Reduced response to chronic mild stress in PACAP mutant mice is associated with blunted FosB expression in limbic forebrain and brainstem centers

Neuroscience. 2016 Aug 25;330:335-58. doi: 10.1016/j.neuroscience.2016.06.004. Epub 2016 Jun 6.


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.

Keywords: FosB; corticotropin-releasing factor; dorsal raphe nucleus; serotonin; stress; urocortin 1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antidepressive Agents, Tricyclic / pharmacology
  • Brain Stem / drug effects
  • Brain Stem / metabolism*
  • Brain Stem / pathology
  • Chronic Disease
  • Depressive Disorder / drug therapy
  • Depressive Disorder / metabolism
  • Depressive Disorder / pathology
  • Disease Models, Animal
  • Imipramine / pharmacology
  • Limbic System / drug effects
  • Limbic System / metabolism*
  • Limbic System / pathology
  • Male
  • Mice, Knockout
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurons / pathology
  • Pituitary Adenylate Cyclase-Activating Polypeptide / deficiency*
  • Pituitary Adenylate Cyclase-Activating Polypeptide / genetics
  • Prosencephalon / drug effects
  • Prosencephalon / metabolism*
  • Prosencephalon / pathology
  • Proto-Oncogene Proteins c-fos / metabolism*
  • Serotonin / metabolism
  • Stress, Psychological / drug therapy
  • Stress, Psychological / metabolism*
  • Stress, Psychological / pathology


  • Adcyap1 protein, mouse
  • Antidepressive Agents, Tricyclic
  • Fosb protein, mouse
  • Pituitary Adenylate Cyclase-Activating Polypeptide
  • Proto-Oncogene Proteins c-fos
  • Serotonin
  • Imipramine