Exercise-mimetic AICAR transiently benefits brain function

Exercise enhances learning and memory in animals and humans. The role of peripheral factors that may trigger the beneficial effects of running on brain function has been sparsely examined. In particular, it is unknown whether AMP-kinase (AMPK) activation in muscle can predict enhancement of brain plasticity. Here we compare the effects of running and administration of AMPK agonist 5-Aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR, 500 mg/kg), for 3, 7 or 14 days in one-month-old male C57BL/6J mice, on muscle AMPK signaling. At the time-points where we observed equivalent running- and AICAR-induced muscle pAMPK levels (7 and 14 days), cell proliferation, synaptic plasticity and gene expression, as well as markers of oxidative stress and inflammation in the dentate gyrus (DG) of the hippocampus and lateral entorhinal cortex (LEC) were evaluated. At the 7-day time-point, both regimens increased new DG cell number and brain-derived neurotrophic factor (BDNF) protein levels. Furthermore, microarray analysis of DG and LEC tissue showed a remarkable overlap between running and AICAR in the regulation of neuronal, mitochondrial and metabolism related gene classes. Interestingly, while similar outcomes for both treatments were stable over time in muscle, in the brain an inversion occurred at fourteen days. The compound no longer increased DG cell proliferation or neurotrophin levels, and upregulated expression of apoptotic genes and inflammatory cytokine interleukin-1β. Thus, an exercise mimetic that produces changes in muscle consistent with those of exercise does not have the same sustainable positive effects on the brain, indicating that only running consistently benefits brain function. One-month-old C57BL/6J male mice (Jackson Laboratory, Bar Harbor, ME) were individually housed in standard conditions with food and water ad libitum, and were maintained in accordance with the National Institutes of Health guidelines. All protocols for procedures were approved by the NIA’s Institutional Animal Care and Use Committee. Animals were divided into 3 groups - control (CTR), AICAR-treated (ACR) or voluntary running (RUN). ACR mice received a daily intraperitoneal injection (IP) of 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR, Toronto Research Chemicals Inc., Canada) of 500 mg/kg/day, dissolved in saline; CTR and RUN animals received IP saline vehicle; RUN animals had free access to running wheels. Animals were sacrificed after deep anesthesia with isofluorane (Henry Schein Animal Health, OH) after 7, 14 or 28 days, and the dentate gyrus (DG) and lateral entorhinal cortex (LEC) were collected and immediately frozen and stored at -80ºC.