Exercise-Induced Hippocampal Neurogenesis

Figure 1. Exercise promotes neurogenesis in the adult hippocampus
Image Unavailable
Photomicrographs in (a, b) show running animals have significantly
more dividing cells (BrdU+) than controls. Immunofluorescent confocal
microscopy (c, d) can be used to identify the newly born neurons,
where double-labeling for proliferation (BrdU+) and a neuronal phenotype
(NeuN+) appears orange. Adapted from Figure 2 in [47].

It is now widely recognized that neurogenesis—the birth, differentiation, and long term survival of new neurons—continues to occur in select regions of the adult mammalian brain throughout the lifespan [1]. This proliferation occurs primarily in the sub-ventricular zone and the dentate gyrus of the hippocampus and may be influenced by numerous endogenous and exogenous factors [2].

One important promoter of hippocampal neurogenesis in rodents and humans alike is aerobic exercise (Figure 1). Several molecular mechanisms have been proposed to underlie this effect, including the stimulation of growth factors, changes in angiogenesis, or activation of neurotransmitter systems following exercise [1].

Physical activity has been shown to act as an effective treatment in major depressive disorder [3]. In parallel, certain commonly-prescribed antidepressants have been shown to promote hippocampal neurogenesis. Taken together, these findings suggest hippocampal neurogenesis may serve as a common therapeutic mechanism for exercise and pharmacological interventions in depression [4].

Thus, mounting evidence continues to reveal the significant and relevant effects of exercise on the brain [5], and in particular, how the structural and functional changes associated with exercise-induced neurogenesis may have implications for cognition, mood, and overall psychological wellbeing.

1. Adult neurogenesis in the mammalian brain

Video: Neurogenesis in the Adult Brain
An introduction to neurogenesis in the adult brain: Dr. Tracey Shors,
Professor in the Department of Psychology at Rutgers (State University of New Jersey),
discusses her research on adult hippocampal neurogenesis and its implications in learning and memory.
Video source: http://www.youtube.com/watch?v=Im1qnPM3Y7w

1.1 Place of occurrence

Following the development of the nervous system, neurogenesis—the birth, differentiation, and long term survival of new neurons—has been shown to continue in only two regions in the adult mammalian brain [2]. The first site is the sub-ventricular zone (SVZ), from which immature neurons migrate rostrally to the olfactory bulb, whereby they develop into mature olfactory interneurons [6]. The second site of neurogenesis is the dentate gyrus (DG), a region of the hippocampal formation in the medial temporal lobe. Here new neurons are born from a population of neuronal progenitor cells found in the subgranular zone (SGZ) and gradually mature into excitatory granule cells that project out of the dentate gyrus [7], [8].

1.2 Regulation of hippocampal neurogenesis

The birth of neurons destined for the olfactory bulb and the hippocampus is believed to continue throughout the lifespan and is a highly regulated process [2]. Numerous endogenous and exogenous factors have been shown to affect neurogenesis, each playing an important role at one or more of its specific stages (i.e. early proliferation, differentiation, and long term survival) [3]. Neurogenesis in the dentate gyrus is a dynamic process whose rate is correlated with activity in the hippocampus [2], which plays a critical role in many aspects of human memory. Thus, intrinsic and extrinsic factors or behaviours that increase hippocampal activity (such as learning or environmental enrichment; see video above for more information) also promote neurogenesis [9],[10]. Likewise, factors such as stress, aging, and neuropathology, such as Alzheimer's disease, which can impair hippocampal function and memory, have also been implicated in the inhibition of neurogenesis [11],[12],[13].

2. Exercise promotes hippocampal neurogenesis

One important promoter of hippocampal neurogenesis is aerobic exercise [1]. This phenomenon has been most extensively studied in rodent models; more recently however, researchers have also begun to examine the effects of physical activity in the human brain.

2.1 Evidence in rodent models

It is now known that physical exercise in adult rodents regulates cell proliferation in the hippocampus, increasing neurogenesis in the dentate gyrus [14].

