Construct and face validity of a new model for the three-hit theory of depression using PACAP mutant mice on CD1 background

József Farkas, László Kovács, László Gáspár, Anna Nafz, Tamás Gaszner, Balázs Ujvári, Viktória Kormos, V. Csernus, Hitoshi Hashimoto, D. Reglodi, B. Gaszner

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Major depression is a common cause of chronic disability. Despite decades of efforts, no equivocally accepted animal model is available for studying depression. We tested the validity of a new model based on the three-hit concept of vulnerability and resilience. Genetic predisposition (hit 1, mutation of pituitary adenylate cyclase-activating polypeptide, PACAP gene), early-life adversity (hit 2, 180-min maternal deprivation, MD180) and chronic variable mild stress (hit 3, CVMS) were combined. Physical, endocrinological, behavioral and functional morphological tools were used to validate the model. Body- and adrenal weight changes as well as corticosterone titers proved that CVMS was effective. Forced swim test indicated increased depression in CVMS PACAP heterozygous (Hz) mice with MD180 history, accompanied by elevated anxiety level in marble burying test. Corticotropin-releasing factor neurons in the oval division of the bed nucleus of the stria terminalis showed increased FosB expression, which was refractive to CVMS exposure in wild-type and Hz mice. Urocortin1 neurons became over-active in CMVS-exposed PACAP knock out (KO) mice with MD180 history, suggesting the contribution of centrally projecting Edinger–Westphal nucleus to the reduced depression and anxiety level of stressed KO mice. Serotoninergic neurons of the dorsal raphe nucleus lost their adaptation ability to CVMS in MD180 mice. In conclusion, the construct and face validity criteria suggest that MD180 PACAP HZ mice on CD1 background upon CVMS may be used as a reliable model for the three-hit theory.

Original languageEnglish
Pages (from-to)11-29
Number of pages19
JournalNeuroscience
Volume354
DOIs
Publication statusPublished - Jun 23 2017

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Pituitary Adenylate Cyclase-Activating Polypeptide
Reproducibility of Results
Depression
Knockout Mice
Anxiety
Maternal Deprivation
History
Serotonergic Neurons
Neurons
Septal Nuclei
Body Weight Changes
Aptitude
Calcium Carbonate
Corticotropin-Releasing Hormone
Genetic Predisposition to Disease
Corticosterone
Animal Models
Mutation
Genes

Keywords

  • chronic variable mild stress
  • CRF
  • FosB
  • maternal deprivation
  • serotonin
  • Urocortin1

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Construct and face validity of a new model for the three-hit theory of depression using PACAP mutant mice on CD1 background. / Farkas, József; Kovács, László; Gáspár, László; Nafz, Anna; Gaszner, Tamás; Ujvári, Balázs; Kormos, Viktória; Csernus, V.; Hashimoto, Hitoshi; Reglodi, D.; Gaszner, B.

In: Neuroscience, Vol. 354, 23.06.2017, p. 11-29.

Research output: Contribution to journalArticle

Farkas, József ; Kovács, László ; Gáspár, László ; Nafz, Anna ; Gaszner, Tamás ; Ujvári, Balázs ; Kormos, Viktória ; Csernus, V. ; Hashimoto, Hitoshi ; Reglodi, D. ; Gaszner, B. / Construct and face validity of a new model for the three-hit theory of depression using PACAP mutant mice on CD1 background. In: Neuroscience. 2017 ; Vol. 354. pp. 11-29.
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AU - Gaszner, Tamás

AU - Ujvári, Balázs

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