Treadmill exercise prevents aging-induced failure of memory through an increase in neurogenesis and suppression of apoptosis in rat hippocampus

doi:10.1016/j.exger.2010.02.005

Experimental Gerontology

Volume 45, Issue 5, May 2010, Pages 357-365

https://doi.org/10.1016/j.exger.2010.02.005 Get rights and content

Abstract

Aging leads to functional changes in the hippocampus, and consequently induces cognitive deficits, such as failure of memory. Neurogenesis in the hippocampal dentate gyrus continues throughout life, but steadily declines from early adulthood. Apoptosis occurs under various pathologic and physiologic conditions, and excessive apoptotic cell death can cause a number of functional disorders in humans. Apoptosis in the hippocampus also disturbs cognitive functions. In this study, we examined the effect of treadmill exercise on memory in relation to neurogensis and apoptosis in the hippocampal dentate gyrus of old-aged rats. The present results showed that loss of memory by aging was associated with a decrease in neurogenesis and an increase in apoptosis in the hippocampal dentate gyrus. Treadmill exercise improved short-term and spatial memories by enhancing neurogenesis and suppressing apoptosis in the hippocampal dentate gyrus of old-aged rats. In the present study, we showed that treadmill exercise is a very useful strategy for preventing failure of memory in the elderly.

Introduction

Cognitive functions, such as learning and memory, declines as aging is in process. Aging leads to functional changes of the hippocampus that plays a pivotal role in learning and memory, resulting in a disturbance of cognitive functions (Jarrard, 1995, Mattson and Magnus, 2006).

Newly generated neurons in the hippocampal dentate gyrus improve or maintain learning and memory functions (Cao et al., 2004, van Praag et al., 2005). Neurogenesis in the adult hippocampus is known to be decreased by various factors, such as aging, irradiation, and stress (Karten et al., 2005, Kuhn et al., 1996, Madsen et al., 2003). In particular, aging is a potent factor causing a decrease of neurogenesis. Kuhn et al. (1996) reported that the production rate of new cells in the hippocampal dentate gyrus is dramatically decreased in aged animals. It has been suggested that an age-related reduction of neurogenesis is due to reduced neurotrophic stimulation. Brain-derived neurotrophic factor (BDNF) is involved in the age-related decline of neurogenesis, and the level of nerve growth factor is also decreased with age (Hattiangady et al., 2005). This was also supported by the observation that administration of neurotrophic factors successfully improved the age-related decrease in hippocampal neurogenesis (Scharfman et al., 2005).

Apoptosis in the hippocampus also affects memory functions. Apoptosis has two main pathways (the extrinsic and intrinsic pathways). A class of cysteine proteases, such as caspase-8, caspase-9, and caspase-3, is commonly involved in these pathways (Aggarwal, 2000, Nuñez et al., 1998, Skulachev, 1998). Besides caspases, the Bcl-2 family proteins also play important roles in regulation of apoptosis. The Bcl-2 family proteins are classified into anti-apoptotic proteins, including Bcl-2 and Bcl-2_XL, and pro-apoptotic proteins, such as Bax and Bid. The balance between pro-apoptotic and anti-apoptotic Bcl-2 family members determines the mitochondrial response to apoptotic stimuli (Upadhyay et al., 2003). Although apoptosis plays a crucial role in the adult dentate gyrus by preventing excessive growth of the granule cells, neuronal apoptosis in the cortex and hippocampus changes learning and memory, and excessive neuronal apoptosis in hippocampus contributes to dysfunction of the central nervous system (Kuhn et al., 2005, Sun et al., 2009).

The beneficial effects of physical exercise on brain function, such as spatial learning and memory, have been reported in many studies (Fordyce and Wehner, 1993, Samorajski et al., 1985). Kim et al. (2003) reported that treadmill exercise increased cell proliferation in the dentate gyrus in various age groups. Although previous studies have documented that physical exercise increases cell proliferation in the dentate gyrus, the effect of physical exercise on memory in relation to neurogenesis and apoptosis in the hippocampal dentate gyrus in old-aged rats has not been fully explored. Therefore, in the present study, we investigated the effect of treadmill exercise on short-term and spatial memories in relation to neurogenesis and apoptosis in the hippocampal dentate gyrus of old-aged rats, using behavioral tests, immunohistochemistry, immunostaining, and Western blot.

Section snippets

Animals

Five-month-old Sprague–Dawley rats (n = 20) were used as the young-aged group and 24-month-old rats (n = 20) were used as the old-aged group. The experimental procedures were performed in accordance with the animal care guidelines of the National Institutes of Health (NIH) and the Korean Academy of Medical Sciences. The rats were housed under controlled temperature (20 ± 2 °C) and lighting (07:00 to 19:00 h) conditions with food and water available ad libitum. The rats were randomly divided into 4

Effect of treadmill exercise on short-term memory

To evaluate the effect of treadmill exercise on short-term memory, a step-down avoidance task was performed. The results of the step-down avoidance task are presented in Fig. 1A. The latency time was 172.90 ± 38.41 s in YC group, 205.22 ± 31.72 s in YE group, 14.20 ± 7.93 s in OC group, and 46.62 ± 15.65 s in OE group.

The present results showed that the latency time of the old-aged group was conspicuously shorter than that of the young-aged group (p < 0.05). In contrast, treadmill exercise increased the

Discussion

Aging-related structural and physiological impairments of the hippocampus processing memory can occur with aging, and such changes contribute to spatial memory decline (Driscoll and Sutherland, 2005, Rosenzweig and Barnes, 2003). Actually, Jacobson et al. (2008) reported that aged rats performed worse than younger group on hippocampus-dependent tasks. Our data through behavioral tests revealed that aging incapacitated short-term and spatial memories. However, treadmill exercise enhanced

Acknowledgement

This work was supported by the Korea Science and Engineering Foundation (KOSEF) grant funded by the Korea government (MEST) (No. R11-2008-036-03004-0).

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Treadmill exercise prevents aging-induced failure of memory through an increase in neurogenesis and suppression of apoptosis in rat hippocampus

Abstract

Introduction

Section snippets

Animals

Effect of treadmill exercise on short-term memory

Discussion

Acknowledgement

Neurobiol. Aging

Biochem. Pharmacol.

Neuroscience

Brain Res.

Exp. Neurol.

Exp. Gerontol.

Behav. Brain Res.

Brain Res. Dev. Brain Res.

Trends Neurosci.

Brain Dev.

Curr. Opin. Cell Biol.

J. Diabetes Complications

Neuroscience

J. Biol. Chem.

Neuron

Prog. Neurobiol.

Lancet Neurol.

Neurobiol. Aging

Exp. Neurol.

Physiol. Behav.

Neurosci. Lett.

FEBS Lett.

Behav. Brain Res.

Brain Res. Bull.

Brain Res. Mol. Brain Res.

Subtle shifts in the ratio between pro- and antiapoptotic molecules after activation of corticosteroid receptors decide neuronal fate

FASEB J.