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

• Published in: Pharmacology, biochemistry and behavior Vol. 135; pp. 70 - 82
• Main Authors: Li, Yan, Abdourahman, Aicha, Tamm, Joseph A., Pehrson, Alan L., Sánchez, Connie, Gulinello, Maria
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2015
• Subjects: Aging - psychology; Animals; Antidepressant; Antidepressive Agents - pharmacology; Antidepressive Agents - therapeutic use; Cell Proliferation - drug effects; Cognition Disorders - drug therapy; Cognition Disorders - psychology; Female; Fluoxetine - pharmacology; Fluoxetine - therapeutic use; Forced swim test; Gene Expression - drug effects; Hippocampus - drug effects; Hippocampus - metabolism; Intercellular Signaling Peptides and Proteins - biosynthesis; Intercellular Signaling Peptides and Proteins - genetics; Mice; Mice, Inbred C57BL; Motor Activity - drug effects; Neural Stem Cells - drug effects; Neuronal Plasticity - drug effects; Neuronal Plasticity - genetics; Novel object placement; Piperazines - pharmacology; Piperazines - therapeutic use; Recognition (Psychology) - drug effects; Serotonin Plasma Membrane Transport Proteins - metabolism; Spatial memory; SSRI (selective serotonin reuptake inhibitor); Sulfides - pharmacology; Sulfides - therapeutic use; Swimming - psychology; Vortioxetine; Antidepressant; Forced swim test; TBS; BDNF; VEGF; Novel object placement; NT-3; SSRI (selective serotonin reuptake inhibitor); IGF-1; NGF; SSRI; SERT; FLX; ANOVA; VEH; VOR; 5-HT; Vortioxetine; BrdU; PCR; ELISA; Spatial memory
• ISSN: 0091-3057; 1873-5177
• DOI: 10.1016/j.pbb.2015.05.013

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. •Middle-aged mice had visuospatial memory deficits in a hippocampus-dependent task.•Middle-aged mice had lower neuroplasticity-related gene expression in the hippocampus.•Middle-aged mice had less stem cell proliferation in the hippocampus.•Vortioxetine improved visuospatial memory in middle-aged mice.•Vortioxetine increased expression of neuroplasticity-related genes in 12month old mice.