The effects of aerobic exercise on depression-like, anxiety-like, and cognition-like behaviours over the healthy adult lifespan of C57BL/6 mice

•Lifetime exercise can reduce overt anxiety in healthy ageing mice.•However lifetime exercise may increase neurogenesis-associated anxiety.•Exercise related freezing extended spatial learning latencies in young female mice.•Cognition in healthy ageing is both enhanced and impaired by lifelong exercise.•During healthy ageing, lifelong exercise did not impact notably on depression. Preclinical studies have demonstrated exercise improves various types of behaviours such as anxiety-like, depression-like, and cognition-like behaviours. However, these findings were largely conducted in studies utilising short-term exercise protocols, and the effects of lifetime exercise on these behaviours remain unknown. This study investigates the behavioural effects of lifetime exercise in normal healthy ageing C57BL/6 mice over the adult lifespan. 12 week-old C57BL/6 mice were randomly assigned to voluntary wheel running or non-exercise (control) groups. Exercise commenced at aged 3 months and behaviours were assessed in young adult (Y), early middle age (M), and old (O) mice (n=11–17/group). The open field and elevated zero maze examined anxiety-like behaviours, depression-like behaviours were quantified with the forced swim test, and the Y maze and Barnes maze investigated cognition-like behaviours. The effects of lifetime exercise were not simply an extension of the effects of chronic exercise on anxiety-like, depression-like, and cognition-like behaviours. Exercise tended to reduce overt anxiety-like behaviours with ageing, and improved recognition memory and spatial learning in M mice as was expected. However, exercise also increased anxiety behaviours including greater freezing behaviour that extended spatial learning latencies in Y female mice in particular, while reduced distances travelled contributed to longer spatial memory and cognitive flexibility latencies in Y and O mice. Lifetime exercise may increase neurogenesis-associated anxiety. This could be an evolutionary conserved adaptation that nevertheless has adverse impacts on cognition-like function, with particularly pronounced effects in Y female mice with intact sex hormones. These issues require careful investigation in future rodent studies.