Anxiety disorders belong to the most common psychiatric disorders with enormous burden to the patient and the society. Many of them are precipitated by stress and associated with exaggerated fear responses, which often result from classical and operant conditioning processes. In this context, studies in animal models revealed the importance of the two stress hormone systems with adrenaline/ noradrenaline and corticosterone as the main effectors. There is a close interdependence between these two systems at various brain structures implicated in the formation of fear memories, including the basolateral amygdala (BLA). At the same time, there are hints for an additional involvement of the endocannabinoid system. For instance, corticosterone has the potential to activate endocannabinoid signaling which in turn affects noradrenaline release, by yet unknown mechanisms. This project will study the neurochemical underpinnings of the fear memory enhancing effects of corticosterone. Specifically we will (i) validate memory-enhancing effects of corticosterone in contextual and auditory-cued fear conditioning in mice; (ii) demonstrate the involvement of glucocorticoid receptors (GR) at level of the BLA and dissect the neuronal subpopulation affected by corticosterone, using cell-type specific GR-KO; (iii) demonstrate the involvement of noradrenaline signaling by optogenetic means; and (iv) assess the contribution of cannabinoid receptor type 1 (CB1) on GABAergic neurons. We hypothesize that corticosterone-mediated activation of endocannabinoid signaling reduces GABA release and, thereby, unleashes noradrenaline transmission which promotes the formation of fear memories. Together, this unique undertaking is combining cutting-edge genetic, optical and neurochemical techniques to assess the multiple interactions of three different classes of neuromessengers (steroid hormones, monoamines and lipidergic transmitters) during the formation of fear memories. The experiments will not only broaden our knowledge about such processes in mice, but may provide novel strategies for the treatment of psychiatric diseases which are associated with exaggerated fear responses.
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