Sex-dependent effects of chronic exercise on cognitive flexibility but not hippocampal Bdnf in aging mice

Abstract

Cognitive impairments associated with advanced age involve alterations in the hippocampus that changes to experience throughout life. The hippocampus is critical for cognitive flexibility involved with extinction and reinstatement of conditioned fear. It is widely accepted that regular exercise can be beneficial for hippocampal function. Therefore, we asked whether chronic voluntary exercise in middle-aged mice can improve extinction and/or reinstatement of conditioned fear compared to standard housing. Eight-month-old male and female C57Bl/6J mice had access to a running wheel or remained in standard housing until 11 months of age. Alongside control standard-housed young adult (3-month-old) mice, they received tone-footshock pairings, which were subsequently extinguished with tone-alone presentations the next day. Half of the mice then received a reminder in the form of a single footshock. Male and female 11-month-old mice housed in standard conditions exhibited impaired reinstatement compared to young adult mice. However, for males that had access to a running wheel from 8 months of age, the reminder treatment rescued reinstatement ability. This was not observed in females. Additionally, exercise during middle age in both sexes increased expression of Bdnf mRNA in the hippocampus, specifically exon 4 mRNA. These results show that, at least for males, physical exercise is beneficial for reducing age-related decline in cognitive abilities. Despite not affecting reinstatement, exercise also increased Bdnf gene expression in the female hippocampus, which could potentially benefit other forms of hippocampus-dependent cognition.

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

“…A previous meta-analysis reported greater AT benefits on nonspatial memory tasks in healthy male older rodents compared to female rodents (Barha et al, 2017b). Similarly, Short et al, (2022) BDNF Val/Val mice showed an increase in ventral DCX-expressing cells compared to sedentary controls, whereas BDNF Met/Met showed minimal running and no significant increase in DCXexpressing cells compared to sedentary controls. Interestingly, the lack of an AT effect on neurogenesis in BDNF Met/Met is consistent with previous research done in younger male mice (Ieraci et al, 2016), even though these younger male mice did run as much as the younger BDNF Val/Val mice (Ieraci et al, 2016).…”

“…A previous meta-analysis reported greater AT benefits on non-spatial memory tasks in healthy male older rodents compared to female rodents (Barha et al, 2017b). Similarly, Short et al, (2022) found beneficial effects of AT on cognitive flexibility in male, but not in female, middle-aged mice. It is possible that different genotypes and sexes require different amounts of AT to improve cognition, and future studies could explore longer AT interventions in the Val/Val mice.…”

“…Exercise, sex, and estrogens influence BDNF (Barha et al, 2017a(Barha et al, , 2017bChan and Ye, 2017). BDNF levels are increased after exercise in humans (plasma and serum) and rodents (hippocampus, corpus striatum and amygdala) (Bastioli et al, 2022;Barha et al, 2017aBarha et al, , 2017cErickson et al, 2011;Liu et al, 2009;Marais et al, 2009;Pietrelli et al, 2018;Short et al, 2022;Triviño-Paredes et al, 2016;Voss et al, 2013). BDNF is a neurotrophin strongly involved in the neurogenic process, and modulates the effects of exercise on brain outcomes (Berchtold et al, 2001;Cowansage et al, 2010;Triviño-Paredes et al, 2016;Voss et al, 2013).…”

Long-term memory, synaptic plasticity and dopamine in rodent medial prefrontal cortex: Role in executive functions

“…Moreover, an increase in plasticity-related immediate-early gene expression (c-fos) in mPFC during a similar task was reported, while its suppression was found to produce learning deficits (Morrow et al, 1999 ). However, subsequent investigations revealed the key role of the basolateral amygdala in associating sensory and shock-related inputs (Quirk and Mueller, 2008 ) and a hippocampal involvement in the reinstatement of extinguished fear (Frohardt et al, 2000 ; Short et al, 2022 ), whereas mPFC was shown to mediate primarily the consolidation of extinction. More specifically, the learning to inhibit a fear response was shown to be associated with synaptic changes in mPFC, as tested by an electric stimulation of medio-dorsal thalamus or ventral hippocampus synapses to mPFC neurons (Milad and Quirk, 2002 ; Quirk et al, 2006 ; Hugues and Garcia, 2007 ).…”

Walking, Running, Swimming: An Analysis of the Effects of Land and Water Aerobic Exercises on Cognitive Functions and Neural Substrates

“…In animals, a multidimensional high-level stimulation is modeled by the experimental paradigm of environmental enrichment [ 15 , 16 , 17 ]. However, several studies have specifically focused on the analysis of the effects of physical activity in animal models, both in physiological and pathological conditions [ 18 , 19 , 20 ]. The use of rodent-based exercise models provides a number of advantages in comparison to human studies, because of their shorter gestational period and lifespan, more numerous progenies, superior genetical and physiological homogeneity, higher control in experimental procedure choices, and the larger possibility of investigation in the nervous system [ 21 ].…”