title: Intensity of anxiety is modified via complex integrative stress circuitries.
abstract: Escalation of anxious behavior while environmentally and socially relevant contextual events amplify the intensity of emotional response produces a testable gradient of anxiety shaped by integrative circuitries. Apprehension of the Stress-Alternatives Model apparatus (SAM) oval open field (OF) is measured by the active latency to escape, and is delayed by unfamiliarity with the passageway. Familiar OF escape is the least anxious behavior along the continuum, which can be reduced by anxiolytics such as icv neuropeptide S (NPS). Social aggression increases anxiousness in the SAM, reducing the number of mice willing to escape by 50%. The apprehension accompanying escape during social aggression is diminished by anxiolytics, such as exercise and corticotropin releasing-factor receptor 1 (CRF1) antagonism, but exacerbated by anxiogenic treatment, like antagonism of α2-adrenoreceptors. What is more, the anxiolytic CRF1 and anxiogenic α2-adrenoreceptor antagonists also modify behavioral phenotypes, with CRF1 antagonism allowing escape by previously submissive animals, and α2-adrenoreceptor antagonism hindering escape in mice that previously engaged in it. Gene expression of NPS and brain-derived neurotrophic factor (BDNF) in the central amygdala (CeA), as well as corticosterone secretion, increased concomitantly with the escalating anxious content of the mouse-specific anxiety continuum. The general trend of CeA NPS and BDNF expression suggested that NPS production was promoted by increasing anxiousness, and that BDNF synthesis was associated with learning about ever-more anxious conditions. The intensity gradient for anxious behavior resulting from varying contextual conditions may yield an improved conceptualization of the complexity of mechanisms producing the natural continuum of human anxious conditions, and potential therapies that arise therefrom.
authors.affiliation: 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; Institute of Possibility, 322 E. 8th Street, Suite 302, Sioux Falls, SD 57103, USA; Sanford Health, 2301 E. 60th St. N., Sioux Falls, SD 57104, USA.
authors.forename: Justin P
authors.initials: JP
authors.lastname: Smith
authors.affiliation: 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.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Prince
authors.affiliation: 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.
authors.forename: Justin K
authors.initials: JK
authors.lastname: Achua
authors.affiliation: 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.
authors.forename: James M
authors.initials: JM
authors.lastname: Robertson
authors.affiliation: Department of Biology, University of South Dakota, Vermillion, SD 57069, USA; Department of Biochemistry, West Virginia University School of Medicine, 1 Medical Center Dr., Morgantown, WV 26506, USA.
authors.forename: Raymond T
authors.initials: RT
authors.lastname: Anderson
authors.affiliation: 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; Avera Research Institute, Avera McKennan Hospital & University Health Center, Sioux Falls, SD 57105, USA; Laboratory for Clinical and Translational Research in Psychiatry, Department of Veterans Affairs Medical Center, Denver, CO 80220, USA; Department of Psychiatry, Sanford School of Medicine, University of South Dakota, Vermillion, SD 57069, USA.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Ronan
authors.affiliation: 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.
authors.forename: Cliff H
authors.initials: CH
authors.lastname: Summers
mesh_terms: D000374:Aggression / Q000187:drug effects / Q000523:psychology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D001007:Anxiety / Q000473:pathology / Q000503:physiopathology / Q000523:psychology*; D001522:Behavior, Animal / Q000187:drug effects; D004924:Escape Reaction / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D009415:Nerve Net / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D010805:Physical Conditioning, Animal / Q000502:physiology; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors; D012720:Severity of Illness Index; D013315:Stress, Psychological / Q000473:pathology / Q000503:physiopathology / Q000523:psychology*
chemical_list: D014151:Anti-Anxiety Agents; D018019:Receptors, Corticotropin-Releasing Hormone
keywords: CRF(1) receptors; Continuum; Exercise; Gradient; NPS; α(2) receptors