Reduced response to chronic mild stress in PACAP mutant mice is associated with blunted FosB expression in limbic forebrain and brainstem centers.
Pituitary adenylate cyclase-activating polypeptide (PACAP) has been implicated in stress adaptation with potential relevance in mood disorder management. PACAP deficient (KO) mice on CD1 background were shown to have depression-like phenotype. Here we aimed at investigating effects of chronic variable mild stress (CVMS) in non-injected, vehicle and imipramine-treated KO mice vs. wildtype (WT) counterparts. We hypothesized reduced FosB neuronal activity in stress-related centers, altered activity and peptide/neurotransmitter content of corticotropin-releasing factor (CRF) cells of the oval (ovBST) bed nucleus of stria terminalis (BST), urocortin 1 (Ucn1) neurons of centrally projecting Edinger-Westphal nucleus (cpEW) and serotonin (5HT) cells of dorsal raphe (DR) in PACAP deficiency. CVMS caused decreased body weight and increased adrenal size, corticosterone (CORT) titers and depression-like behavior in WT mice, in contrast to KO animals. CVMS increased FosB in the central (CeA) and medial amygdala, dorsomedial (dmBST), ventral (vBST), ovBST, CA1 area, dentate gyrus (DG), ventral lateral septum, parvo- (pPVN) and magnocellular paraventricular nucleus, lateral periaqueductal gray, cpEW and DR. Lack of PACAP blunted the CVMS-induced FosB rise in the CeA, ovBST, dmBST, vBST, CA1 area, pPVN and DR. The CVMS-induced FosB expression in ovBST-CRF and cpEW-Ucn1 neurons was abolished in KO mice. Although CVMS did not induce FosB in 5HT-DR neurons, PACAP KO mice had increased 5HT cell counts and 5HT content. We conclude that PACAP deficiency affects neuronal reactivity in a brain area-specific manner in stress centers, as well as in ovBST-CRF, cpEW-Ucn1 and 5HT-DR neurons leading to reduced CVMS response and altered depression level.
Department of Anatomy, MTA-PTE "Lendület" PACAP Research Team, University of Pécs Medical School, H-7624 Pécs, Szigeti 12, Hungary; Department of Pharmacology and Pharmacotherapy, János Szentágothai Research Center, MTA PTE NAP B Pain Research Group, University of Pécs Medical School, H-7624 Pécs, Szigeti 12, Hungary.
Viktória
V
Kormos
Department of Anatomy, MTA-PTE "Lendület" PACAP Research Team, University of Pécs Medical School, H-7624 Pécs, Szigeti 12, Hungary.
László
L
Gáspár
Department of Anatomy, MTA-PTE "Lendület" PACAP Research Team, University of Pécs Medical School, H-7624 Pécs, Szigeti 12, Hungary.
László Á
LÁ
Kovács
Department of Anatomy, MTA-PTE "Lendület" PACAP Research Team, University of Pécs Medical School, H-7624 Pécs, Szigeti 12, Hungary.
József
J
Farkas
Department of Anatomy, MTA-PTE "Lendület" PACAP Research Team, University of Pécs Medical School, H-7624 Pécs, Szigeti 12, Hungary.
Tamás
T
Gaszner
Department of Anatomy, MTA-PTE "Lendület" PACAP Research Team, University of Pécs Medical School, H-7624 Pécs, Szigeti 12, Hungary.
Valér
V
Csernus
Department of Medical Biology, University of Pécs Medical School, H-7624 Pécs, Szigeti 12, Hungary.
András
A
Balogh
Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan; Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; iPS Cell-Based Research Project on Brain Neuropharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
Hitoshi
H
Hashimoto
Department of Anatomy, MTA-PTE "Lendület" PACAP Research Team, University of Pécs Medical School, H-7624 Pécs, Szigeti 12, Hungary; Centre for Neuroscience, University Pécs Medical School, Pécs H-7624, Hungary.
Dóra
D
Reglődi
Department of Pharmacology and Pharmacotherapy, János Szentágothai Research Center, MTA PTE NAP B Pain Research Group, University of Pécs Medical School, H-7624 Pécs, Szigeti 12, Hungary; PharmInVivo Ltd., Pécs H-7624, Hungary; Centre for Neuroscience, University Pécs Medical School, Pécs H-7624, Hungary.
Zsuzsanna
Z
Helyes
Department of Anatomy, MTA-PTE "Lendület" PACAP Research Team, University of Pécs Medical School, H-7624 Pécs, Szigeti 12, Hungary. Electronic address: balazs.b.gaszner@aok.pte.hu.
Balázs
B
Gaszner
D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D001933:Brain Stem / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002908:Chronic Disease; D003866:Depressive Disorder / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D007099:Imipramine / Q000494:pharmacology; D008032:Limbic System / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000172:deficiency* / Q000235:genetics; D016548:Prosencephalon / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism; D013315:Stress, Psychological / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology
C495402:Adcyap1 protein, mouse; D000929:Antidepressive Agents, Tricyclic; C483819:Fosb protein, mouse; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D016760:Proto-Oncogene Proteins c-fos; D012701:Serotonin; D007099:Imipramine
FosB; corticotropin-releasing factor; dorsal raphe nucleus; serotonin; stress; urocortin 1