroup. Together, these results show that the cortisol response to anticipation of stress and/or to stress in the elderly specifically affects those memory functions that are dependent on hippocampal activity. They also suggest that an altered cortisol responsivity to acute and/or chronic stress, with its detrimental effects on memory, could be an important factor explaining the genesis of memory deficits in aged populations.

Aged↗
PubMed1996

Phasic hyperactivity of the HPA axis resulting from chronic central IL-2 administration.

Intracerebroventricular infusion of interleukin-2 (IL-2, 15 U h-1 for 14 days) chronically activated the hypothalamic-pituitary-adrenocortical (HPA) axis in rats. IL-2 induced increases in plasma levels of adrenocorticotropic hormone (ACTH, up to two-fold) and corticosterone (up to four-fold) compared with controls. Continuously elevated brain levels of IL-2 did not lead to a persistent HPA activation, but resulted in (two) periods of hormonal hypersecretion. ACTH and corticosterone levels were elevated between days 3 and 5, with changes in corticosterone preceding those of ACTH. Concentrations of corticosterone, but not of ACTH, increased again on day 11. Underscoring its importance as a neuroendocrine regulator, this study reveals that, in addition to its immediate effects, IL-2 induces a complex pattern of chronic HPA stimulation. These findings may functionally relate to several CNS disorders and certain endocrine dysfunctions observed during IL-2 immunotherapy.

Adrenocorticotropic Hormone↗
PubMed1996

Regulation of glucocorticosteroid receptor expression in rat hippocampal cell cultures by nerve growth factor.

Dispersed hippocampal cells cultured in serum-free conditions were used to study the effects of nerve growth factor (NGF) on the expression of type I (mineralocorticosteroid or MR) and type II (glucocorticosteroid or GR) corticosteroid receptors. Cells, plated at a density of 1.2 x 10(6) cells/ml in 60 mm Petri dishes, were mainly identified as neurons (90-95%) and maintained for at least 2 weeks. A 7-day treatment with 10-50 ng NGF/ml induced a concentration-dependent decrease of GR binding (40% decrease) compared to untreated cells. In contrast, MR density was unaffected by a 7-day treatment with 50 ng NGF/ml. Data are discussed as possible direct and/or indirect effects of NGF at the level of both neuronal and glial cells.

Animals↗
PubMed1996

The inhibitory effect of testosterone on hypothalamic-pituitary-adrenal responses to stress is mediated by the medial preoptic area.

In gonadectomized (GDX) animals replaced with subcutaneous steroid implants supplying physiological levels of testosterone (T; 1-10 ng/ml), the magnitude of adrenocorticotropic hormone (ACTH) and corticosterone (B) responses to restraint was negatively correlated with the level of T replacement, reflecting the inhibitory influence of T on hypothalamic-pituitary-adrenal (HPA) responses to stress. Although T had no effect on resting-state levels of corticotropin-releasing hormone (CRH) in the median eminence, arginine vasopressin (AVP) levels were significantly lower in GDX animals replaced with higher T levels, and the magnitude of the ACTH response to restraint was strongly correlated with median eminence levels of AVP. High physiological levels of T increased glucocorticoid receptor binding in the medial preoptic area (MPOA), with no effect on mineralocorticoid receptor binding or on glucocorticoid receptor binding in other regions. Crystalline T or B implants in the MPOA significantly reduced plasma ACTH and B responses to 10 min of restraint stress compared with cholesterol-implanted controls. Moreover, B or T MPOA implants also decreased resting-state levels of AVP but not CRH in the median eminence, and these effects were correlated with ACTH responses to restraint. Finally, lesioning the MPOA blocked the inhibitory effects of high peripheral T levels on ACTH and B responses to restraint. Thus, variations in the magnitude of HPA responses to stress among males are explained in part by individual differences in circulating T levels, and the MPOA is a critical site for this effect via the inhibition of hypophysial AVP.

