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Papers by patricia rosenfeld

Developmental Brain Research, Jul 1, 1988

The ontogeny of the Type 2 glucocorticoid receptor (GR) in the rat brain was examined using a mon... more The ontogeny of the Type 2 glucocorticoid receptor (GR) in the rat brain was examined using a monoclonal antibody raised against the rat liver GR. Marked changes both in the intensity and in the localization of GR immunoreactivity (GR-ir) were found to occur as a function of age and brain area examined. First, GR-ir was high perinatally and decreased to a low intensity of immunostaining around postnatal day 12 (pnd 12). Thereafter, GR-ir increased to a moderate intensity, which resembled adult levels by pnd 20 in most brain areas. Second, in some regions, such as the hippocampal CA3-4 pyramidal cell fields and the suprachiasmatic nucleus of the hypothalamus, GR-ir was only clearly present during the first postnatal week. Third, in the hippocampus, GR-ir localization showed a distinctive developmental trend towards greater compactness within the CA1-2 pyramidal cell fields and a greater restriction of immunoreactive staining to these cell fields with exclusion of the adjoining areas. Fourth, adrenalectomy reduced overall GR-immunopositive staining, which could be reversed by administration of the selective glucocorticoid agonist, RU 28362. Our results suggest that during ontogeny the glucocorticoid receptor system displays considerable plasticity. Such plasticity may provide a basis for understanding the role of glucocorticoids during brain development.

Physiology & Behavior, 1992

Physiology & Behavior, 1991

In the following studies, we investigated the effects of 24-h maternal deprivation on the infant&... more In the following studies, we investigated the effects of 24-h maternal deprivation on the infant's hypothalamic-pituitary-adrenal system. Experiment 1 examined the effect of deprivation on the infant's corticosterone (CORT) response to adrenocorticotropin hormone (ACTH) injection. At all ages studied, deprivation resulted in a potentiation of the response. At some ages, deprived nontreated pups had higher CORT levels than nondeprived pups. Experiment 2 examined the ontogeny of the deprivation-induced stress response, and the capacity of the mother to inhibit it. From 8 days of age onwards, deprived animals showed a CORT response to saline injection that was either absent or far smaller in nondeprived pups. Saline-induced CORT secretion was diminished, or prevented, by returning the infant to its dam. Maternal reunion had no effect on ACTH-induced CORT elevations. Finally, Experiment 3 investigated the effects of deprivation over a more extended period of time. In maternally deprived pups, ACTH-induced CORT elevations persisted for at least 2 h following reunion, but by 6 h had returned to baseline. These data suggest that maternal factors are involved in the regulation of the responsiveness of the pup's hypothalamic-pituitary-adrenal system.

Neuroendocrinology, 1993

Prolonged maternal deprivation during early ontogeny results in increased basal and stress-induce... more Prolonged maternal deprivation during early ontogeny results in increased basal and stress-induced corticosterone levels. In the following experiments we examined whether these increases were due, at least in part, to augmented ACTH secretion. Thus, ACTH levels were measured in 24-hour maternally deprived and nondeprived 6-, 9-, and 12-day-old pups exposed to a mild stressor (i.e. saline injection followed by placement in a novel environment at room temperature). The results showed: (1) nondeprived pups showed a small response to saline--the response of deprived pups, however, was greater than that of nondeprived pups; (2) the magnitude of the response increased with age; (3) ACTH levels remained elevated for at least 30 min. Subsequent experiments examined whether the continuous exposure to novelty and/or loss of body heat could explain the persistence of this response. Neither variable affected the ACTH response to saline. Our results indicate that factors of maternal origin are partly responsible for the regulation of the ACTH response to stress. Furthermore, the persistence of the response suggests that the negative feedback system in the infant is immature.

