SEROTONINERGIC NEURONS OF DORSAL RAPHE NUCLEUS IN THE THREE HIT THEORY OF DEPRESSION
01/29/2020
Farkas József1, Gaszner Tamás1, Kovács László Ákos1, Gaszner Balázs1
1 University of Pécs, Medical School, Department of Anatomy, Pécs
The pathogenesis of depression is unknown, partially because of the lack of animal models. Three hit theory of depression proposes simultaneous occurrence of genetic, epigenetic and environmental factors cause depression. Partial/total lack of pituitary adenilate cyclase-activating polypeptide (PACAP) causes depression-like behaviour in mice. Therefore, these animals can be applied as models for genetic predisposition. Maternal deprivation is widely applied to model epigenetic effects of early life stress. The chronic variable mild stress(CVMS) is a model of daily stress. The hypothalamus-pituitary-suprarenal gland axis and higher order centres (e.g.serotoninergic neurons of dorsal raphe nucleus-DR)play crucial role in stress adaptation. FosB is a chronic neuronal activation marker, expressed upon stress. We hypothesised, mice exposed to three hits will show depression-like behaviour. We anticipated alterations in serotonin and FosB expression in DR, which also may prove the validity of our model. PACAP-KO, heterozygous and wild type mice were exposed to short(15 min) and long term(180 min) maternal separation on the first 14 postnatal days. Half of animals of each group were exposed to CVMS between postnatal days 106 and 120 followed by forced swim test(FST). Next day, mice were transcardially perfused, followed by immunofluorescence for serotonin and FosB in DR. In FST, maternally separated mice showed increased depression-like behaviour. Mice with maternal deprivation history upon CVMS showed significant FosB and tendentious serotonin cell count decrease in all genotypes. Our results supports that in genetically predisposed animals, maternal deprivation blunts the function of DR-serotonin systems. Altered stress response proves the validity of our model. OTKA-PD100706