title: Reversal of age-associated cognitive deficits is accompanied by increased plasticity-related gene expression after chronic antidepressant administration in middle-aged mice.
abstract: 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.
authors.affiliation: Lundbeck Research USA, 215 College Road, Paramus, NJ 07652, United States.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Lundbeck Research USA, 215 College Road, Paramus, NJ 07652, United States.
authors.forename: Aicha
authors.initials: A
authors.lastname: Abdourahman
authors.affiliation: Lundbeck Research USA, 215 College Road, Paramus, NJ 07652, United States.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Tamm
authors.affiliation: Lundbeck Research USA, 215 College Road, Paramus, NJ 07652, United States.
authors.forename: Alan L
authors.initials: AL
authors.lastname: Pehrson
authors.affiliation: Lundbeck Research USA, 215 College Road, Paramus, NJ 07652, United States.
authors.forename: Connie
authors.initials: C
authors.lastname: Sánchez
authors.affiliation: Behavioral Core Facility, Department of Neuroscience, Albert Einstein College of Medicine, 1410 Pelham Pkwy S., Bronx, NY 10461, United States. Electronic address: maria.gulinello@einstein.yu.edu.
authors.forename: Maria
authors.initials: M
authors.lastname: Gulinello
mesh_terms: D000375:Aging / Q000523:psychology*; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D049109:Cell Proliferation / Q000187:drug effects; D003072:Cognition Disorders / Q000188:drug therapy* / Q000523:psychology*; D005260:Female; D005473:Fluoxetine / Q000494:pharmacology / Q000627:therapeutic use; D015870:Gene Expression / Q000187:drug effects*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D058953:Neural Stem Cells / Q000187:drug effects; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000235:genetics*; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D021641:Recognition, Psychology / Q000187:drug effects; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D013440:Sulfides / Q000494:pharmacology / Q000627:therapeutic use; D013550:Swimming / Q000523:psychology; D000078784:Vortioxetine
chemical_list: D000928:Antidepressive Agents; D036341:Intercellular Signaling Peptides and Proteins; D010879:Piperazines; D050486:Serotonin Plasma Membrane Transport Proteins; D013440:Sulfides; D005473:Fluoxetine; D000078784:Vortioxetine
keywords: Antidepressant; Forced swim test; Novel object placement; SSRI (selective serotonin reuptake inhibitor); Spatial memory; Vortioxetine