title: Depressive-like behaviours and decreased dendritic branching in the medial prefrontal cortex of mice with tumors: A novel validated model of cancer-induced depression.
abstract: Depression is commonly comorbid in cancer patients and has detrimental effects on disease progression. Evidence suggests that biological mechanisms may induce the onset of cancer-induced depression (CID). The present investigation aims to establish a validated preclinical animal model of CID. Female BALB/c mice were allocated to four groups: control (n=12), chronic oral exposure to corticosterone (CORT) (n=12), CORT exposure followed by chronic low dose fluoxetine (FLX) treatment (n=12), and subcutaneous inoculation of 4T1 mammary carcinoma cells (n=13). Anhedonia was evaluated using the sucrose preference test (SPT), and behavioural despair was evaluated using the forced swim test (FST) and tail suspension test (TST). Sholl analyses were used to examine the dendritic morphology of Golgi-Cox impregnated neurons from the medial prefrontal cortex (mPFC). CORT exposure and tumor burden were both associated with decreased sucrose preference, increased FST immobility, and decreased basilar and apical dendritic branching of neurons in the mPFC. CORT-induced behavioural and dendritic morphological changes were reversible by FLX. No differences in TST immobility were observed between groups. On the secondary TST outcome measure, CORT exposure and tumor burden were associated with a trend towards decreased power of movement. CORT exposure induced a positive control model of a depressive-like state, with FLX treatment confirming the predictive validity of the model. This verified the sensitivity of behavioural and histological tests, which were used to assess the CID model. The induction of a depressive-like state in this model represents the first successfully validated animal model of CID.
authors.affiliation: Department of Pathology & Molecular Medicine, McMaster University, Hamilton, ON L8N 3Z5, Canada; Michael G. DeGroote Institute for Pain Research and Care, McMaster University, Hamilton, ON L8N 3Z5, Canada.
authors.forename: Mina G
authors.initials: MG
authors.lastname: Nashed
authors.affiliation: Department of Pathology & Molecular Medicine, McMaster University, Hamilton, ON L8N 3Z5, Canada; Michael G. DeGroote Institute for Pain Research and Care, McMaster University, Hamilton, ON L8N 3Z5, Canada.
authors.forename: Eric P
authors.initials: EP
authors.lastname: Seidlitz
authors.affiliation: Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON L8N 3Z5, Canada; Mood Disorders Program and Women's Health Concerns Clinic, St. Joseph's Healthcare Hamilton, ON L8P 3P6, Canada.
authors.forename: Benicio N
authors.initials: BN
authors.lastname: Frey
authors.affiliation: Department of Pathology & Molecular Medicine, McMaster University, Hamilton, ON L8N 3Z5, Canada; Michael G. DeGroote Institute for Pain Research and Care, McMaster University, Hamilton, ON L8N 3Z5, Canada. Electronic address: singhg@mcmaster.ca.
authors.forename: Gurmit
authors.initials: G
authors.lastname: Singh
mesh_terms: D059445:Anhedonia / Q000187:drug effects / Q000502:physiology; D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology; D045744:Cell Line, Tumor; D003345:Corticosterone; D003712:Dendrites / Q000473:pathology* / Q000502:physiology; D003866:Depressive Disorder / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology*; D019422:Dietary Sucrose; D005260:Female; D005473:Fluoxetine / Q000494:pharmacology; D008325:Mammary Neoplasms, Experimental / Q000473:pathology* / Q000503:physiopathology* / Q000523:psychology; D008807:Mice, Inbred BALB C; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009368:Neoplasm Transplantation; D017397:Prefrontal Cortex / Q000473:pathology* / Q000503:physiopathology; D011897:Random Allocation
chemical_list: D018687:Antidepressive Agents, Second-Generation; D019422:Dietary Sucrose; D005473:Fluoxetine; D003345:Corticosterone
keywords: Anhedonia; Animal model; Behavioural despair; Cancer; Depression; Medial prefrontal cortex