Developmental Psychobiology, 1991

Prolonged (i.e., 24-hr) maternal deprivation leads to a marked disinhibition of the infant rat's ... more Prolonged (i.e., 24-hr) maternal deprivation leads to a marked disinhibition of the infant rat's adrenocortical response to stress and/or ACTH. In the following study we examined the time course over which these effects develop. Pups were maternally deprived for varying lengths of time (i.e.. 0, 2, 4, 8, & 24 hr); at the end of this period, corticosterone (CORT) secretion in response to stress (novelty or novelty plus saline injection) and ACTH injection was measured. Basal levels of CORT increased progressively over time in 7-and I I-(but not 3-) day-old pups. CORT release in response to stress followed a similar pattern. In contrast, ACTH injection resulted in marked increases in CORT levels regardless of the length of maternal deprivation in 3-day-old animals; at older ages, however, 24 hr of deprivation led to a much larger increase. These findings support the hypothesis that the hypothalamic-pituitary-adrenal axis of the neonatal rat is subject to maternal regulation. A large body of literature indicates that hormones act on the developing brain to produce long-term irreversible changes. The effects of gonadal hormones on sexual differentiation, for example, have been extensively documented (for review see Toran-Allerand, 1986). Neonatal exposure to high levels of glucocorticoids (GCs) leads to a decrease in mitosis and myelination, as well as altered neural morphogenesis and synaptogenesis. In addition, neuroendocrine function is affected, and behavioral deficits have also been documented (for review see Bohn, 1984).

Developmental Brain Research, 1996

In the brain, corticosteroids bind to two types of receptors, the classical glucocorticoid recept... more In the brain, corticosteroids bind to two types of receptors, the classical glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). The effects of different manipulations taking place during early ontogeny on GR and MR binding properties were examined in the adult hippocampus. Infant rats at postnatal day (pnd) 3 were deprived of maternal contact for 24 h and injected with saline or ACTH l-z4 at the end of the deprivation period. They were then returned to their dams and weaned on pnd 21. At pnd 48, they were sacrificed (24 h post adrenalectomy) and the hippocampal MR and GR measured using an in vitro cytosol binding assay. In the male rats, deprivation and deprivation + ACTH resulted in a reduction of GRs. MRs were also significantly down regulated in the deprived males. In the female rats, saline injections in deprived female rats resulted in increased GR capacity and ACTH injections led to a further up-regulation of the GRs. None of the early manipulations influenced the regulation of the MRs in females. The binding affinity for corticosteriod receptors was also altered by some of the early manipulations. These results in adult (7-week-old) rats indicate that the receptor systems for corticosteroids in the brain are sensitive to brief manipulations occurring early in development. These changes in receptor capacity and/or affinity may affect corticosteroid-mediated processes in the adult rat.

Developmental Brain Research, 1993

Twenty-four hours of maternal separation results in increased secretion of ACTH and corticosteron... more Twenty-four hours of maternal separation results in increased secretion of ACTH and corticosterone (CORT), suggesting the hypothalamic-pituitary-adrenal (HPA) axis is regulated by some aspect of maternal behavior. Previous results indicate that feeding plays a role in maintaining low levels of CORT in 12-day-old pups. In Experiment 1 basal and stress levels of CORT and ACTH were measured in maternally-deprived pups either provided or not with milk to determine whether: (1) feeding maintains ACTH secretion at low levels, and/or (2) feeding maintains the adrenal insensitive to ACTH. The results showed that, although ACTH levels were markedly low (compared to previous values reported by this laboratory) for both groups, only non-fed pups showed a robust increase in basal and stress CORT levels. During the deprivation period in Experiment 1, all pups were manually stroked to induce urination and defecation, suggesting an effect of stroking on ACTH secretion. Experiment 2 examined this hypothesis. Stroking suppressed stress-induced elevations of ACTH secretion due to maternal deprivation. CORT levels, however, were elevated in all deprived pups. The results indicate that maternal regulation of the infant's HPA axis occurs at multiple levels. Feeding appears to regulate adrenal sensitivity, whereas anogenital stroking inhibits the activation of centrally-controlled components of the axis.

Cellular and Molecular Neurobiology, 1993

In the brain, glucocorticoids bind to both the glucocorticoid receptor (GR) and the mineralocorto... more In the brain, glucocorticoids bind to both the glucocorticoid receptor (GR) and the mineralocortocoid receptor (MR). These receptors show clearly distinct developmental patterns in the infant rat. 2. Low levels of GRs are present around the time of birth throughout the brain. Concentrations rise slowly, and do not achieve adult levels until the third week of life, approximately. GR affinity for corticosterone is higher perinatally than at later ages. Receptor microdistribution changes dramatically during ontogeny. In particular, certain regions, such as the suprachiasmatic nucleus of the hypothalamus, express high levels of receptor only during the first week of life. GRs may show impaired capacity to undergo transformation and/or nuclear translocation during the second postnatal week. Environmental manipulations during early ontogeny (e.g., early handling) may have permanent effects on GR capacity. 3. MRs are present at very low concentrations in the first days of life. Binding capacity rises rapidly thereafter and resembles that found in the adult by the end of 1 week. Neither binding affinity in vitro nor overall distribution changes with age. As in the adult, low doses of corticosterone, in vivo, bind mainly to the MRs. Levels of corticosterone are low and relatively unperturbable