Many early studies examining the impact of aerobic fitness on hippocampal neurogenesis utilized an environmental enrichment model, whereby animals had access to running wheels as well as other sensory and motor stimuli [15]. However, the relative contribution of wheel running versus exposure to other components of an enriched environment in stimulating rodent hippocampal neurogenesis was confounded and difficult to discern in such experimental settings. Recently, Mustroph et al. (2012) demonstrated that aerobic exercise, as opposed to environmental enrichment alone, is the critical variable that can significantly promote rodent hippocampal neurogenesis (Figure 2) [15].

Figure 2. Exercise is the critical variable promoting hippocampal neurogenesis
Image Unavailable
BrdU staining shows significantly more cell proliferation in the dentate gyrus of animals with access to a
running wheel (RUN and EE+RUN) than the environmental enrichment (EE) condition alone.
Adapted from Figure 3 in [15].

2.1.1 Acute versus long term structural effects

Mice are active runners and will voluntarily run between 3 – 8 km per night, when they are most active [3]. This natural activity is sufficient to produce a two- to three- fold increase in the number of cells in the dentate gyrus as early as 24 hours following the start of physical activity [16]. In the acute phase, exercise appears to enhance the cell proliferation of precursor cells, with the greatest up-regulation seen after about 3 days of exercise [17], [18]. This upregulation effect diminishes over time—instead, exercise continued over the long term appears to preferentially favour the survival of late progenitor cells and the maintenance of intermediate precursor cells [18].

2.1.2 Older mouse models

In its promotion of hippocampal neurogenesis, chronic exercise may help to offset age-related declines in cell proliferation in the aging brain [5]. Indeed, evidence for a protective effect of aerobic exercise against an aging-related decline in neurogenesis has been shown in animal models [19], [20]. At the same time, studies have also failed to find an increase in neurogenesis in older mouse models [21]. This remains a controversial area in need of further research, as it is still unclear to what extent and by which mechanism chronic exercise may help offset the age-related decline of cell proliferation in the hippocampus of an aging brain.

2.2 Evidence in humans

Although animal models have proved essential for the study of exercise-induced hippocampal neurogenesis, an important consideration is the extent to which these findings are applicable to humans. Aside from brain imaging studies examining changes in brain volumes, few studies have examined structural changes in the human brain following exercise [5].

2.2.1 Brain imaging studies

Brain imaging studies by Colcombe and colleagues (2003; 2006) have shown that physical fitness correlates with structural changes in the frontal, parietal, and temporal cortices [22], [23]. Further to this, a simple exercise intervention (three-times weekly walking over six months) in sedentary adults produced significant increases in cortical volumes of the frontal and temporal lobes [23].

Figure 3. Exercise increases anterior hippocampal volume in humans
Image Unavailable
An aerobic exercise intervention in humans was found to
selectively increase volume in the anterior hippocampus.
Adapted from Figure 2 in [24].

More specifically, aerobic exercise training was found to lead to increased volume in the anterior hippocampus within the medial temporal lobe (Figure 3) [24]. In a single-blind, randomized control trial, Erickson et al. (2011) compared brain volumes between participants assigned to an aerobic exercise intervention and controls, who were assigned to stretching alone. Aerobic exercise led to a 2% increase in the anterior hippocampus volume, corresponding to the approximate hippocampal volume that may be lost every one to two years in the aging brain [24]. Thus, the results of this study suggest that aerobic exercise can induce significant structural changes in the brain, thereby protecting against age-related neuronal loss and functional decline.

Erickson et al.’s (2011) research is especially important as the structural changes were identified in a region of the brain that is consistent with the animal literature [24]. The anterior hippocampus contains the dentate gyrus, which has been implicated as the site of exercise-induced neurogenesis in rodent studies. Therefore, Erickson et al.’s (2011) results provide an important bridge between animal work and human studies and suggest there may be some convergence in rodents and humans regarding the effects of exercise on the brain [24].

