Exercise, antidepressant treatment, and BDNF mRNA expression in the aging brain

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Abstract

Principal mental disorders affecting the geriatric population include dementia and depression. A lack of trophic support is thought to contribute to the pathology of these disorders. Physical activity and antidepressant treatment increase the expression of brain-derived neurotrophic factor (BDNF) in the young rat hippocampus. Herein, we investigated the responsiveness of the aging rat hippocampus to antidepressant treatment and voluntary exercise. In situ hybridization revealed that, in young animals, exercise, antidepressant treatment, or their combination elevated BDNF mRNA levels in several hippocampal regions, most notably in the CA3, CA4, and dentate gyrus (DG). This effect was rapid (detectable at 2 days) and sustainable to 20 days. In aged (22-month-old) rats, hippocampal responsiveness to antidepressant treatment and exercise was also rapid and sustainable, but evident mostly in the CA1 and CA2. Daily swimming also revealed that small amounts of activity led to marked elevations in hippocampal BDNF mRNA. The differences in regional patterns of BDNF mRNA elevations between young and aged animals observed with running were maintained with this different exercise modality. Our results indicate that the aged brain is responsive to exercise and antidepressant treatment, and changes in regional response patterns may reflect shifts in hippocampal physiology during the lifespan.

Introduction

The principal mental disorders affecting late life are dementias, such as Alzheimer's disease (AD) and the primary mood disorder, depression. Emotional disturbances, such as depressed mood, apathy, anxiety, and aggression, are among the most common and problematic symptoms in neurodegenerative disorders (Reisberg et al., 1987). Many have theorized that neuronal atrophy and death in neurodegenerative disorders result, in part, from a lack of trophic support (Appel, 1981). In fact, a key member of the neurotrophin family, brain-derived neurotrophic factor (BDNF), is diminished in the hippocampi of AD patients Murray et al., 1994, Phillips et al., 1991. BDNF, the most widely distributed neurotrophin within the adult central nervous system (CNS), is present in highest concentrations within the hippocampus, a brain area with vital functions in learning and memory as well as in behavioral regulation (Hofer et al., 1990).

Previous studies have shown that BDNF promotes the growth and survival of several neuronal classes, including mesencephalic dopaminergic neurons (Knüsel et al., 1991), septal and basal forebrain cholinergic neurons (Nonner et al., 1996), and striatal GABAergic neurons (Ventimiglia et al., 1995). BDNF also serves as a neurotransmitter modulator Frerking et al., 1998, Kafitz et al., 1999 and participates in use-dependent plasticity mechanisms, such as long-term potentiation and learning Figurov et al., 1996, Levine et al., 1995, Lindsay et al., 1994. After binding to its tyrosine kinase receptor, trkB, BDNF activates a number of growth and survival-promoting intracellular signaling pathways, including the Ras/MAP kinase and phosphotidylinositol-3 kinase/Akt cascades (Yuan and Yankner, 2000).

Hippocampal BDNF is down-regulated in response to stress (Smith et al., 1995). Both clinical and animal studies have indicated that prolonged and severe stress may play an important role in the pathophysiology of depression and other psychiatric disorders. Neuronal atrophy and cell death have been observed in the hippocampi of animals exposed to chronic stress Sapolsky, 2000, Watanabe et al., 1992, and animals subjected to stress also show behavioral changes associated with a depressive state Benelli et al., 1999, Redrobe and Bourin, 1999. In addition, humans with a history of chronic, recurrent depression, or posttraumatic stress disorder have shown significant hippocampal atrophy in imaging studies Bremner et al., 1995, Sheline et al., 1996.

One measure taken to treat emotional symptoms associated with mental disorders of aging is the administration of antidepressant medications. In recent years, evidence has been gathering that BDNF expression may be a downstream target of monoamine-enhancing, mood-stabilizing antidepressant treatments, and could be an important agent for therapeutic recovery from depression and the protection against stress-induced neuronal damage (D'Sa and Duman, 2002). The direct infusion of BDNF into the midbrain has been shown to produce an antidepressant-like effect in behavioral models, such as the learned helplessness and forced swim paradigms Shirayama et al., 2002, Siuciak et al., 1997. Moreover, chronic treatment with a variety of antidepressant medications has been shown to up-regulate the cAMP–CREB (cyclic AMP response element-binding protein) cascade and expression of BDNF mRNA levels in the rat hippocampus Nibuya et al., 1996, Thome et al., 2000.

