Little Exercise, Big Effects: Reversing Aging and Infection-Induced Memory Deficits, and Underlying Processes

Abstract

We have previously found that healthy aged rats are more likely to suffer profound memory impairments following a severe bacterial infection than are younger adult rats. Such a peripheral challenge is capable of producing a neuroinflammatory response, and in the aged brain this response is exaggerated and prolonged. Normal aging primes, or sensitizes microglia and this appears to be the source of this amplified inflammatory response. Among the outcomes of this exaggerated neuroinflammatory response are impairments in synaptic plasticity, and reductions of brain derived neurotrophic factor (BDNF), both of which have been associated with cognitive impairments. Since it has been shown that physical exercise increases BDNF mRNA in the hippocampus, the present study examined voluntary exercise in 24 mos old F344xBN rats as a neuroprotective therapeutic in our bacterial infection model. Although aged rats ran only an average of 0.7 km per week, this small amount of exercise was sufficient to completely reverse infection-induced impairments in hippocampus-dependent long-term memory compared to sedentary animals. Strikingly, exercise prevented the infection-induced exaggerated neuroinflammatory response and the blunted BDNF mRNA induction seen in the hippocampus of sedentary rats. Moreover, voluntary exercise abrogated age-related microglial sensitization, suggesting a possible mechanism for exercise-induced neuroprotection in aging.

Microglia Modulate Hippocampal Neural Precursor Activity in Response to Exercise and Aging

“…Importantly, exercise effectively countered the naturally occurring age-related decline in CX 3 CL1 levels within the hippocampus of aged mice, restoring them to those seen in young animals. These findings are supported by a recent study by Barrientos et al (2011), who suggested a potential beneficial link between running and altered neuroinflammatory responses. In our study, direct evidence for a role of CX 3 CL1 in regulating NPC activity was demonstrated via intraparenchymal infusion of a CX 3 CR1 blocking antibody into the hippocampus, which largely abolished the positive effect that microglia normally exert on these cells during running.…”

Neuronal-Glial Mechanisms of Exercise-Evoked Stress Robustness

“…Given that, BDNF is required for consolidation of hippocampal-dependent memory (Alonso et al 2002a, b;Tyler et al 2002), a reduction in this plasticityrelated molecule could be critical for the hippocampal-dependent memory disturbances produced by US. And finally, although the mechanisms for stressorand pathogen-evoked cytokine release are not interchangeable (Campeau et al 2010;Campisi et al 2012;Maslanik et al 2012), it is interesting to note that wheel running was recently reported to reduce hippocampal microglia activation, brain proinflammatory cytokine responses, and BDNF reductions after peripheral bacterial challenge in older rats (Barrientos et al 2011) lending additional support to our hypothesis that regular physical activity may quiet stressor-evoked hippocampal microglia activation, and protect against BDNF down-regulation and reduced neurogenesis.…”

The Effect of Preventive, Therapeutic and Protective Exercises on Hippocampal memory Mediators in Stressed Rats

“…Hence, the present findings suggested that the exercise before, after, and during stress could keep the balance of hippocampal IL-1 β level in the stress conditions. Conversely, Barrientos et al reported that exercise had no effect on the basal hippocampal IL-1β level (44).…”

“…Some studies reported that stress increased the central IL-1β level (43,44). On the other hand, it was also demonstrated that IL-1β is an important neurochemical mediator in the stress-induced stimulation of the hypothalamicpituitary-adrenal (HPA) axis and the secretion of adrenocorticotropin (ACTH) and corticosterone (CORT) (45,46).…”