Increase of urocortin-like immunoreactivity in the rat supraoptic nucleus after dehydration but not food deprivation

doi:10.1016/S0304-3940(97)00419-9

Neuroscience Letters

Volume 229, Issue 1, 20 June 1997, Pages 65-68

https://doi.org/10.1016/S0304-3940(97)00419-9 Get rights and content

Abstract

The effects of dehydration and food deprivation on urocortin-like immunoreactivity (Ucn-IR) in the rat supraoptic nucleus (SON) and the paraventricular nucleus (PVN) were examined by immunohistochemistry. Water deprivation for 48 h caused a significant increase in the number of Ucn-IR neurons in the SON, compared with control. Ucn-IR fibers and varicosities in the SON and the internal zone of the median eminence (ME) were increased, but a few and faint Ucn-IR neurons and fibers were observed in the PVN. On the other hand, food deprivation for 48 h caused a significant decrease in the number of Ucn-IR neurons in the SON, compared with control. Ucn-IR fibers and varicosities in the SON and the ME were fewer than those in controls. Ucn-IR neurons and fibers in the PVN were not detected after food deprivation. These results suggest that Ucn in the SON may be involved in the central regulation of water balance and nutrient homeostasis.

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Acknowledgements

The technical assistance of Miss Rieko Nishi is greatly appreciated. This study was supported by Grants-in-Aid for Scientific Research, no. 07507004, International Scientific Research, no. 07044296 for H.Y. from the Ministry of Education, Science, Sports and Culture, Japan and Special Grant by the Ministry of Labor for `Occupational Health Studies'.

