The underlying mechanisms of the orexin (hypocretin) system in anxiety and fear

Simple item page
dc.contributor.authorWang, Huiying
dc.contributor.examiningcommitteeVrontakis, Maria (Human Anatomy and Cell Science) Wang, Jun-Feng(Pharmacology and Therapeutics) Scott,James (Oral Biology) Bhatnagar, Seema (University of Pennsylvania)en_US
dc.contributor.supervisorKirouac, Gilbert (Oral Biology)en_US
dc.date.accessioned2017-08-21T18:20:48Z
dc.date.available2017-08-21T18:20:48Z
dc.date.issued2010en_US
dc.date.issued2015en_US
dc.date.issued2017en_US
dc.degree.disciplineOral Biologyen_US
dc.degree.levelDoctor of Philosophy (Ph.D.)en_US
dc.description.abstractAnxiety and fear are emotions that are vital for individuals when dealing with difficult challenges and threats. However, persistent vigilance and frequent recall of memories associated with a fearful experience can lead to generalized anxiety disorder, posttraumatic stress disorder (PTSD), and phobias. Orexins (hypocretins) are neuropeptides that play a critical role in promoting arousal. Accumulating evidence suggests that orexin neurons are activated in animals exposed to stressful conditions and that orexins are involved in the regulation of anxiety and fear. In this thesis, the role of the orexins in anxiety and fear was studied using behavioral, biochemical, and pharmacological methods. Experiments were done to identify some of the possible mechanisms involved. First, microinjections of orexin peptides (orexin-A and orexin-B) into the paraventricular nucleus of the thalamus (PVT) induced anxiety-like behaviors. The anxiogenic effect produced by microinjections of orexin-A in the PVT was attenuated by blocking receptors for the stress-related peptides, corticotropin-releasing factor (CRF) and dynorphin. Second, the mRNA levels for prepro-orexin (ppOX) and the orexin 1 receptor (OX1R) were found to be increased in the posterior hypothalamus of shocked rats at 2 weeks post-shock. Third, 2 weeks after the footshocks, an enhanced level of CRF mRNA in the amygdala and ppOX mRNA in the posterior hypothalamus were detected in a subset of shocked rats that displayed an acute fear response to a novel tone and that eventually resulted in a generalized anxiety (high responders, HR). Fourth, the dual orexin antagonist TCS1102 (20 mg/kg; i.p.) and OX1R antagonist SB334867 (20 and 30 mg/kg; i.p.) decreased fear level when tested at 2 weeks post-shock. These results suggest that endogenously released orexins regulate anxiety through acting on the PVT and that the brain kappa and CRF systems could be involved. The results also indicate that changes in orexins and CRF occur specifically in HR. These findings provide a better understanding of the brain mechanisms contributing to hyperarousal and anxiety. In addition, the results support the use of orexin receptor antagonists, especially OX1R antagonists, in the treatment of anxiety disorders including PTSD, panic attacks, and phobias.en_US
dc.description.noteOctober 2017en_US
dc.identifier.citationAPAen_US
dc.identifier.citationNumbereden_US
dc.identifier.urihttp://hdl.handle.net/1993/32358
dc.language.isoengen_US
dc.publisherElsevieren_US
dc.publisherSpringeren_US
dc.rightsopen accessen_US
dc.subjectOrexinen_US
dc.subjectHypocretinen_US
dc.subjectAnxietyen_US
dc.subjectFearen_US
dc.subjectOrexin antagonisten_US
dc.subjectDynorphinen_US
dc.subjectMidline thalamusen_US
dc.subjectCorticotropin releasing factoren_US
dc.subjectEnkephalinen_US
dc.subjectAmygdalaen_US
dc.subjectBed nucleus of the stria terminalisen_US
dc.subjectStriatumen_US
dc.subjectPosterior hypothalamusen_US
dc.subjectPosttraumatic stress disorderen_US
dc.titleThe underlying mechanisms of the orexin (hypocretin) system in anxiety and fearen_US
dc.typedoctoral thesisen_US
Files
Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
Wang_ Huiying .pdf
Size:
3.67 MB
Format:
Adobe Portable Document Format
Description:
Download
License bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
license.txt
Size:
2.2 KB
Format:
Item-specific license agreed to upon submission
Description:
Download
Collections
FGS - Electronic Theses and Practica