Role of orexin type-2 receptor variants in energy homeostasis and reward processing

The hypothalamus is a major regulatory center for homeostasis, wakefulness and reward behavior. Orein (hypocretin) is a neuropeptide mainly expressed in the lateral hypothalamus an area knwon as feeding center (Tsujino and Sakurai, 2013). Orexin type-1 receptors (OX1R) and type-2 receptor (OX2R) belong to the G-protein coupled receptor family and act via Ca2+ signaling. In addition to its putative effect on feeding behavior, orexins regulate energy homeostasis, stress or fear related behavior, sleep and the reward system.

The dopaminergic (DA) system, located in the midbrain, is a well-known center for reward and motivational behavior. Orexin neurons are connected to the ventral tegmental area (VTA) reward system (Fadel and Deutch, 2002). Accordingly, orexins directly activate and regulate DA neurons of the VTA (Korotkova et al., 2003; Vittoz et al., 2008; Espana et al., 2011). The blockage of OX1R in VTA dopaminergic neurons shows a decrease in addiction effects of morphine, carbachol or sucrose in conditioned place preference (CPP) test (Harris et al., 2005; Cason and Aston-Jones, 2014; Zarepour et al., 2014). Considering the extent of research on the roles of orexin receptor subtypes for motivational components of arousal and feeding hoever and the fact that both receptor subtypes are expressed in DA neurons of VTA (Korotkova et al., 2003), the role of OX2R subtypes in the function of food and reward behavior is not well characterized thus far (Baimel et al., 2015).

By generating mice specifically and acutely expressing the human OX2Rv1 and the newly identified dominant-negative OX2Rv2 in DA VTA neurons, we will analyze the impact of OX2R signaling on energy homeostasis and reward-related feeding behavior. We hypothesize that overexpression of the OX2Rv1 will increase food reward seeking behavior but also energy expenditure and that overexpression of the OX2Rv2 shows an opposite effect.