Department of Biology, University of South Dakota, Vermillion, SD 57069, USA; Neuroscience Group, Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD 57069, USA; Veterans Affairs Research Service, Sioux Falls VA Health Care System, Sioux Falls, SD 57105, USA.
Department of Biology, University of South Dakota, Vermillion, SD 57069, USA; Department of Biology, University of Massachusetts, Boston, 100William T. Morrissey Blvd, Boston, MA 02125, USA.
Neuropharmacology. 2018 Dec;143:79-94. doi: 10.1016/j.neuropharm.2018.09.016. Epub 2018 Sep 18.
Knockdown of orexin/hypocretin 2 receptor (Orx) 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 Orx 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 Orx 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 Orx 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 Orx antagonist. Escape mice were also Resilient, and Stay mice Susceptible to stress (SIP), with both conditions reversed by Orx antagonism or stimulation respectively. Together, these results suggest that the Orx receptor may be a useful potential target for anxiolytic or antidepressive therapeutics.
下丘脑外侧区（BLA）中食欲素/下丘脑分泌素 2 受体（Orx）的敲低会影响焦虑和抑郁行为。我们使用了一种新的行为范式，即应激替代模型（SAM），旨在提高转化的影响。SAM 通过来自较大老鼠的攻击来诱导成年雄性小鼠的社会压力，从而允许对逃避做出适应性决策。在这种模型中，老鼠留在（Stay）椭圆形 SAM 竞技场或通过仅对较小老鼠足够大的路线从社会攻击中逃脱（Escape）。我们假设脑室内（icv）刺激 Orx 受体将在 SAM 相关的社会行为和社交互动/偏好（SIP）测试中具有抗焦虑和抗抑郁作用。相反，我们预测 icv 拮抗 Orx 受体将在这些相同的测试中促进焦虑和抑郁行为。与 Escape 表型的老鼠相比，Stay 表型的老鼠更经常表现出诸如冻结（提示和冲突）和惊吓等焦虑行为。对逃生路线保持注意的时间在 Escape 老鼠中更频繁。在 Stay 老鼠中，刺激 Orx 受体可减少恐惧条件反射、冲突冻结和惊吓，并促进对逃生孔的更多关注。这种抗焦虑作用伴随着杏仁核中一组抑制性神经元的激活。一小部分 Stay 老鼠也开始逃跑；而 Orx 拮抗剂则逆转了 Escape。Escape 老鼠也具有弹性，而 Stay 老鼠对压力（SIP）敏感，Orx 拮抗剂或刺激分别逆转了这两种情况。总之，这些结果表明，Orx 受体可能是抗焦虑或抗抑郁治疗的有用潜在靶标。
