Sex and BDNF Val66Met polymorphism matter for exercise-induced increase in neurogenesis and cognition in middle-aged mice

• Published in: Hormones and behavior 2023-02, Vol.148, p.105297-105297, Article 105297
• Main Authors: Islas-Preciado, Dannia, Splinter, Tallinn F.L., Ibrahim, Muna, Black, Natasha, Wong, Sarah, Lieblich, Stephanie E., Liu-Ambrose, Teresa, Barha, Cindy K., Galea, Liisa A.M.
• Format: Article
• Language: English
• Subjects: Animals; Brain-Derived Neurotrophic Factor - genetics; Cognition - physiology; Cognitive flexibility; Female; Genotype; hippocampus; Humans; Male; Mice; Mice, Inbred C57BL; Middle Aged; Neurogenesis - genetics; Polymorphism, Single Nucleotide; Prefrontal cortex; Voluntary running
• ISSN: 0018-506X; 1095-6867
• DOI: 10.1016/j.yhbeh.2022.105297

Females show greater benefits of exercise on cognition in both humans and rodents, which may be related to brain-derived neurotrophic factor (BDNF). A single nucleotide polymorphism (SNP), the Val66Met polymorphism, within the human BDNF gene, causes impaired activity-dependent secretion of neuronal BDNF and impairments to some forms of memory. We evaluated whether sex and BDNF genotype (Val66Met polymorphism (Met/Met) versus wild-type (Val/Val)) influenced the ability of voluntary running to enhance cognition and hippocampal neurogenesis in mice. Middle-aged C57BL/6J (13 months) mice were randomly assigned to either a control or an aerobic training (AT) group (running disk access). Mice were trained on the visual discrimination and reversal paradigm in a touchscreen-based technology to evaluate cognitive flexibility. BDNF Met/Met mice had fewer correct responses compared to BDNF Val/Val mice on both cognitive tasks. Female BDNF Val/Val mice showed greater cognitive flexibility compared to male mice regardless of AT. Despite running less than BDNF Val/Val mice, AT improved performance in both cognitive tasks in BDNF Met/Met mice. AT increased neurogenesis in the ventral hippocampus of BDNF Val/Val mice of both sexes and increased the proportion of mature type 3 doublecortin-expressing cells in the dorsal hippocampus of female mice only. Our results indicate AT improved cognitive performance in BDNF Met/Met mice and increased hippocampal neurogenesis in BDNF Val/Val mice in middle age. Furthermore, middle-aged female mice may benefit more from AT than males in terms of neuroplasticity, an effect that was influenced by the BDNF Val66Met polymorphism. •BDNF Met/Met mice performed worse than BDNF Val/Val mice in middle-age.•Aerobic training (AT) increased cognitive performance in BDNF Met/Met mice.•AT increased neurogenesis in middle-aged BDNF Val/Val mice only.•Female BDNF Val/Val mice had better cognitive flexibility than males regardless of AT.•AT increased more mature new neurons in middle-aged female mice.