Recent evidence also suggests that our daily behaviors and lifestyle influence the level of BDNF expression in the brain. Experiences often associated with enhanced emotional health, such as exercise and environmental enrichment, increase transcription of this important neurotrophin Ickes et al., 2000, Neeper et al., 1995, Schoups et al., 1995 and also regulate adult neurogenesis within the hippocampus Duman et al., 2001, van Praag et al., 1999. The ability of exercise to improve the psychiatric status of young and middle-aged depressed patients has been suggested for some time now Hill et al., 1993, Labbe et al., 1988. In addition, Singh et al. (2001) have shown that unsupervised exercise in elderly subjects maintained an antidepressant effect over a 20-week period. Studies from our laboratory suggest that physical activity both enhances and accelerates BDNF mRNA up-regulation brought about by antidepressant treatment in the rat (Russo-Neustadt et al., 2000). These studies also suggest that the interventions of exercise and antidepressant treatment enhance BDNF expression via similar intracellular pathways. Taken together, current evidence suggests that a BDNF deficit may play an important role in the pathophysiology of mental illness, and its enhancement may play an important role in treatment.

Pharmacological treatment in geriatric patients is challenging, as the aging brain is thought to be less plastic and more beset by complications, such as oxidative damage and metabolic changes Navarro et al., 2002, Stewart, 1982, Toescu et al., 2000. In our study, we have assessed the responsiveness of the aging rat hippocampus to antidepressant treatment and exercise. We have employed the use of commercially available, aged Fischer-344 (F-344) rats in our experiments. To ensure continuity and comparability with our previous studies of hippocampal BDNF expression, we have also used Sprague–Dawley (SD) rats as animal subjects. We have asked whether antidepressant treatment may enhance BDNF expression in the aging hippocampus, and whether this response could be accelerated or augmented by voluntary physical exercise, as is evident in the young animal.

Section snippets

Animal subjects

Three-month-old male SD rats (Charles River), 3-month-old male F-344 rats (National Institute of Aging/Harlan), and 22-month-old male F-344 rats (National Institute of Aging/Harlan) were housed singly with food and water ad libitum in a vivarium with controlled temperature and humidity and a 12:12-h (06:00–18:00 h) light/dark cycle. All rats were allowed to acclimate to the vivarium for 1 week prior to the start of experiments. For the voluntary wheel-running experiment, animals were randomly

BDNF mRNA levels with acute treatment (2 days)

In young SD rats, the combination of tranylcypromine and physical activity led to small but significant elevations in hippocampal BDNF mRNA levels after 2 days of treatment in all subregions examined, except in the CA2 [CA1, F(3,24)=5.130, P<.01, 16% above controls; CA3, F(3,24)=3.772, P<.05, 66% above controls; CA4, F(3,23)=5.080, P<.01, 81% above controls; and dentate gyrus (DG), F(3,24)=2.655, P<.05, 37% above controls] (Fig 1A). Individually, tranylcypromine elevated BDNF mRNA levels in the

Discussion

Our previous studies revealed that in young adult rats, antidepressant treatment, voluntary physical exercise, or the two interventions combined resulted in significant increases in hippocampal BDNF mRNA expression after 2, 7 (Russo-Neustadt et al., 2000), or 20 (Russo-Neustadt et al., 1999) days. The largest BDNF mRNA increases were observed in the CA3, CA4, and DG subfields. To ensure continuity and comparability with these previous studies, we used young rats of the same strain (SD rats) for

Acknowledgements

This work was supported by U.S. Public Health Service Grant MH-59776, a NASAD Young Investigator Award to A.R.N., and MBRS-RISE support to A.A.G. and C.G.

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