Chronic exercise has been reported to improve cognitive function. However, whether and how different types of exercise affect various learning and memory tasks remain uncertain. To address this issue, male BALB/c mice were trained for 4 weeks under two different exercise protocols: moderate treadmill running or voluntary wheel running. After exercise training, their spatial memory and aversive memory were evaluated by a Morris water maze and by one-trial passive avoidance (PA), respectively. Levels of neural plasticity-related proteins, i.e. brain-derived neurotrophic factor (BDNF), tropomyosin-related kinase B (TrkB) and synaptotagmin I (Syt I), in hippocampus and amygdala were determined by ELISA or immunoblotting. Finally, the functional roles of these proteins in the basolateral amygdala were verified by locally blocking them with K252a (a TrkB kinase inhibitor), or lentivirus expressing Syt I shRNA. We found that (1) although both moderate treadmill running and wheel running improved the Morris water maze performance, only the former improved PA performance; (2) likewise, both exercise protocols upregulated the BDNF-TrkB pathway and Syt I in the hippocampus, whereas only treadmill exercise upregulated their expression levels in the amygdala; (3) local injection of K252a abolished the treadmill exercise-facilitated PA performance and upregulation of amygdalar TrkB and Syt I; and (4) local administration of Syt I shRNA abolished the treadmill exercise-facilitated PA performance and upregulation of amygdalar Syt I. Therefore, our results support the notion that different forms of exercise induce neuroplasticity changes in different brain regions, and thus exert diverse effects on various forms of learning and memory.

The long-term effects of brief but repetitive febrile seizures (FS) on memory have not been as thoroughly investigated as the impact of single and prolonged seizure in the developing brain. Using a heated-air FS paradigm, we subjected male rat pups to one, three, or nine episodes of brief FS on days 10 to 12 postpartum. Neither hippocampal neuronal damage nor apoptosis was noted within 72 hours after FS, nor was there significant hippocampal neuronal loss, aberrant mossy fiber sprouting, or altered seizure threshold to pentylenetetrazol in any FS group at adulthood. The adult rats subjected to nine episodes of early-life FS, however, showed long-term memory deficits as assessed by the Morris water maze. They also exhibited impaired intermediate and long-term memory but spared short-term memory in the inhibitory avoidance task. Three hours after inhibitory avoidance training, phosphorylation of cAMP response-element binding (CREB) protein in the hippocampus was significantly lower in nine-FS-group rats than in controls. Furthermore, rolipram administration, which activated the cAMP-CREB signaling pathway by inhibiting phosphodiesterase type IV, reversed the long-term memory deficits in nine-FS-group rats by enhancing hippocampal CREB phosphorylation. These results raise concerns about the long-term cognitive consequences of even brief frequently repetitive FS during early brain development.

This study was to examine the effects of treadmill exercise on the expression of brain-derived neurotrophic factor (BDNF) in rat hippocampus. After 1-wk treadmill familiarization, animals in exercise groups received a 4-wk exercise training or an acute exercise. They were sacrificed 2 h or 2 d after exercise and their hippocampal BDNF mRNA and protein levels were determined. We demonstrated that 1) hippocampal BDNF mRNA and protein levels were both elevated in response to exercise training at 2 h after the last run but not after 2 d; 2) an acute moderate exercise (1 or 3 d) increased BDNF protein levels; 3) acute severe exercise increased BDNF protein and mRNA levels in animals under a familiarization regimen, while suppressed the BDNF mRNA level in rats without treadmill familiarization, paralleling the stress effect of immobilization/water exposure. We conclude that compulsive treadmill exercise with pre-familiarization acutely upregulates rat hippocampal BDNF gene expression.

New neurons are continuously generated in hippocampal subgranular zone throughout life, and the amount of neurogenesis is suggested to be correlated with the hippocampusdependent function. Several extrinsic stimuli are known to modulate the neurogenesis process. Among them, physical exercise has advantageous effects on neurogenesis and brain function, while inflammation shows the opposite. Herein we showed that a moderate running exercise successfully restored the peripheral lipopolysaccharide (LPS)-impaired neurogenesis in the dentate area. LPS treatment obstructed neuronal differentiation, but not proliferation. Exercise training facilitated both the proliferation of the neural stem cells and their differentiation into neurons. Interestingly, exercise replenished the LPS-reduced levels of brain-derived neurotrophic factor and its receptor, TrkB, and rescued the LPSdisturbed performance in water maze; while the LPS-elicited up-regulation of tumor necrosis factor-alpha and interleukin1b remained unaltered. In conclusion, our findings suggest that running exercise effectively ameliorates the LPS-disturbed hippocampal neurogenesis and learning and memory performance. Such advantageous effects of running exercise are not due to the alteration of inflammatory response, but possibly by the restoring the LPS-lessened brain-derived neurotrophic factor signaling pathway.

The present study has adopted the PCR differential display method to identify cDNA clones associated with memory formation in rats. The one-way inhibitory avoidance learning task was used as the behavioral paradigm. Total RNA isolated from the hippocampus of poor-memory (<80 sec) and good-memory (600 sec) rats 3 hr after training was used for comparison. Three cDNA fragments corresponding to different spliced forms of integrin-associated protein (IAP) mRNA were found to be differentially expressed in the hippocampus of good-memory rats. Quantitative reverse transcription-PCR revealed approximately four fold higher of IAP mRNA level in good-memory rats. This result was confirmed further by in situ hybridization analysis, and the major difference was in the dentate gyrus. It has been demonstrated that this difference in IAP mRNA expression is not attributable to different sensitivities of individual rats to electric shock. Rapid amplification of cDNA ends obtained the full-length IAP cDNA, which is 1192 bp in length excluding the poly(A+) tail. The IAP mRNA expression was significantly upregulated by NMDA and amphetamine injections to the dentate gyrus of the hippocampus. On the other hand, injection of antisense oligonucleotide complementary to the IAP transcript markedly impaired memory retention in rats and decreased the amplitude and slope of EPSP in the in vivo long-term potentiation paradigm. These results together suggest that IAP gene expression plays an important role in memory formation and synaptic plasticity in rat hippocampus.