A quantitative study of the pulsatile parameters of CRH-41 secretion in unanesthetized free-moving rats

“CRH is the main neuropeptide regulating basal ACTH secretion in the rat, and, because episodic release of CRH has also been shown in the rat (Ixart et al., 1991, 1993, 1994) (Figure 1), the existence of a hypothalamic CRH pulse generator was not questioned.”

“rapid fluctuations in CRH levels in the median eminence of freely behaving rats (83,85), and pulsatile patterns of CRH and AVP in the hypophysial-portal circulation of conscious sheeps”

“, this has led to speculation that oscillations in the pituitary-adrenal system are a consequence of a neuronal “pulse generator” within the hypothalamus. However, there is a lack of concordance between pulsatile patterns of hypothalamic factors and the ultradian ACTH and glucocorticoid oscillation. In the rat, for in…”

“that CRH follows an irregular pulsatile mode of secretion, with a frequency of approximately 3 pulses/h (50).”

“The pulse controller is believed to be located in the pituitary given that CRH pulse frequency is much greater (relative to ACTH and cortisol) [55], and because the timing and intensity of a glucocorticoid stress response is influenced by the timing of the stressor (i.”

“Indeed, Mershon et al. (1992) did detect an episodic release of CRH from macaque hypothalamic explants while rapid changes in CRH levels were detected both from the median eminence of rat (Ixart et al., 1991) and portal blood from the sheep (Caraty et al., 1998).”

“…is a mismatch between the frequency of CRH pulses, and the frequency of ACTH and corticosterone oscillations, as in the rat CRH pulse frequency is higher (~3 pulses/h) (Ixart et al., 1991) than the near-hourly oscillation in ACTH (Carnes et al., 1988a) and corticosterone (Windle et al., 1998b).”

“Corticotrophinreleasing hormone (52, 53), adrenocorticotropic hormone (54, 55), as well as the glucocorticoids (CORT) (56, 57) are all rhythmically secreted into the circulation with pulse frequencies typically in the hourly range in rat (56–58) and man (59–61).”

“Although there is some evidence for pulsatility of CRH (1, 2), our recent work suggests that ACTH and CORT pulsatility is predominantly generated by a subhypothalamic oscillator within the pituitary–adrenal system (3, 4).”

“Further supporting this idea is the observation that in the rat there is a mismatch between the frequency of CRH pulses (w3 pulses/h) (Ixart et al. 1991) and the near-hourly frequency of ACTH and CORT oscillations (Carnes et al.”

“Despite the fact that pulsatile release of CRH has been observed in rats and macaques (19, 33), glucocorticoids are known to have a slow effect on CRH (29), and sheep, whose hypothalamus and pituitary were surgically disconnected, maintained pulsatile glucocorticoid release (11).”

“5- to 3-h URs in CRH neuron excitation and CRH release have been observed in rodents, rams, and macaque hypothalamus but not extensively characterized (Caraty et al., 1988; Ixart et al., 1991; Mershon et al., 1992; Ono et al., 2015; Vrang et al., 1995).”

“Moreover, ultradian rhythms in in vitro cell cultures have been reported for glucocorticoid release (17, 18), single-cell firing (19), andprotein synthesis (20) suggesting that these rhythms are intrinsically driven at the cellular level, but mechanisms driving them remain unknown.”

“…these two species have provided information on the pituitary portal characteristics of endogenous pulses of CRH in rat (Plotsky & Vale, 1984; Plotsky et al., 1985; Barbanel et al., 1990; Ixart et al., 1991) and VP and CRH in sheep (Caraty et al., 1988; Caraty et al., 1990; Battaglia et al., 1998).”

“This is not to say that TRH and CRH are not released into 20 the portal circulation in pulses, where measurement has been made release is pulsatile (30-33) 21 but this may be more related to maintaining responsiveness of target cells rather than pulse 22 generation per se (34).”

“1992) and for rapid changes in CRH in the median eminence of rats (Ixart et al. 1991) and portal blood of sheep (Caraty et al.”

“While ultradian rhythms in CRH secretion have been observed previously 17-21 , the reported period of these rhythms is variable ranging from minutes to hours.”

“Characterizing the dynamics of CRH release at high temporal resolution has been challenging due to its low amount 2,9,10 and the lack of the juxtaposed postsynaptic targets at the ME for intrinsic signal recordings.”