Adrenocorticotropic Hormone↗
PubMed1996

Plaque-forming cell responses and antibody titers following injection of sheep red blood cells in nonstressed, acute, and/or chronically stressed handled and nonhandled animals.

Given the bidirectional nature of the communication between the immune and hypothalamic-pituitary-adrenal (HPA) systems, we examined whether animals that exhibit differences in HPA responses to stress would also exhibit differences in their plaque-forming cell (PFC) responses to sheep red blood cells (SRBC). Neonatally handled (H) animals exhibit lower HPA responses to a number of acute stressors in adulthood compared to nonhandled (NH) animals. Furthermore, these differences also emerge as a function of chronic, intermittent cold stress. We hypothesized that H and NH animals may exhibit differences in the PFC response to SRBC under conditions of acute and/or chronic stress (H CHR and NH CHR). Exposure to acute (4 hr) cold decreased PFC responses in both H and NH animals compared to nonstressed H and NH animals. The decrease in PFC response produced by chronic, intermittent cold stress was similar in H and NH animals and was not different from that found in acutely stressed animals. In H CHR animals reexposed to cold stress, the PFC response was not different from acutely stressed or chronically stressed H and NH animals. In contrast, the PFC response in NH CHR animals reexposed to cold stress was lower than all other groups studied. Thus, neonatal handling prevented prior chronic stress-induced suppression of the PFC response to a subsequent stress. These data suggest that there may be subpopulations of individuals in whom prior chronic stress does not exacerbate the immune suppression produced by acute stress. However, those chronically stressed individuals in whom immune suppression does occur may be more vulnerable to infection and disease.

Aging↗
PubMed1996

The effects of early postnatal stimulation on Morris water-maze acquisition in adult mice: genetic and maternal factors.

Following stressor exposure BALB/cByJ mice exhibit hypersecretion of corticosterone and marked brain catecholamine alterations. In addition, mice of this strain exhibit impairments of performance in a Morris water-maze, which may be exacerbated by footshock application. In the present investigation it was demonstrated that early-life handling of mouse pups (coupled with brief separation periods from the dam over the course of 21 days postpartum) reduced the learning impairments seen when mice were tested in the Morris water-maze at 120 days of age and also prevented stress-induced disturbances in this task. Likewise, cross-fostering BALB/cByJ mice with a C57BL/6ByJ dam prevented the performance deficits. In contrast, C57BL/6ByJ mice cross-fostered to a BALB/cByJ dam exhibited proficient performance. Thus, maternal factors may be important in determining the Morris water-maze disturbances, provided that this was applied on the BALB/cByJ genetic background. Stressor exposure exacerbated the performance disturbances in BALB/cByJ mice, while diazepam treatment disrupted Morris water-maze performance in both BALB/cByJ and C57BL/6ByJ mice. Paralleling the behavioral changes associated with handling, the stress-induced hypercorticosterone secretion characteristic of the BALB/cByJ mouse was attenuated by the early handling procedure. Stressor exposure also produced strain-dependent variations of NE and 5-HT, but these effects were not appreciably influenced by the handling procedure. These data are consistent with the proposition that performance disturbances of BALB/cByJ mice tested in the Morris water-maze task are associated with excessive hypothalamic-pituitary-adrenal reactivity. Moreover, it appears that the influence of early-life stimulation may interact with genetic factors in determining endocrine and behavioral stress responses.

Analysis of Variance↗
PubMed1996

Ionotropic glutamate receptor subtypes in the aged memory-impaired and unimpaired Long-Evans rat.

