This project examines the expression of the neuropeptide Corticotropin-Releasing Hormone (CRH) at the mRNA and peptide levels in the developing rat brain, utilizing techniques from the realms of molecular biology, quantitative neuroanatomy and behavioral neurophysiology. CRH was first found in the hypothalamus, where its effect on ACTH and glucocorticosteroid secretion in response to stressors is now well established. The role of CRH located in specific extra- hypothalamic brain regions is less well defined. Moreover, little is known about the CRH neuronal system in perinatal and immature animals. While during late fetal life steroid levels rise with noxious stimuli, there is a hiatus in their ability to generate a stress response in the first 2 weeks of life. A transient decrease in hypothalamic CRH content during the first postnatal days has been reported. We will study CRH-mRNA expression in selected brain regions of the developing rat, using in situ hybridization; peptide content of the same discrete brain regions will be assessed by radioimmunoassay of tissue specimen microdissected ('punched') from brain slices. We will manipulate peptide and/or mRNA content by altering hormonal feedback, to gain further insight into the molecular level of control mechanisms. The significance of the perinatal perturbations of the CRH neuronal system to seizure susceptibility will be explored. CRH has been shown to be a convulsant, causing epileptiform discharges and neuronal excitation in the amygdala, hippocampus and locus ceruleus in rats. Furthermore, a seizure disorder unique to infants responds to manipulations of the CRH system, while anticonvulsants are less effective. We will use the maximal electroshock seizure model and chemically induced seizures to study whether the CRH neuronal system and its manipulation, or exogenous CRH administration alter the suspectibility of the immature brain to seizures.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Clinical Investigator Award (CIA) (K08)
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Neurological Disorders Program Project Review B Committee (NSPB)
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Children's Hospital of Los Angeles
Los Angeles
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Chang, D; Yi, S J; Baram, T Z (1996) Developmental profile of corticotropin releasing hormone messenger RNA in the rat inferior olive. Int J Dev Neurosci 14:69-76
Baram, T Z; Schultz, L (1995) ACTH does not control neonatal seizures induced by administration of exogenous corticotropin-releasing hormone. Epilepsia 36:174-8
Chang, D; Baram, T Z (1994) Status epilepticus results in reversible neuronal injury in infant rat hippocampus: novel use of a marker. Brain Res Dev Brain Res 77:133-6
Yi, S J; Baram, T Z (1994) Corticotropin-releasing hormone mediates the response to cold stress in the neonatal rat without compensatory enhancement of the peptide's gene expression. Endocrinology 135:2364-8
Yi, S J; Masters, J N; Baram, T Z (1994) Glucocorticoid receptor mRNA ontogeny in the fetal and postnatal rat forebrain. Mol Cell Neurosci 5:385-93
Yi, S J; Baram, T Z (1993) Methods for implanting steroid-containing cannulae into the paraventricular nucleus of neonatal rats. J Pharmacol Toxicol Methods 30:97-102
Baram, T Z (1993) Pathophysiology of massive infantile spasms: perspective on the putative role of the brain adrenal axis. Ann Neurol 33:231-6
Baram, T Z; Hirsch, E; Schultz, L (1993) Short-interval amygdala kindling in neonatal rats. Brain Res Dev Brain Res 73:79-83
Yi, S J; Masters, J N; Baram, T Z (1993) Effects of a specific glucocorticoid receptor antagonist on corticotropin releasing hormone gene expression in the paraventricular nucleus of the neonatal rat. Brain Res Dev Brain Res 73:253-9
Baram, T Z; Hirsch, E; Snead 3rd, O C et al. (1992) Corticotropin-releasing hormone-induced seizures in infant rats originate in the amygdala. Ann Neurol 31:488-94

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