Ventromedial Hypothalamic Lesions Inhibit Corticosteroid Feedback Regulation of Basal ACTH during the Trough of the Circadian Rhythm

Abstract

We have determined the effects of bilateral electrolytic lesions of the ventromedial hypothalamus (VMH) on activity in the hypothalamo-pituitary-adrenal (HPA) system. Acutely, during the first 5 days, lesions of the anterior-medial VMH caused loss of the diurnal rhythms in food intake and plasma corticosterone (B) levels. Plasma B concentrations were elevated during the time of the normal trough of the basal diurnal rhythm in HPA axis activity and the diurnal rhythm in food intake was abolished, in agreement with the results of others. Consistent with hyperactivity in the HPA axis, lesioned rats had increased adrenal weight, decreased thymus and body weights and decreased plasma transcortin concentrations. To determine how lesions of the VMH provoke these increases in activity of the HPA system, the sensitivity of ACTH in adrenalectomized, lesioned rats to replacement with exogenous B was determined under basal conditions during the trough (morning – AM) and peak (evening -PM) of the diurnal rhythm in HPA axis activity. ACTH in lesioned rats in the AM was insensitive to feedback over the very low range of plasma B of 1-4 µg/dl, whereas sham-lesioned controls exhibited the normal, high sensitivity of ACTH to B at this time of day. There was no difference between the sensitivity of ACTH to this low range of B in the PM in VMH- and sham-lesioned rats. Two to 5 weeks after VMH lesions, as found by others, mean daily plasma B levels did not differ from sham-lesioned controls; however, plasma B during the AM was still mildly elevated in these rats. Inhibition of plasma B in the PM by dexamethasone was less effective in lesioned rats. Although HPA system responses to hypoglycemia, corticotropin-releasing factor and ACTH were normal, the lesioned rats exhibited obesity, hyperinsulinemia, hyperglycemia, hypertension and tachycardia, all signs consistent with mild hyperactivity of the PHA axis. Occupancy of type I, high-affinity corticosteroid receptors is known to control basal activity of the HPA system during the trough of the diurnal rhythm and to interact with glucocorticoid receptors to affect basal activity during the peak of the diurnal rhythm and during AM stress. We conclude that VMH lesions disrupt transmission of inhibitory signals, mediated by occupancy of type I corticosteroid receptors, that are initiated by a B feedback site.

Down-Regulation of Hypothalamic Corticotropin-Releasing Hormone Messenger Ribonucleic Acid (mRNA) Precedes Early-Life Experience-Induced Changes in Hippocampal Glucocorticoid Receptor mRNA**This work was supported by NIH Grants NS-28912 and NS-39307.

“…Thus, altered maternal sensory input (e.g. licking and grooming) was found to influence CRH-CRF 2 signaling in the hypothalamic ventromedial nucleus (25), a region shown previously to regulate stressrelated PVN function (48,49). Further evidence for modulation of CRH expression in structures comprising this sensory integration pathway (e.g.…”

A Diurnal Rhythm of Stimulatory Input to the Hypothalamo–Pituitary–Adrenal System as Revealed by Timed Intrahypothalamic Administration of the Vasopressin V1Antagonist

“…Contrary to the corticosterone data, ACTH levels showed no diurnal variation during the different Ringer's infusions ( p Ͼ 0.5), although variability during the CT10 experiment was considerably higher than at any other time of the day (16.8 Ϯ 2.8 vs 6.8 Ϯ 1.9, 7.6 Ϯ 2.3, 10.6 Ϯ 1.1, and 11.0 Ϯ 2.4 pg/ml). A number of previous studies have reported diurnal variations in plasma ACTH levels Carnes et al, 1989;Bagdy et al, 1991;Kwak et al, 1992;Ixart et al, 1993), but quite a few others failed to detect significant diurnal variations (Wilkinson et al, 1979;Akana et al, 1986;Carnes et al, 1986;Cascio et al, 1987;Kwak et al, 1993;Suemaru et al, 1995). Important factors that may contribute to the difficulty of finding a circadian ACTH rhythm are the low amplitude of the rhythm, the episodic secretion of ACTH, the sampling protocol used (Carnes et al, 1986;Turek and Van Cauter, 1988;Carnes et al, 1989), and the assay variability (e.g., CT times in different assays).…”

The developmental profile of the corticotropin releasing factor receptor (CRF2) in rat brain predicts distinct age-specific functions

“…The VMH is also a key structure in the complex coordination of diurnal variation in the hypothalamic-pituitary-adrenal (HPA) axis tone [41] VMH lesions disrupt a number of functions including the circadian rhythms of food intake, insulin secretion and adrenocortical function [13]. A key mechanism by which the VMH mediates signals inhibiting the HPA axis is via occupancy of mineralocorticoid receptors on VMH neurons [41].…”

“…A key mechanism by which the VMH mediates signals inhibiting the HPA axis is via occupancy of mineralocorticoid receptors on VMH neurons [41]. However, a role for activation of CRF 2 receptors in modulating some aspects of the diurnal cycle of the HPA axis tone cannot be excluded [12].…”