Corticotropin-releasing hormone, a major neuromodulator of the neuroendocrine stress response, is expressed in the immature hippocampus, where it enhances glutamate receptor-mediated excitation of principal cells. Since the peptide influences hippocampal synaptic efficacy, its secretion from peptidergic interneuronal terminals may augment hippocampal-mediated functions such as learning and memory. However, whereas information regarding the regulation of corticotropin-releasing hormone's abundance in CNS regions involved with the neuroendocrine responses to stress has been forthcoming, the mechanisms regulating the peptide's levels in the hippocampus have not yet been determined. Here we tested the hypothesis that, in the immature rat hippocampus, neuronal stimulation, rather than neuroendocrine challenge, influences the peptide's expression. Messenger RNA levels of corticotropin-releasing hormone in hippocampal CA1, CA3 and the dentate gyrus, as well as in the hypothalamic paraventricular nucleus, were determined after cold, a physiological challenge that activates the hypothalamic pituitary adrenal system in immature rats, and after activation of hippocampal neurons by hyperthermia. These studies demonstrated that, while cold challenge enhanced corticotropin-releasing hormone messenger RNA levels in the hypothalamus, hippocampal expression of this neuropeptide was unchanged. Secondly, hyperthermia stimulated expression of hippocampal immediate-early genes, as well as of corticotropin-releasing hormone. Finally, the mechanism of hippocampal corticotropin-releasing hormone induction required neuronal stimulation and was abolished by barbiturate administration.Taken together, these results indicate that neuronal stimulation may regulate hippocampal corticotropin-releasing hormone expression in the immature rat, whereas the peptide's expression in the hypothalamus is influenced by neuroendocrine challenges. Keywordshippocampus; corticotropin-releasing factor; c-fos; rat; hypothalamus; stress Corticotropin-releasing hormone (CRH) is a peptide with both neuroendocrine and neurotransmitter properties. 57 The neuroendocrine effects of CRH, the key mediator of the stress response, originate from clusters of peptidergic cells in the hypothalamic paraventricular nucleus (PVN). 24,34 CRH also functions as a neuromodulator in a number of NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2011 July 5. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript limbic and autonomic brain circuits. 21,22,24,43 CRH-producing neurons are widely but specifically distributed in the brain, 49 including a substantial CRH-expressing neuronal population located in the central nucleus of the amygdala (ACe), 22,53 a region considered as a major source for extra-endocrine CRH-mediated neurotransmission. 24 Abundant target neurons for CRH, expressing cognate receptors, have been demonstrated in the hippocampus. 2,13,15 In addition, physiological effects of CRH on hippocampal neuron...