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Increased oxytocin-monomeric red fluorescent protein 1 fluorescent intensity with urocortin-like immunoreactivity in the hypothalamo-neurohypophysial system of aged transgenic rats
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The oxytocin-mRFP1 transgenic rats showed significant increases in mRFP1 fluorescent intensity in the PP, SON and PVN after chronic salt loading (Katoh et al., 2011) and both acute and chronic nociceptive stimuli (Matsuura et al., 2015; Matsuura et al., 2016). Second, we examined whether urocortin-like immunoreactive (urocortin-LI) cells co-exist with mRFP1 in the SON and PVN of aged oxytocin-mRFP1 transgenic rats because we reported previously that the numbers of urocortin-LI cells in the SON and the PVN were significantly increased in aged rats (Hara et al., 2000) as well as salt-loaded and dehydrated rats (Hara et al., 1997a; Hara et al., 1997b). Urocortin was discovered as a member of the corticotropin-releasing factor (CRF) family (Vaughan et al., 1995).
To visualize oxytocin in the hypothalamo-neurohypophysial system, we generated a transgenic rat that expresses the oxytocin-monomeric red fluorescent protein 1 (mRFP1) fusion gene. In the present study, we examined the age-related changes of oxytocin-mRFP1 fluorescent intensity in the posterior pituitary (PP), the supraoptic nucleus (SON) and the paraventricular nucleus (PVN) of transgenic rats. The mRFP1 fluorescent intensities were significantly increased in the PP, the SON and the PVN of 12-, 18- and 24-month-old transgenic rats in comparison with 3-month-old transgenic rats. Immunohistochemical staining for urocortin, which belongs to the family of corticotropin-releasing factor family, revealed that the numbers of urocortin-like immunoreactive (LI) cells in the SON and the PVN were significantly increased in 12-, 18- and 24-month-old transgenic rats in comparison with 3-month-old transgenic rats. Almost all of urocortin-LI cells co-exist mRFP1-expressing cells in the SON and the PVN of aged transgenic rats. These results suggest that oxytocin content of the hypothalamo-neurohypophysial system may be modulated by age-related regulation. The physiological role of the co-existence of oxytocin and urocortin in the SON and PVN of aged rats remains unclear.
Urocortins: Actions in health and heart failure
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In the brain, Ucn1 is expressed most prominently in the Edinger–Westphal nucleus and lateral superior olive, but is also present in the hypothalamus, lateral superior olive cerebellum, substantia nigra pars compacta and ventral tegmental area, hippocampus, basal ganglia, medial septum and paraventricular nucleus [12,13]. Ucn1 immunoreactivity in the rat is increased in the supraoptic nucleus by dehydration and salt loading - suggesting an involvement in the regulation of water and salt homeostasis [14,15], and is colocalized with dopamine in the basal ganglia and hypothalamus. Ucn1 has also been verified in multiple peripheral tissues including the heart, adrenal gland (especially the medulla), kidney, lung, spleen, thymus, skeletal muscles, placenta, skin, immune system and the gastrointestinal tract [16].
The urocortins (Ucns), endogenous peptides belonging to the corticotropin-releasing factor (CRF) family, are increasingly recognized as having diverse and important multi-system functions, especially within the cardiovascular system. The biological actions of the three Ucns (Ucn1, Ucn2, Ucn3) are mediated via G-protein-coupled CRF receptors, with both peptides and receptors widely distributed throughout tissues and organs contributing to pressure/volume homeostasis including the heart, vasculature, kidneys and adrenals. The Ucns activate a variety of signaling cascades in cardiomyocytes, vascular smooth muscle cells and endothelial cells including, but not limited to, adenyl cyclase/cAMP and several kinase pathways, with downstream effects comprising vasodilation, augmented cardiac contractility, and protection against hypoxic injury. Increasing evidence suggests the Ucns may be clinically significant molecules in the pathogenesis, treatment and/or management of several conditions, with some of the most compelling data demonstrating a therapeutic potential for the peptides in the setting of heart failure. Circulating levels of the Ucns are elevated in this setting, and antagonism of the endogenous peptides exacerbates manifestations of the syndrome in animal models. All three Ucns exert salutary hemodynamic, neurohormonal and renal effects in experimental heart failure and recent clinical trials have demonstrated hemodynamic benefits of Ucn2 administration.
Physiology, pharmacology, and therapeutic relevance of urocortins in mammals: Ancient CRF paralogs
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Similarly, unlike CRF antisera, peripheral administration of specific Ucn 1 antisera does not modify basal, stress-induced or adrenalectomy-induced ACTH levels [179,278]. Finally, unlike the distribution of CRF, Ucn 1-immunoreactive fibers are scarce in the PVN and the external layer of the median eminence under basal conditions [100,101,158]. It remains possible, however, that the type 2 Ucns modulate HPA-axis activity at the hypothalamic level in paracrine or autocrine fashion.
