Behavioural Brain Research 320 (2017) 210–218 Contents lists available at ScienceDirect Behavioural Brain Research journal homepage: www.elsevier.com/locate/bbr Increased anxiety but normal fear and safety learning in orexin-deficient mice Radwa Khalil a,1 , Markus Fendt a,b,∗ a Institute for Pharmacology and Toxicology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany b Center of Behavioral Brain Sciences, Otto-von-Guericke University Magdeburg, Magdeburg, Germany h i g h l i g h t s • Orexin knockout mice were used to investigated orexin’s role in fear and anxiety. • Orexin deficiency did not change locomotor behavior. • Orexin deficiency did not affect fear and safety learning. • Orexin deficiency did not affect the locomotor response to foot shocks. • Orexin deficiency increased anxiety in open field, light-dark box and predator avoidance. g r a p h i c a l a b s t r a c t a r t i c l e i n f o Article history: Received 19 October 2016 Received in revised form 6 December 2016 Accepted 7 December 2016 Available online 10 December 2016 Keywords: Hypocretin Light-dark box Locomotor activity Open field Predator odor avoidance Unconditioned fear a b s t r a c t The loss of orexin neurons in humans leads to the disease narcolepsy, characterized by daytime sleepiness and cataplexy. Recent data suggest that orexin is also involved in emotional processing. The goal of the present study was to evaluate fear and safety learning as well as unconditioned fear (anxiety) in orexin-deficient animals. Orexin-deficient mice are an established animal model used to investigate the neuropathology and potential treatments for narcolepsy. Here, we present novel data showing that orexin-deficient mice express increased anxiety in the open field, light-dark box test and carnivore odor- induced avoidance, but are normal in fear and safety learning. These findings suggest an important role of orexin in brain areas involved in anxiety. © 2016 Published by Elsevier B.V. 1. Introduction The neuropeptide orexin (also called hypocretin) plays an important role in the regulation of sleep/wakefulness, feed- ∗ Corresponding author at: Institute for Pharmacology and Toxicology, Leipziger Straße 44, D-39120 Magdeburg, Germany. E-mail address: markus.fendt@med.ovgu.de (M. Fendt). 1 Present address: Center for Molecular and Behavioral Neuroscience, Behavioral and Neural Science Graduate Program, Rutgers University, Newark, USA. ing behavior, reward processes, and energy homeostasis [1–4]. Although orexin-containing neurons are only located in the lateral hypothalamus, they have projections throughout the whole brain [5]. In the termination areas, released orexin activates two different postsynaptic receptor subtypes, orexin-1 receptor and orexin-2 receptor [6]. Activation of these receptors promotes waking and is essential for a normal sleep/wake cycle [7]. Disturbances of the orexin system lead to characteristic changes in humans and animals. In humans, the loss of orexin neurons results in narcolepsy [8]. Narcolepsy is characterized by excessive http://dx.doi.org/10.1016/j.bbr.2016.12.007 0166-4328/© 2016 Published by Elsevier B.V.