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Nadine Faesel (PhD-student)

Role of the orexin system in panic-like anxiety

Fear and anxiety constitute major parts in animal and human life in order to cope with potentially dangerous situations. However, disturbances in these processes can lead to anxiety disorders, which are one of the most prevalent neuropsychiatric disorders and a massive burden for the patients and their environment. They are divided into several subtypes like post-traumatic stress disorder or panic disorders. In this context, clinical studies reported patients suffering from panic disorders to be highly vulnerable to develop panic attacks after exposure to panicogenic stimuli like carbon dioxide, sodium lactate or cholecystokinin tetrapeptide (CCK-4).

This PhD project, which is conducted in close cooperation with Prof. Dr. Markus Fendt (Magdeburg), aims at investigating the role of the orexin system in panic-like anxiety. This neuropeptide system comprises two peptides exclusively expressed in the dorsomedial/lateral hypothalamus and perifornical area, namely orexin A and B (or hypocretin 1 and 2) and its receptors. In addition to its essential role in the regulation of sleep/wakefulness and feeding behavior, the orexin system was suggested to be crucially involved in anxiety- and panic-like responses.

In this study, the panicogenic substance CCK-4 is injected intracerebroventricularly in orexin deficient mice, which are subsequently tested in behavioural paradigms for measuring anxiety. We hypothesize the deficiency of orexin to result in an absence of panic-like anxiety, which is in contrast to wild-type animals.

Furthermore, the effects of CCK-4 on the hormonal stress axis and neural activity are analysed to elucidate the pathways involved in panic-like anxiety, with a focus on orexinergic neurons and projections. In conclusion, this study could emphasize the potential applicability of orexin receptor antagonists as future pharmacological therapies of human panic disorders.

Immunohistochemical staining for orexin A and c-Fos expression in the lateral hypothalamus of a wild-type mouse after intracerebroventricular CCK-4 treatment
Immunohistochemical staining for orexin A and c-Fos expression in the lateral hypothalamus of a wild-type mouse after intracerebroventricular CCK-4 treatment. Scale bar: 50µm