Corticotropin-Releasing Hormone and Arginine Vasopressin Gene Transcription in the Hypothalamic Paraventricular Nucleus of Unstressed Rats: Daily Rhythms and Their Interactions with Corticosterone

Abstract

To drive the daily ACTH secretory rhythm from anterior pituitary corticotropes signals from the circadian clock schedule CRH and, to lesser extent, arginine vasopressin (AVP) release from neuroendocrine terminals. In turn, releasable pools of CRH and AVP in neuroendocrine terminals are sustained by synthetic mechanisms in the medial parvicellular paraventricular nucleus, a critical component of which involves transcribing primary (heteronuclear (hn)) RNA transcripts from their cognate genes. To determine the fundamental daily patterns of ACTH secretagogue gene transcription in unstressed rats, we measured CRH and AVP hnRNA levels at 1- to 4-h intervals throughout the day using in situ hybridization. Crh gene transcription is readily detectable throughout the day, and shows a pronounced rhythm that is temporally correlated with CRH mRNA levels, but is uncoupled from ACTH release. However, avp gene transcription is barely detectable and shows no discernable rhythm. We then performed similar experiments in adrenalectomized rats with or without corticosterone replacement. Corticosterone-dependent mechanisms regulate CRH hnRNA levels at the nadir and peak as well as the onset of nocturnal crh gene transcription. A prominent rhythm of avp hnRNA seen in adrenalectomized animals was dampened by corticosterone. This study shows, first, CRH synthesis in intact animals is maintained by a nocturnal episode of crh gene transcription, parameters of which are modulated by corticosterone-dependent mechanisms; second, circulating corticosterone is sufficient to completely inhibit a daily rhythm of avp gene transcription present in adrenalectomized rats; third, the neural systems that activate crh gene transcription can be uncoupled from those driving ACTH release.