Stress from the aspect of CRH neurons in the median raphe region
Bibiána Török1, 2, Krisztina Horváth2, 3, Csilla Fazekas1, 2, Balázs Gaszner4, Pedro Correia1, 2, Tiago Chaves1, Eszter Sipos1, András Szőnyi5, Krisztina Kovács3, Gábor Nyíri5, Dóra Zelena1, 6
Dysfunctions of median raphe region (MRR) were associated with stress-related psychiatric disorders, due to its serotoninergic content. Recently we found that the main hypothalamic regulator of stress axis, corticotropin releasing hormone (CRH) is also abundant in this area. We aimed to reveal the contribution of these peptidergic cells in stress adaptation. Pharmacogenetic technique was used in CRH-Cre mouse strain. Control, stimulatory or inhibitory DREADD sequence was injected into the MRR using adeno-associated virus vector. Clozapine-N-oxide was used as ligand. Parallel with changes in stress-hormone concentration anxiety- and depression-like behavior was also measured. Accuracy of injections, c-Fos activation, co-localizations, output and input brain areas were investigated by immunohistochemistry. Stress-induced c-Fos activation was found in MRR CRH neurons. CRH was found in GABAergic cells and got input mainly from lateral habenula, laterodorsal tegmental nucleus and nucleus incertus. The main target was the dorsal raphe, nucleus incertus and ventral tegmental area. Stimulation of CRH neurons in MRR increased corticosterone levels parallel with anxiety-like behavior in elevated plus maze and light-dark test compared to controls. During tail suspension test, depression-like behavior appeared in stimulated animals. Inhibition of these cells decreased the freezing behavior both during the trauma and contextual freezing, but not the cue-induced immobility. To summarize, stimulation of MRR CRH neurons may induce stress-hormone elevation as well as anxiety- and depression-like behavior, while their inhibition may diminish the reaction to trauma. Thus, they play a key role in regulating stress adaptation both at hormonal and behavioral level.