Early Environmental Regulation of Forebrain Glucocorticoid Receptor Gene Expression: Implications for Adrenocortical Responses to Stress; pp. 61–72

Abstract

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.

Adverse Neurodevelopmental Effects of Dexamethasone Modeled in PC12 Cells: Identifying the Critical Stages and Concentration Thresholds for the Targeting of Cell Acquisition, Differentiation and Viability

“…Our results reinforce the fact that brain development is among the processes most vulnerable to glucocorticoids, with disruption of cell acquisition and differentiation achieved at concentrations well below those required for therapeutic interventions. The demonstration of these actions in neural cell cultures, reproducing all the essential findings from glucocorticoid treatment in vivo (Bohn, 1984;Fuxe et al, 1994Fuxe et al, , 1996Gilad et al, 1998;Gould et al, 1997;Kreider et al, 2005aKreider et al, , b, 2006Maccari et al, 2003;Matthews, 2000;Matthews et al, 2002;McEwen, 1992;Meaney et al, 1996;Weinstock, 2001;Welberg and Seckl, 2001), indicates that disrupted neurodevelopment is a direct glucocorticoid effect, not secondary to growth impairment, neuroendocrine disruption or other confounding actions in the fetus, neonate or mother. The successful prevention of respiratory distress in tens of thousands of preterm infants annually in the USA needs to be balanced against the adverse effects on brain development in the hundreds of thousands of individuals that receive the treatment.…”

“…First, glucocorticoid use in preterm labor could contribute directly to adverse neurobehavioral outcomes, over and above the confounds of preterm delivery or of secondary effects on the maternalfetal unit, maternal-neonatal interactions, or maternal or offspring neuroendocrine function. Second, the wide window of vulnerability of neurodevelopment to disruption by DEX means that adverse effects, such as those already noted for glucocorticoid administration in vivo (Bohn, 1984;Fuxe et al, 1994Fuxe et al, , 1996Gilad et al, 1998;Gould et al, 1997;Kreider et al, 2005aKreider et al, , b, 2006Maccari et al, 2003;Matthews, 2000;Matthews et al, 2002;McEwen, 1992;Meaney et al, 1996;Weinstock, 2001;Welberg and Seckl, 2001), are likely to be exerted at any stage in the period of 24-34 weeks of gestation in which these agents are recommended for use (Gilstrap et al, 1995). Third, the targeting of multiple stages of neurodevelopment means that the net outcome will differ according to the maturational timetable for neurogenesis and differentiation in each brain region (Bayer et al, 1993).…”

“…By themselves, glucocorticoids administered during development can lead to persistent stunting of somatic growth, outright cerebral atrophy, and endocrine disruption, along with a host of behavioral anomalies (Bohn, 1984;Fuxe et al, 1994Fuxe et al, , 1996Gilad et al, 1998;Gould et al, 1997;Maccari et al, 2003;Matthews, 2000;Matthews et al, 2002;McEwen, 1992;Meaney et al, 1996;Weinstock, 2001;Welberg and Seckl, 2001). Nevertheless, most of the animal literature concerns doses of glucocorticoids well above those in clinical use and/or encompass prolonged exposure periods or periods outside the neurodeve-lopmental stages appropriate to mimic the use in humans.…”

The Effects of Early Rearing Environment on the Development of GABAA and Central Benzodiazepine Receptor Levels and Novelty-Induced Fearfulness in the Rat

“…The development of behavioral and endocrine responses to acute stress is greatly influenced by the early postnatal rearing environment (for reviews see Levine 1975;Denenberg 1964;Meaney et al 1996). These environmental effects persist throughout the life of the animal, resulting in stable individual differences in stress reactivity.…”

“…As adults, handled animals showed reduced startle responsivity, increased exploration in a novel open field, and decreased novelty-induced suppression of feeding relative to the handled (H) and/or maternal separation (MS) groups. As compared with handled animals, both nonhandled (NH) and MS animals displayed: (1) reduced GABA A receptor levels in the locus coeruleus (LC) and the n. tractus solitarius (NTS); (2) reduced CBZ receptor sites in the central and lateral n. of the amygdala, the frontal cortex, and in the LC and NTS; and (3) The development of behavioral and endocrine responses to acute stress is greatly influenced by the early postnatal rearing environment (for reviews see Levine 1975;Denenberg 1964;Meaney et al 1996). These environmental effects persist throughout the life of the animal, resulting in stable individual differences in stress reactivity.…”