Reversal of age-associated cognitive deficits is accompanied by increased plasticity-related gene expression after chronic antidepressant administration in middle-aged mice

Yan Li, Aicha Abdourahman, Joseph A. Tamm, Alan L. Pehrson, Connie Sánchez, Maria Gulinello

Research output: Contribution to journalArticle

44 Scopus citations


Cognitive decline occurs during healthy aging, even in middle-aged subjects, via mechanisms that could include reduced stem cell proliferation, changed growth factor expression and/or reduced expression of synaptic plasticity genes. Although antidepressants alter these mechanisms in young rodents, their effects in older animals are unclear. In middle-aged mice, we examined the effects of a selective serotonin reuptake inhibitor (fluoxetine) and a multimodal antidepressant (vortioxetine) on cognitive and affective behaviors, brain stem cell proliferation, growth factor and gene expression. Twelve-month-old female C57BL/6 mice exhibited impaired visuospatial memory in the novel object placement (location) task associated with reduced expression of several plasticity-related genes. Chronic treatment with vortioxetine, but not fluoxetine, improved visuospatial memory and reduced depression-like behavior in the forced swim test in middle-aged mice. Vortioxetine, but not fluoxetine, increased hippocampal expression of several neuroplasticity-related genes in middle-aged mice (e.g., Nfkb1, Fos, Fmr1, Camk2a, Arc, Shank1, Nlgn2, and Rab3a). Neither drug reversed the age-associated decrease in stem cell proliferation. Hippocampal growth factor levels were not consistent with behavioral outcomes. Thus, a change in the expression of multiple genes involved in neuronal plasticity by antidepressant treatment was associated with improved cognitive function and a reduction in depression-like behavior in middle-aged mice.

Original languageEnglish (US)
Pages (from-to)70-82
Number of pages13
JournalPharmacology Biochemistry and Behavior
StatePublished - Jun 3 2015



  • Antidepressant
  • Forced swim test
  • Novel object placement
  • SSRI (selective serotonin reuptake inhibitor)
  • Spatial memory
  • Vortioxetine

ASJC Scopus subject areas

  • Biochemistry
  • Toxicology
  • Pharmacology
  • Clinical Biochemistry
  • Biological Psychiatry
  • Behavioral Neuroscience

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