Anxiolytic function of the orexin 2/hypocretin A receptor in the basolateral amygdala.
The orexin/hypocretin system interacts with many of the same circuitries contributing to stress-associated disorders like depression and anxiety. These include potentially reciprocal connections with corticotropin releasing factor (CRF) neurons which drive the hypothalamic-pituitary-adrenal (HPA) endocrine response in addition to having an anxiogenic effect in the central amygdala (CeA). Antagonism of the orexin type 1 receptor (Orx1) in the hypothalamus has also been shown to block panic attacks. However, few studies have investigated the effect of orexinergic signaling in the basolateral amygdala (BLA) which is responsible for contextual fear, and modulates the activity of the CeA. To this end, we chronically stressed c57bl/6 mice with social defeat and examined the gene expression of the orexin receptors in the BLA. We found that the transcripts for the Orx1 and Orx2 receptors diverged in the BLA with Orx1 increasing and Orx2 decreasing in animals that were susceptible to the chronic defeat. These changes were not seen in the prelimbic cortex (PrL) which sends efferents to the BLA. We then tried to recapitulate these expression patterns in the BLA using short hairpin interfering sequences delivered by adeno-associated viruses to knock down the orexin receptors. While the Orx1 knockdown did reduce locomotor activity, it did not decrease depressive or anxious behaviors. Knocking down the Orx2 receptors in the BLA increased anxious behavior as measured by reduced social preference and reduced time spent in the center of an open field. Due to the divergent expression patterns of the two receptors in response to chronic stress, orexinergic activity in the BLA may be responsible for bidirectional modulation of anxious behavior. Furthermore, these data raise the possibility that an Orx2 agonist may serve as an effective means to treat anxiety disorders.
Department of Psychiatry, Indiana University of School of Medicine, Indianapolis, IN 46202, USA; 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; Research Service, Sioux Falls VA Medical Center, Sioux Falls, SD, USA.
David H
DH
Arendt
Department of Biology, University of South Dakota, Vermillion, SD 57069, USA.
James
J
Hassell
Department of Biology, University of South Dakota, Vermillion, SD 57069, USA.
Hao
H
Li
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; Research Service, Sioux Falls VA Medical Center, Sioux Falls, SD, USA.
Justin K
JK
Achua
Division of Molecular Psychiatry, Ribicoff Research Facilities, Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
Douglas J
DJ
Guarnieri
Division of Molecular Psychiatry, Ribicoff Research Facilities, Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
Ralph J
RJ
Dileone
Neuroscience Group, Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD 57069, USA; Avera Research Institute, Sioux Falls, SD, USA; Research Service, Sioux Falls VA Medical Center, Sioux Falls, SD, USA; Department of Psychiatry, Sanford School of Medicine, University of South Dakota, Vermillion, SD, USA.
Patrick J
PJ
Ronan
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. Electronic address: cliff@usd.edu.
Cliff H
CH
Summers
D000679:Amygdala / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified; D014151:Anti-Anxiety Agents / Q000378:metabolism; D001007:Anxiety / Q000235:genetics* / Q000378:metabolism*; D001522:Behavior, Animal / Q000187:drug effects; D004291:Dominance-Subordination; D005239:Fear / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D055500:Resilience, Psychological / Q000187:drug effects
D014151:Anti-Anxiety Agents; C501103:Cd200r1 protein, mouse; C497459:Hcrtr1 protein, mouse; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors; D034741:RNA, Small Interfering
Amygdala; Anxiety; Basolateral amygdala; Hypocretin; Knockdown; Orexin; Orexin 2 receptor; shRNA