Does midbrain urocortin 1 matter? A 15-year journey from stress (mal)adaptation to energy metabolism

Abstract

This review summarizes some of the milestones of the research on the biological functions(s) of midbrain urocortin 1 (Ucn1) since its discovery 15 years ago. Detailed characterization of Ucn1 in the midbrain revealed its overall significance in food intake and regulation of homeostatic equilibrium and mood under stress. In addition, we have recently found a conspicuous alteration in midbrain Ucn1 levels in brains of depressed suicide victims. Furthermore, from the results from the genetically modified animals, a picture is emerging where corticotrophin-releasing factor promotes the initial reactions to stress, whereas Ucn1 seems to be crucial for management of the later adaptive phase. In the case of imbalance in action of these principle stress mediators, vulnerability to stress-related brain diseases is enhanced.

Appetite-suppressing effects and interactions of centrally administered corticotropin-releasing factor, urotensin I and serotonin in rainbow trout (Oncorhynchus mykiss)

“…The fact that CRF neurons in the paraventricular nucleus (PVN) (Liposits et al, 1987) and the nucleus preoptic (NPO) (Lillesaar et al, 2009) receive serotonergic inputs, and that direct application of 5-HT into the PVN decreases food intake (Leibowitz, 1986), suggest that serotonergic fibers may directly engage CRF in the regulation of food intake (Figure 6). In contrast, although there is some evidence that the UCN neurons of the Edinger–Westphal (EW) nucleus (the principle site of UCN synthesis) are involved in the regulation of food intake (Weitemier and Ryabinin, 2005; Kozicz et al, 2011), the role of UCN-secreting neurons as mediators of the anorexic actions of 5-HT are not known. Similarly, it is not known whether the UI neurons of the nucleus of the medial longitudinal fascicle (NMLF) (the primary site of UI synthesis; Alderman and Bernier, 2007; Bräutigam et al, 2010), or those of the NPO and the hypothalamus, contribute to the anorexic actions of 5-HT in fish.…”

“…In mammals, while CRF and UCN fibers can modulate the stress response and stress-related behaviors by regulating dorsal raphe serotonergic activity (Kozicz, 2010; Waselus et al, 2011), the anorexigenic effects of CRF-related peptides appear to be mediated through non-serotonergic targets such as the ventromedial hypothalamic nucleus, the basolateral amygdala, the lateral septum and the bed nucleus of the stria terminalis (Jochman et al, 2005; Kozicz et al, 2011; Ohata and Shibasaki, 2011). Similarly, while the effects of CRF-related peptides on locomotor activity, aggression and anxiety-like behaviors in salmonids may be at least partly mediated through the serotonergic system (Clements et al, 2003; Carpenter et al, 2007, 2009; Backström et al, 2011), the appetite-suppressing actions of i.c.v.…”

The Serotonin Transporter and Early Life Stress: Translational Perspectives

“…Urocortin 1 (Ucn1), belonging to the CRF family of proteins, complements the actions of CRF in the stress response regulation and is highly expressed in the Edinger-Westphal nucleus in the midbrain (Kozicz et al, 2011; Ryabinin et al, 2012) and interestingly these neurons do not habituate to chronic stress (Korosi et al, 2005). CRF and Ucn1 act through two G-protein coupled receptors, CRF R1 and R2.…”

MicroRNA-326 acts as a molecular switch in the regulation of midbrain urocortin 1 expression

“…This postulate was tested in a stress-sensitive model system, the midbrain urocortin 1 (Ucn1) neuronal system. Ucn1 neurons in the rostroventral midbrain, within the centrally projecting Edinger-Westphal nucleus (EWcp) are sensitive to stress: [17][18][19][20][21] mice lacking Ucn1 reveal anxiogenic behaviour, 22 while depressed suicide completers have upregulated midbrain Ucn1 mRNA expression compared with naturally deceased control individuals. 23 Here, we report that the brain-enriched miR-326 acts as an upstream regulator of Ucn1 during a neuronal stress response.…”