Urocortins, three paralogs of the stress-related peptide corticotropin-releasing factor (CRF) found in bony fish, amphibians, birds, and mammals, have unique phylogenies, pharmacologies, and tissue distributions. As a result and despite a structural family resemblance, the natural functions of urocortins and CRF in mammalian homeostatic responses differ substantially. Endogenous urocortins are neither simply counterpoints nor mimics of endogenous CRF action. In their own right, urocortins may be clinically relevant molecules in the pathogenesis or management of many conditions, including congestive heart failure, hypertension, gastrointestinal and inflammatory disorders (irritable bowel syndrome, active gastritis, gastroparesis, and rheumatoid arthritis), atopic/allergic disorders (dermatitis, urticaria, and asthma), pregnancy and parturition (preeclampsia, spontaneous abortion, onset, and maintenance of effective labor), major depression and obesity. Safety trials for intravenous urocortin treatment have already begun for the treatment of congestive heart failure. Further understanding the unique functions of urocortin 1, urocortin 2, and urocortin 3 action may uncover other therapeutic opportunities.
Effect of starvation on Fos and neuropeptide immunoreactivities in the brain and pituitary gland of Xenopus laevis
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In mammals complex interactions between various brain structures and neuropeptides such as corticotropin-releasing factor (CRF) and urocortin 1 (Ucn1) underlay the control of feeding by the brain. Recently, in the amphibian Xenopus laevis, CRF- and Ucn1-immunoreactivities were shown in the hypothalamic magnocellular nucleus (Mg) and evidence was obtained for their involvement in food intake. To gain a better understanding of the brain structures controlling feeding in X. laevis, the effects of 16 weeks starvation on neurones immunoreactive (ir) to Fos and neuropeptides in various brain structures were quantified. In the Mg, compared to controls, starved animals showed fewer neurones immunopositive for Fos (−55.9%), Ucn1 (−44.0%), cocaine and amphetamine-regulated transcript (CART) (−94.3%) and metenkephalin (ENK) (−65.0%), whereas CRF-ir neurones were 2.1 times more numerous. These differences were mainly apparent in the ventral part of the Mg, followed by the medial and dorsal part of the nucleus. In the neural lobe of the pituitary gland a 22.5% lower optical density of CART-ir was observed. In the four other brain structures investigated, starvation had different effects. The dorsomedial part of the suprachiasmatic nucleus showed 5.9 times more NPY-ir cells and in the ventromedial thalamic area a lower number of NPY-ir cells (−33.6%) was found, whereas the Edinger–Westphal nucleus contained fewer CART-ir cells (−42.2%); no effect of starvation was seen in the ventral hypothalamic nucleus. Our results support the hypothesis that in X. laevis, the Mg plays a pivotal role in feeding-related processes and, moreover, that starvation also has neuropeptide- and brain structure-specific effects in other parts of the brain and in the pituitary gland, suggesting particular roles of these structures and their neuropeptides in physiological adaptation to starvation.
Chapter 2.4 The roles of urocortins 1, 2, and 3 in the brain
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The prominent synthesis of urocortin 2 in magno-cellular SON and PVN neurons also is consistent with a possible osmoregulatory role of urocortin 2. Interestingly, salt loading, dehydration, and hypophysectomy increased urocortin in magno-cellular SON and PVN neurons (Hara et al., 1997a,b, 2000), whereas food deprivation decreased urocortin-LI in the SON (Hara et al., 1997b). The antibody’s specificity for urocortin 1 as opposed to urocortin 2 is unknown, but specific increases in magnocellular SON urocortin 1 mRNA expression also have been observed following salt loading (Imaki et al., 2001).
The neuropeptides urocortin 1, urocortin 2, and urocortin 3 share a family resemblance. Each shows some sequence identity with the stress-related neuropeptide corticotropin-releasing factor (CRF), high affinity for the CRF₂ receptor, predominantly subcortical distributions and anorectic properties when administered centrally. In substantive ways, however, the peptides differ from one another. Urocortin 1 differs pharmacologically, as it also exhibits affinity for the CRF₁ receptor and CRF-binding protein. Brain distributions also differ. Urocortin 1 shows predominant correspondence with hindbrain CRF₁ and CRF₂ receptors and a much more limited correspondence with forebrain CRF receptors. In contrast, urocortin 3 shows almost exclusive correspondence with forebrain CRF₂ receptors unique from those innervated by urocortin 1 projections. Urocortin 2 is synthesized in yet another set of hypothalamic and brainstem nuclei, distinct from those that prominently express urocortin 1 and urocortin 3. Brain urocortins may be involved in the regulation of diverse functions, including: osmotic balance; activity of the somatotropic and pituitary-gonadal neuroendocrine axes; modulation of arousal, attention, anxiety-like behavior, and learning and memory; control of autonomic functions, including cardiovascular and gastrointestinal responses; and the regulation of energy balance, both in terms of food intake and energy expenditure. Commonly described as being stress mediators for their structural resemblance to CRF, available evidence suggests that the type 2 urocortins, urocortin 2 and urocortin 3, do not share the activating and anxiogenic-like properties of stress- or CRF-induced CRF₁ receptor activation. The endogenous role of each urocortin in the autonomic/energy balance components of stress-related responses remains to be determined.

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Increase of urocortin-like immunoreactivity in the rat supraoptic nucleus after dehydration but not food deprivation

Abstract

Section snippets

Acknowledgements

Regulation of the hypothalamic-pituitary-adrenal axis during water deprivation

Endocrinology

Altered expression of hypothalamic neuropeptide mRNAs in food-restricted and food-deprived rats

Neuroendocrinology

Oxytocinergic neurons in rat hypothalamus

Neuroendocrinology

Cloning and characterization of human urocortin

Endocrinology