Neuroscience & Biobehavioral Reviews, 1992

The hypothalamic-pituitary-adrenal system shows an overall diminished responsiveness throughout o... more The hypothalamic-pituitary-adrenal system shows an overall diminished responsiveness throughout ontogeny. Thus, during this period, the sensitivity of the adrenal gland to ACTH is markedly reduced. Furthermore, basal and stress-induced concentrations of corticosterone (CORT), ACTH and hypothalamic secretagogues remain at very low levels. Both structural immaturity and active inhibitory processes appear to underlie this overall hyporesponsiveness. The available data indicate that the characteristic developmental pattern of the HPA system results from multiple regulatory factors acting in conjunction at various levels of the axis. The primary rate-limiting steps, however, are probably at the brain and adrenal levels. The ultimate "goal" appears to be to keep CORT levels within the narrow range of concentrations required for normal development.

Developmental Brain Research, 1990

The ontogeny of high affinity [3H]corticosterone uptake and retention in brain and pituitary of 2... more The ontogeny of high affinity [3H]corticosterone uptake and retention in brain and pituitary of 24-h adrenalectomized rats was examined using autoradiography of in vivo labeled brain sections. Our data indicate: (1) There is specific uptake of radiolabeled steroid in both brain and pituitary already at 2 days of age, following administration of a tracer (2 pCi/g body wt.) dose of [3H]corticosterone. This uptake is maximum around 4-8 days of age and decreases towards adult values around postnatal day 16. (2) High affinity uptake, at least in the brain, probably represents mostly binding to the mineralocorticoid receptor (MR) and not to the glucocorticoid receptor (GR), as it was not displaced by an excess dose of a GR antagonist, RU 38486, and its location in the hippocampus resembled that of MRs in the adult animal. The tracer amounts of [3H]corticosterone circulating after injection in the rat pups resulted in steroid levels comparable to basal levels of non-adrenalectomized animals of equivalent age. Thus, MRs may be the receptors mainly responsible for mediating physiological effects of glucocorticoids during early ontogeny.

Progress in Brain Research, 1988

... This article is not included in your organization's subscription. However, you may be ab... more ... This article is not included in your organization's subscription. However, you may be able to access this article under your organization's agreement with Elsevier. E. Ronald De Kloet 1 , Patricia Rosenfeld 2 , J. Anke M. Van Eekelen 1 , Winardi Sutanto 1 and Seymour Levine 2. ...

Developmental …, 1993

Basal and stress-induced corticosterone release in the infant rat has been shown to be inhibited ... more Basal and stress-induced corticosterone release in the infant rat has been shown to be inhibited by some aspect of maternal care. The following studies examined specific maternal cues that might be responsible for this regulation. In Experiments 1 and 2, 12-day-old pups remained with their dam but were either prevented or not from feeding; at the end of 24 hr, basal and stress-induced corticosterone levels were measured. Only those animals that were able to feed showed the hyporesponsiveness characteristic of nondeprived animals, suggesting that feeding rather than some other aspect of maternal care was the critical variable. In Experiment 3 , all animals were maternally deprived, and some of them were fed via an intracheek cannula. Once again, feeding led to a pronounced diminution in both basal and stress-induced levels of corticosterone. Our results point to feeding as one of the critical features responsible for the inhibitory effect of the dam on the infant's adrenocortical activity.

The ontogeny of the corticoid receptors in the rat hippocampus was examined by in vitro [3H]corti... more The ontogeny of the corticoid receptors in the rat hippocampus was examined by in vitro [3H]corticosterone (CORT) binding to soluble molecules in the cytosol, using the selective Type II glucocorticoid agonist, RU 28362, to discriminate between Type I and Type II receptor sites. Type I receptors were undetectable until 8 days after birth. From this age on, the receptor showed adult characteristics for both the binding capacity (Bmax) and affinity (Kd). The Type II receptor concentration increased gradually over the observed period; however, at 3 weeks of age concentrations were still only about 65% those found in adults. The binding affinity of Type II to CORT was high during the first week of life but decreased thereafter towards adult value. These data thus suggest clear distinctions in the developmental patterns of Type I and Type II receptors for corticosteroids in the rat.