Abstract
Knockdown of orexin/hypocretin 2 receptor (Orx2) in the basolateral amygdala (BLA) affects anxious and depressive behavior. We use a new behavioral paradigm, the Stress Alternatives Model (SAM), designed to improve translational impact. The SAM induces social stress in adult male mice by aggression from larger mice, allowing for adaptive decision-making regarding escape. In this model, mice remain (Stay) in the oval SAM arena or escape from social aggression (Escape) via routes only large enough for the smaller mouse. We hypothesized intracerebroventricular (icv) stimulation of Orx2 receptors would be anxiolytic and antidepressive in SAM-related social behavior and the Social Interaction/Preference (SIP) test. Conversely, we predicted that icv antagonism of Orx2 receptors would promote anxious and depressive behavior in these same tests. Anxious behaviors such as freezing (both cued and conflict) and startle are exhibited more often in Stay compared with Escape phenotype mice. Time spent attentive to the escape route is more frequent in Escape mice. In Stay mice, stimulation of Orx2 receptors reduces fear conditioning, conflict freezing and startle, and promotes greater attention to the escape hole. This anxiolysis was accompanied by activation of a cluster of inhibitory neurons in the amygdala. A small percentage of those Stay mice also begin escaping; whereas Escape is reversed by the Orx2 antagonist. Escape mice were also Resilient, and Stay mice Susceptible to stress (SIP), with both conditions reversed by Orx2 antagonism or stimulation respectively. Together, these results suggest that the Orx2 receptor may be a useful potential target for anxiolytic or antidepressive therapeutics.
Highlights
Anxious Behavior is widely expressed across vertebrate species (Kandel, 1983), and while anxiety is an evolutionarily conserved and adaptive suite of emotions (Bergstrom and Meacham, 2016; Smith et al, 2016; Trimmer et al, 2015), in their pathological forms constitute the most common human psychological disorders (Kessler et al, 2010)
We demonstrated that knockdown of orexin/hypocretin 2 receptor (Orx2) receptors in the basolateral amygdala (BLA) produces anxiogenic responses, suggesting that the natural function of Orx2 is anxiolytic (Arendt et al, 2014)
Consistent with our previous work, the results reported here indicate that Orx2 receptor activity, in contrast with Orx1 receptor actions, are anxiolytic and anti-depressive (Arendt et al, 2014; Arendt et al, 2013)
Summary
Anxious Behavior is widely expressed across vertebrate species (Kandel, 1983), and while anxiety is an evolutionarily conserved and adaptive suite of emotions (Bergstrom and Meacham, 2016; Smith et al, 2016; Trimmer et al, 2015), in their pathological forms constitute the most common human psychological disorders (Kessler et al, 2010). Orexin-related effects classically include promotion of foraging and feeding, maintaining homeostasis, arousal, modulation of sleep-wake circadian cycles (whereas lack of Orx or it receptors may result in sleep dysregulation or narcolepsy), and motivation (Berridge and Espana, 2005; Chemelli et al, 1999; Rodgers et al, 2002; Saper et al, 2005; Scammell and Saper, 2005). These functions and behaviors are mediated via two orexin receptors, Orx and Orx, which have high binding affinity for OrxA. Orexinergic neurons in the LHDMH/PeF have extensive anatomical associations and functional interactions via the two orexin receptors in most brain regions (Chen et al, 1999; Marcus et al, 2001; Nambu et al., 1999; Sakurai, 2005; Trivedi et al, 1998; Yoshida et al, 2006; Zhang et al, 2005) and these projections are responsive to stressors (Arendt et al, 2014; Arendt et al, 2013; Berridge et al, 2010; Giardino et al, 2018)
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