The comparative quantitative autoradiographic distribution of ionotropic glutamate receptor subtypes were investigated in young adults (six months) and aged (24-25 months) cognitively impaired and unimpaired male Long-Evans rats. Aged rats were behaviorally characterized as either cognitively impaired or unimpaired based upon their performances in the Morris water maze task compared to the young adult controls. The status of the N-methyl-D-aspartate, [125I]dizocilpine maleate, [3H]kainate and amino-3-hydroxy-5-methylisoxasole-4-propionate (AMPA, [3H]AMPA) receptor binding sites were then established in these three subgroups of animals as a function of their cognitive performance in the Morris water maze task. The apparent densities of both N-methyl-D-aspartate/[125I]dizocilpine maleate and kainate binding sites were significantly decreased in various regions of the aged rat brain. Marked losses in [125I]dizocilpine maleate binding sites were observed in outer laminae of the frontal, parietal and temporal cortices, and the stratum radiatum of the CA3 subfield of the hippocampus. Interestingly, losses in [125I]dizocilpine maleate binding sites were generally most evident in the cognitively unimpaired aged subgroup, suggesting a possible inverse relationship between losses of this receptor subtype and cognitive performances in the Morris water maze task. The levels of [3H]kainate binding were most significantly diminished in various cortical and hippocampal areas as well as the striatum and septal nuclei of both groups of aged rats. In contrast, the apparent density of [3H]AMPA binding was increased in most hippocampal subfields and the superficial laminae of the occipital cortex of the cognitively impaired vs young adult rats. Changes in [3H]AMPA labeling failed to reach significance in the unimpaired cohort. Taken together, these results show that while losses in [3H]kainate binding were similar in both subgroups of aged rats, differences were seen with respect to cognitive status for both [125I]dizocilpine maleate/N-methyl-D-aspartate and [3H]AMPA binding sites. Decreases in [125I]dizocilpine maleate binding sites were mostly restricted to cortical areas of cognitively unimpaired rats, while increases in the AMPA binding subtype were seen in the memory-impaired subgroup. It would thus appear that changes in N-methyl-D-aspartate and AMPA receptor subtypes may be more critical than alterations in kainate binding sites for the emergence of the functional deficits seen in the aged cognitively impaired rat.

Aging↗
PubMed1996

Median eminence corticotrophin-releasing hormone content following prenatal stress and neonatal handling.

Neonatal handling produces enduring changes in hypothalamic-pituitary-adrenal (HPA) axis activation in response to acute stress presentation. Handled rats display reduced HPA activity in response to stress, which is associated with increased hippocampal glucocorticoid receptor densities and decreased median eminence corticotrophin-releasing hormone (CRH) content. Prenatal stress (PS) also has long-term consequences on HPA responsivity to stress and related behavioral profiles. On the basis of earlier behavioral data suggesting that PS contributed to the expression of handled responses, we investigated how PS and handling might interact to affect median eminence CRH content. Groups of prenatally stressed rats and controls were subjected to a handling procedure or left undisturbed. Adult rats were killed and median eminence CRH levels were assayed as well as plasma corticosterone (CORT). PS and handling did not affect CRH content; however, handled plus PS rats exhibited significantly reduced CRH levels. Handling decreased plasma CORT concentrations, an effect that was absent in the PS rats. We contend that PS can modulate an animal's sensitivity to later environmental manipulations while producing minimal effects on its own. Researchers interested in early environmental conditions and later physiologic and behavioral responses should monitor their subjects' gestational history.

Analysis of Variance↗
PubMed1996

Changes in plasma adrenocorticotropin, corticosterone, corticosteroid-binding globulin, and hippocampal glucocorticoid receptor occupancy/translocation in rat pups in response to stress.

