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Editorial: Are Glucocorticoids Good or Bad for Brain Development and Plasticity?

Laboratory of Molecular Endocrinology and Department of Anatomy and Physiology Centre Hospitalier de l’Université Laval (CHUL) Research Center and Laval University Québec G1V 4G2, Canada

Address all correspondence and requests for reprints to: Serge Rivest, Ph.D., Laboratory of Molecular Endocrinology, CHUL Research Center and Laval University, 2705 Boulevard Laurier, Québec G1V 4G2, Canada. E-mail: . Serge.Rivest{at}crchul.ulaval.ca

	Introduction

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There is accumulating evidence that increased levels in glucocorticoids (GCs) may have detrimental effects for the brain, especially for specific neurons of the hippocampus, that may lead to memory disorders. The circumstances allowing such increase in circulating levels of GCs are numerous and include genetic factors, environments, gender, and the nature of stressful events. Some individuals exhibit a maintained activation of the hypothalamic-pituitary-adrenal (HPA) axis in response to a rather modest stressful stimulus, whereas others are not affected by the same situation. We do not known exactly why such differences occur between individuals, but the way we perceive and control a particular event is likely to contribute to our degree of stress and the ultimate endocrine outputs. During a lifetime, this may have a great impact on the brain plasticity and neurodegeneration that may be attributable to the presence of high levels of GCs into the hippocampal environment, for example. A famous series of studies performed by Sapolsky and colleagues (1, 2, 3) in wild male baboons living undisturbed in their natural habitat in Africa provided the evidence that sustained social stress has determinant impact on the brain. Indeed, the subordinated group of baboons exhibited higher cortisol levels than dominant baboons (1), which was associated with numerous other endocrine changes and exacerbation in the rate of neuron death during normal aging (2, 3). Although the use of the optical fractionator technique questioned the data of cell death and neuron loss in the hippocampus during normal aging (4), disruption of synaptic plasticity, atrophy of dendritic processes, postnatal neurogenesis (especially in the dentate gyrus), and other fine changes clearly occur in the hippocampal formation of socially stressed animals.

One major question is whether GCs during fetal development play a role in programming the events that will be occurring later in life, especially in the perception and integration of a stressful situation. It has indeed been proposed that exposing the fetal brain to exogenous corticosteroids can produce irreversible effects on specific population of neurons and neuroendocrine functions, especially the HPA axis (5). In the present issue of Endocrinology, Moritz et al. (6) have revised this question in exposing ovine fetuses to a low dose of dexamethasone from d 25 to 45 gestation. They performed a series of analyses from the tissues of fetuses killed at 45 or 130 d or lambs at 2 months and found that twin fetuses had a retard in growth and altered gene expression in the hippocampus but no change in the adrenal steroidogenic gene expression. Of great interest, however, is the lack of persistent, long-term effects of prolonged treatment with dexamethasone in normal ovine fetuses. All the parameters analyzed in this study were essentially normal by 2 months after birth. Although subtle changes may take place, and these remain quite difficult to identify, the study by Moritz et al. (6) challenged the concept that fetal exposure to GCs may cause permanent changes in the central nervous and neuroendocrine systems.

The animal model, the time at which the fetal brain is exposed to steroids, and the methods selected to investigate permanent changes in the brain are obvious critical elements that most likely explain discrepancies between studies. By using chronically catheterized sheep fetuses close to term, as well as neonatal and adult sheep, Forhead et al. (7) looked at the effects of GCs on plasma leptin secretion. They found that plasma leptin increases in association with the postpartum cortisol surge, which was abolished by fetal adrenalectomy and restored by infusion of the steroid or dexamethasone. Once again, though, the effects were not permanent, but were transient; by the fifth day of infusion, plasma leptin was restored to baseline range.

These two papers published in this issue of Endocrinology provided evidence that fetal exposure to GCs may not be associated with permanent changes in the brain and with endocrine functions. More studies are clearly needed to firmly establish the direct link between fetal stress environment, brain plasticity, and permanent consequences. One must therefore be careful before reaching the conclusion that exposing fetuses to GCs will, no doubt, be associated with potential problems during postpartum life. The causes involved in the increased susceptibility to specific stressful situations (such as social stress) and uncontrolled activity of the HPA axis are numerous, but whether fetal exposure to the hormone is involved in this phenomenon still remains an open question. Are then GCs good or bad for the cerebral tissue? As mentioned at the beginning of this editorial, increased activity of the HPA axis is believed to be intimately associated with brain disorders and neurodegeneration. However, the direct evidence and exact mechanisms explaining these effects are still lacking at this point. GCs are the most powerful endogenous immunosuppressors, especially for the innate immune response and the subsequent inflammatory reaction (8). Such a system also exists in the central nervous system (9), and there is accumulating evidence that, once chronically activated, it may lead to neurodegenerative disorders (10, 11). By inhibiting the cerebral innate immune system, GCs would therefore be neuroprotective and prevent overproduction of inflammatory molecules that can be harmful for the neuronal elements. On the other hand, they may have opposite effects in changing the immune status of the organism and may make neurons more susceptible to insults. The time and duration at which the activity of the HPA axis is triggered by stressful stimuli are therefore likely to be the critical factors determining the good or bad roles of GCs in brain development, plasticity, and homeostasis.

	Footnotes

 
Abbreviations: GC, Glucocorticoid; HPA, hypothalamic-pituitary-adrenal.

Received January 15, 2002.

Accepted for publication January 29, 2002.

	References

Top Introduction References

 

1. Sapolsky RM 1983 Individual differences in cortisol secretory patterns in the wild baboon: role of negative feedback sensitivity. Endocrinology 113:2263–2267[Abstract]
2. Sapolsky RM 1986 Stress-induced elevation of testosterone concentration in high ranking baboons: role of catecholamines. Endocrinology 118:1630–1635[Abstract]
3. Uno H, Tarara R, Else JG, Suleman MA, Sapolsky RM 1989 Hippocampal damage associated with prolonged and fatal stress in primates. J Neurosci 9:1705–1711[Abstract]
4. Wickelgren I 1996 Is hippocampal cell death a myth? Science 271:1229–1230[CrossRef][Medline]
5. Matthews SG 2000 Antenatal glucocorticoids and programming of the developing CNS. Pediatr Res 47:291–300[Medline]
6. Moritz K, Butkus A, Hantzis V, Peers A, Wintour EM, Dodic M 2002 Prolonged low-dose dexamethasone, in early gestation, has no long-term deleterious effects on normal ovine fetuses. Endocrinology 143:1159–1165[Abstract/Free Full Text]
7. Forhead AJ, Thomas L, Crabtree J, Hoggard N, Gardner DS, Giussani DA, Fowden AL 2002 Plasma leptin concentration in fetal sheep during late gestation: ontogeny and effects of glucocorticoids. Endocrinology 143:1166–1173[Abstract/Free Full Text]
8. Auphan N, DiDonato JA, Rosette C, Helmberg A, Karin M 1995 Immunosuppression by glucocorticoids: inhibition of NF-B activity through induction of IB synthesis. Science 270:286–290[Abstract/Free Full Text]
9. Laflamme N, Rivest S 2001 Toll-like receptor 4: the missing link of the cerebral innate immune response triggered by circulating gram-negative bacterial cell wall components. FASEB J 15:155–163[Abstract/Free Full Text]
10. Owens T, Wekerle H, Antel J 2001 Genetic models for CNS inflammation. Nat Med 7:161–166[CrossRef][Medline]
11. Nguyen MD, Julien JP, Rivest S, Innate immunity: the missing link in neuroprotection and neurodegeneration? Nat Rev Neurosci, in press

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