Exercise and hippocampal bidirectional synaptic plasticity

点击翻译按钮获取中文摘要

In 1999 we showed for the first time that voluntary exercise can enhance the production of new neurons in the adult hippocampus (called adult neurogenesis) and facilitate spatial memory, a cognitive function that the hippocampus is believed to support. My initial NSERC funding in 2001 allowed me to establish this research program in Canada, and using both mice and rats, we went on to show that exercise can alter the neuro-circuitry of the hippocampus, and enhance the capacity for neurons to communicate with one another (a process called long-term potentiation (LTP) of synaptic efficacy). We subsequently went on to show that exercise also benefited existing cells, helping neurons to grow and sprout more branches and synaptic spines, much like fertilizer can help plants grow and develop more. These structural improvements were also accompanied by functional changes, making these cells more capable of communicating with other cells, and also improving learning and memory performance in the animals that exercised. Thus far, there is considerable evidence to indicate that exercise makes for a more dynamic hippocampus and enhances learning capacity, while animals that do not engage in exercise have a hippocampus that is both morphologically and functionally more restricted and static. Our current work continues to be focused on examining the mechanisms that allow exercise to be beneficial for hippocampal structure and function, however we have expanded our focus to include peripheral signaling molecules. Most of the focus to date has been on how exercise enhances brain-derived neurotrophic factor (BDNF), a growth factor that plays an important role in the growth and differentiation of new neurons. While BDNF is a key factor in mediating the effects of exercise, we have new evidence that indicates that peripheral signalling mechanisms also can play a direct role, possibly by affecting BDNF. Our research program intends to explore two signalling cascades related to the effects of exercise on muscle and adipocytes (fat cells). It has recently been shown that exercise can induce BDNF expression by acting though a PGC-1alpha/FNDC5 pathway. FNDC5 is a small protein, or myokine, that is released from muscles during exercise. Myokines are secreted as glycosylated type 1 membrane proteins. The secreted form of FNDC5 is called irisin, and we have preliminary data that irisin can directly impact synaptic plasticity in the hippocampus. Adiponectin, is a protein-hormone that is secreted from adipocytes into the bloodstream after exercise. Adiponectin receptors are highly expressed in the hippocampus (i.e. ADIPOR1 and ADIPOR2) and their activation leads to the phosphorylation of AMPK (5' adenosine monophosphate-activated protein kinase). AMPK is involved in regulating BDNF expression, and we believe that BDNF induction may be related to the ability of AMPK to activate PGC1-alpha signaling, suggesting a link between adiponectin and irisin release during exercise.