Hippocampal functional hyperemia mediated by NMDA receptor/NO signaling in rats during mild exercise

Abstract

pal functional hyperemia mediated by NMDA receptor/NO signaling in rats during mild exercise. J Appl Physiol 112: 197-203, 2012. First published September 22, 2011 doi:10.1152 doi:10. /japplphysiol.00763.2011rent studies have demonstrated that exercise increases regional cerebral blood flow (rCBF), an index of neuronal activity. However, neuronal regulation of the increased rCBF in the brain parenchyma is poorly understood. We developed a running model with rats for monitoring hippocampal cerebral blood flow (Hip-CBF) and found that mild treadmill running increases Hip-CBF in a tetrodotoxin-dependent manner, suggesting that functional hyperemia, an increase in rCBF in response to neuronal activation, occurs in the running rat's hippocampus (Nishijima T and Soya H. Neurosci Res 54: 186-191, 2006). To further support our hypothesis, it was important to discover the neurogenic pathways behind the increase in Hip-CBF that occurred during running. Here, we examine the possible role of N-methyl-D-aspartate (NMDA) receptor/nitric oxide (NO) signaling and group I metabotropic glutamate receptors in mediating the Hip-CBF increase. Hip-CBF during running was measured by laser-Doppler flowmetry. Intrahippocampal drug administration was performed by microdialysis. Mild treadmill running (10 m/min) increased Hip-CBF, which was remarkably attenuated by either NMDA receptor antagonists (1 mM MK-801) or NO synthase inhibitors (2 mM N G -nitro-L-arginine methyl ester). However, group I metabotropic glutamate receptor antagonists {1 mM 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester ϩ 1 mM 2-methyl-6-(phenylethynyl)pyridine hydrochloride} augmented the running-induced Hip-CBF increase. We also found that rCBF in the olfactory bulb was unchanged with running. These results strongly suggest that Hip-CBF during mild exercise is regulated locally under hippocampal neuronal activity, mediated mainly through NMDA receptor/NO signaling. Collectively, these results, together with our previous findings, support our hypothesis that mild exercise elicits neuronal activation, which then triggers functional hyperemia in the rat hippocampus.

Voluntary wheel running ameliorates symptoms of MK-801-induced schizophrenia in mice

“…Treadmill exercise increases NMDA receptor immunoreactivity and protein level in the hippocampus (44). Nishijima et al (45) suggested that exercise-induced increase in hippocampal cerebral blood flow is regulated by hippocampal neuronal activity, mediated mainly through the NMDA receptor. In the present study, mice that participated in voluntary wheel running demonstrated enhanced NMDA receptor expression in the hippocampus, comparable to the effects of aripiprazole treatment.…”

Mild exercise increases dihydrotestosterone in hippocampus providing evidence for androgenic mediation of neurogenesis

“…On the basis of the LT, the rats were subjected to mild treadmill exercise at a running speed of 13.5 m/min. We previously showed that hippocampal activation is induced by exercise intensities below the LT (17). The rats were habituated to the treadmill apparatus for 10 min (KN-73; Natsume) before training, and then they were subjected to 2 wk of training, five times per week for 30 min at a time.…”

“…Furthermore, mild exercise increases regional cerebral blood flow, an index of neuronal activity, through the glutamatergic pathway, and continuous mild exercise enhances AHN (16,17). These results led us postulate that exercise would enhance androgen synthesis, which may in turn mediate exercise-induced AHN, even though the possible role of androgens in hippocampus plasticity has not been extensively studied, particularly in relation to the effects of exercise.…”

“…We used treadmill running, which can be controlled for speed, and developed a mildintensity treadmill exercise model below the lactate threshold (LT, about 20 m/min) with less blood lactate accumulation and minimal stress response; the LT is a physiologic index of moderate exercise intensity established in rats (25,26) as in humans (27). We have also shown that hippocampal neuronal activity and neurogenesis is induced by the mild-intensity exercise (16,17,28).…”

Mild exercise model for enhancement of hippocampal neurogenesis: A possible candidate for promotion of neurogenesis

“…In addition, to examine the enhancement of neuronal activity in real-time, we monitored local blood flow in CA1 using the laser doppler method 39,40) . As neuronal activity becomes more frequent, local blood flow in the vicinity of the activated area increases to satisfy the increased demand for oxygen energy, a process known as "neurovascular coupling".…”