Pituitary-adrenal responses to stress in the neonatal rat have been reported to be substantially reduced compared to older animals (i.e. a stress hyporesponsive period). This supposed period of endocrine quiescence is characterized by reduced stress-induced increases in both plasma ACTH and corticosterone. At the same time a number of authors have noted the decreased plasma corticosteroid-binding globulin (CBG) levels of the neonate, and there is evidence for an increased percentage of free corticosterone as well as age-related changes in the volume of distribution for corticosterone. These findings suggest that the reduced CBG levels might enhance the biological significance of existing glucocorticoid levels, beyond that assumed on the basis of plasma total corticosterone levels. We examined this question by estimating hippocampal glucocorticoid receptor occupancy and 'translocation' in Day 6, Day 15, and adult animals under basal and stressful conditions. The results showed that: 1) plasma ACTH levels were elevated in Day 6 animals in response to acute exposure to ether, maternal separation, and maternal separation + ether, however, ACTH responses were substantially lower than in Day 15 or adult animals; 2) Plasma total corticosterone levels followed a similar pattern; most noteworthy was the potent glucocorticoid response in Day 15 animals to the combination of maternal separation + ether; 3) Plasma CBG levels in Day 6 animals were extremely low (< 3% adult values); by Day 15 CBG levels were about 25% of adult levels. Interestingly, maternal separation was associated with a substantial decrease in plasma CBG levels; 4) Hippocampal glucocorticoid receptor occupancy/translocation was similar at all ages under both basal and stress conditions. The only notable exception occurred during maternal separation in Day 15 animals, where the percentage of hippocampal glucocorticoid receptor occupancy/translocation was higher than that observed at any time in either Day 6 or adult animals. This finding is likely related to the decrease in plasma CBG that occurs following separation of Day 15 pups from the dam. Thus, despite the higher corticosterone level in the adult, the increase in glucocorticoid receptor occupancy/translocation was generally comparable across all ages either under basal conditions, or following stress. These receptor data underscore the importance of developmental changes in plasma CBG levels.

Adrenalectomy↗
PubMed1996

Early environmental regulation of forebrain glucocorticoid receptor gene expression: implications for adrenocortical responses to stress.

The adrenal glucocorticoids and catecholamines comprise a frontline of defense for mammalian species under conditions which threaten homeostasis (conditions commonly referred to as stress). Glucocorticoids represent the end product of the hypothalamic-pituitary-adrenal (HPA) axis and along with the catecholamines serve to mobilize the production and distribution of energy substrates during stress. The increased secretion of pituitary-adrenal hormones in response to stress is stimulated by the release of corticotropin-releasing hormone (CRH) and/or arginine vasopressin (AVP) from neurons in the nucleus paraventricularis. In this way, a neural signal associated with the stressor is transduced into a set of endocrine and sympathetic responses. The development of the HPA response to stressful stimuli is altered by early environmental events. Animals exposed to short periods of infantile stimulation or handling show decreased HPA responsivity to stress, whereas maternal separation, physical trauma and endotoxin administration enhance HPA responsivity to stress. In all cases, these effects persist throughout the life of the animal and are accompanied by increased hypothalamic levels of the mRNAs for CRH and often AVP. The inhibitory regulation of the synthesis for these ACTH releasing factors is achieved, in part, through a negative feedback loop whereby circulating glucocorticoids act at various neural sites to decrease CRH and AVP gene expression. Such inhibitory effects are initiated via an interaction between the adrenal steroid and an intracellular receptor (either the mineralocorticoid or glucocorticoid receptor). We have found that these early environmental manipulations regulate glucocorticoid receptor gene expression in the hippocampus and frontal cortex, regions that have been strongly implicated as sites for negative-feedback regulation of CRH and AVP synthesis. When the differences in glucocorticoid receptor density are transiently reversed, so too are those in HPA responses to stress. Taken together, our findings indicate that the early postnatal environment alters the differentiation of hippocampal neurons. This effect involves an altered rate of glucocorticoid receptor gene expression, resulting in changes in the sensitivity of the system to the inhibitory effects of glucocorticoids on the synthesis of CRH and AVP in hypothalamic neurons. Changes in CRH and AVP levels, in turn, determine the responsivity of the axis to subsequent stressors; increased releasing factor production is associated with increased HPA responses to stress. Thus, the early environment can contribute substantially to the development of stable individual differences in HPA responsivity to stressful stimuli. These data provide examples of early environmental programming of neural systems. One major objective of our research is to understand how such programming occurs within the brain.

Adrenal Cortex↗