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On the role of urocortin 1 in the non-preganglionic Edinger–Westphal nucleus in stress adaptation

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Abstract

The discovery of novel members of the CRF neuropeptide family, urocortin 1 (Ucn1), urocortin 2 and 3 has provided important insights into stress adaptation pathways, and predicted that stress adaptation involves more systems than the HPA-axis alone. This mini-review aims to summarize our recent data and research by others indicating that an important role is played by Ucn1 in the non-preganglionic Edinger–Westphal nucleus (npEW). These results point to an intriguing possibility that CRF/Ucn1 neuronal circuits comprise two separate, but functionally interrelated entities, which are coordinately regulated by acute stressors, but are inversely coupled during chronic stress. Such collaboration between the two systems would implicate a very important role of Ucn1 in adaptation to stress, and, as a consequence, in stress-related disorders like anxiety, major depression and use of drugs of abuse.

Introduction

In the last two decades several pieces of the jig-saw puzzle of the regulation of the stress response have found their place. Evidence suggests that besides corticotropin-releasing factor (CRF), urocortins are important players in this process too. These neuropeptides have been found within but also outside the central nervous system, and studies on chronically stressed and transgenic animal models have revealed their multiple roles in central and peripheral adaptation processes. First, this mini-review focuses on the diversity of roles of urocortin 1 (Ucn1) in the mammalian central nervous system, and then possible clinical implications of the actions of Ucn1 will be highlighted.

Section snippets

Ucn1 in the non-preganglionic Edinger–Westphal nucleus

In the mammalian brain, the most abundant expression of urocortin 1 (Ucn1) has been reported in neurons located in the midbrain in the Edinger–Westphal nucleus (EW; Kozicz et al., 1998, Bittencourt et al., 1999, Iino et al., 1999, Weitemier et al., 2005, Ryabinin et al., 2005). The EW is compact, cholinergic, preganglionic parasympathetic brain structure primarily involved in oculomotor adaptation (Westphal, 1887, Burde et al., 1982). However, the structure and the function of the EW are more

Ucn1 and the CRF neuropeptide super family

The CRF neuropeptide superfamily consists of four distinct paralogs found on separate chromosomes on vertebrate brain (Fig. 2). Soon after the isolation of CRF (Vale et al., 1981), the second CRF-like lineage was defined by the characterization of urotensin-I (Ichiwara et al., 1982) and sauvagine (Montecucchi et al., 1979). In 1995 the mammalian ortholog of urotensin-I, Ucn1 has been introduced to the world (Vaughan et al., 1995). The expression of Ucn1 in the vertebrate brain is highly

Ucn1 and stress

As appears from the data reviewed above, besides CRF-neurons in the hypothalamic paraventricular nucleus (PVN), Ucn1 neurons in the npEW are involved in stress adaptation processes. The latter are recruited by various acute stressors (Weninger et al., 2000, Kozicz et al., 2001, Kozicz, 2003, Gaszner et al., 2004) and their Ucn1 mRNA expression is up-regulated by acute pain and restraint stress (Weninger et al., 2000, Kozicz et al., 2001).

In a recent study, Viau and Sawchenko (2002) have

Ucn1 and anxiety

Stress-induced increases in Ucn1 mRNA expression may represent an element of the organism’s strategy to cope with the stressor. This notion is supported by the evidence of an increased Ucn1 mRNA expression in the npEW in response to various acute stressors (Weninger et al., 2000, Kozicz et al., 2001, Gaszner et al., 2004), as well as of an increased anxiety-like behavior in Ucn1-deficient mice (Vetter et al., 2002).

On the basis of the substantial evidence for a role of a central Ucn1-system in

Ucn1 and gender-specific stress responses

Differences in neuroendocrine stress response pathways and sexually dimorphic brain regions involved in these responses are key factors responsible for the differences in stress sensitivity found between males and females (Kornstein, 1997, Young, 1998, Frackiewicz et al., 2000). Similarly, an increased susceptibility of females to depression has been well documented (Kornstein, 1997, Frackiewicz et al., 2000, Kudielka and Kirschbaum, 2005), but the underlying mechanisms have been insufficiently

Ucn1 and alcohol consumption

Early studies have shown that acute ethanol administration induces the expression of immediate early genes (IEG) in a pattern different from that seen after intraperitoneal injection of drugs of abuse (for review, see Ryabinin and Weitemier, 2006). In particular, the npEW exhibits a much stronger induction of IEG than the nucleus accumbens (Chang et al., 1995, Ryabinin et al., 1997). These results as well as the identification of Ucn1 in npEW initiated an intense research on the significance of

Does Ucn1 matter?

Considering data on the presence and actions of Ucn1 in the mammalian brain, no definite conclusions, as to the function(s) of Ucn1 can be drawn. On the other hand, there is ample circumstantial evidence to make the following preliminary assumptions:

  • 1.

    Phylogenetic conservation of Ucn1 across various vertebrate species points to the importance of this neuropeptide in promoting the organism’s survival, in particular with respect to adaptations to stress.

  • 2.

    Ucn1 and CRF neuronal systems represent two

Acknowledgments

This work was supported by Nederland Organization for Scientific Research, NWO (#864.05.008).

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