2.3 Potential mechanisms underlying this effect

Physical activity, in particular aerobic exercise, can have widespread effects on the brain and the body through the activation of signalling pathways, growth factors, neurotransmitters and other signalling molecules [1]. With respect to exercise-induced neurogenesis specifically, several hypotheses have been proposed for the molecular mechanisms underlying this effect.

2.3.1 Brain-derived neurotrophic factor (BDNF)

Exercise upregulates several endogenous growth factors in the brain and systemically, which in turn act as regulators of cell proliferation, differentiation, and survival. Growth factors that are known to influence neurogenesis include fibroblast growth factor (FGF), epidermal growth factor(EGF), brain-derived neurotrophic factor (BDNF), insulin-like growth factor I (IGF-I), and vascular endothelial growth factor (VEGF) [1].

Perhaps the best studied of these growth factors is BDNF. Although it is produced throughout the brain, BDNF seems to play a significant role in hippocampal function in particular, where it is found in high concentrations. Its production (i.e. gene expression and protein synthesis) increases following exercise, both in the short term [25] and following a chronic exercise program [26]. The evidence linking BDNF expression and neurogenesis has mostly been correlative in nature. For example, research shows that exercise induces both BDNF expression and neurogenesis while glucocorticoids repress both BDNF and neurogenesis [27].

2.3.2 Insulin-like growth factor (IGF) and vascular endothelial growth factor (VEGF)

Studies have also found convincing evidence that IGF and VEGF may play a role in stimulating neurogenesis following exercise. The concentrations of IGF and VEGF have been shown to increase in the systemic circulation following physical activity [28], [29]. However, hippocampal neurogenesis following running is inhibited in animals where a peripheral block of VEGF and IGF has been applied, preventing these molecules from entering the brain [29], [30]. It is unclear whether these factors stimulate progenitor cells directly, or if their effects are mediated through a mechanism involving vascular changes in the brain following exercise.

Interestingly, recent evidence suggests an interaction may exist between IGF and BDNF, such that IGF modulates the effect of BDNF in promoting exercise-induced neurogenesis in the hippocampus [5]. When IGF receptors were blocked during exercise, the upregulation of BDNF gene expression and protein synthesis in hippocampal cells typically associated with aerobic exercise were not observed [31].

2.3.3 Other molecular mechanisms

Other molecular mechanisms proposed to mediate the effect of exercise on hippocampal neurogenesis include changes in vasculature (i.e. angiogenesis) [32], activation of endogenous opioid systems or monoamines, or up- and down-regulation in the activity of other neurotransmitter systems in the brain following exercise [1], including the glutamatergic system of the dentate gyrus itself [33].

Presumably, many of the beneficial effects of exercise on brain structure and function—including the promotion of adult hippocampal neurogenesis—may be linked to these and other molecular mechanisms activated both systemically and more locally in the brain.

3. Exercise-induced neurogenesis and depression

Although exercise-induced neurogenesis represents firstly a structural change in the brain, it has also been shown to have functional consequences for mood, cognition, and behaviour. For example, it has long been recognized that physical activity can act as an effective antidepressant [3], helping to ameliorate symptoms of mood disorders. Recently, a growing body of research suggests that exercise-induced hippocampal neurogenesis may mediate this therapeutic effect (bibcite huang2012))].

3.1 The antidepressant effects of exercise

Numerous studies provide evidence that exercise is beneficial for both physical health and mental wellbeing [5]. Importantly, exercise may play a therapeutic role in the treatment of major depression. For example, physical activity has been associated with a reduction in depressive symptoms in both clinical populations and healthy controls [34]. Furthermore, a recent meta-analysis examining 13 studies found a significant effect size in favour of using exercise as a therapeutic intervention in major depression, as compared to no treatment, placebo condition, or usual care in clinical populations [35]. Significantly, the effectiveness of exercise treatment in major depression has been shown to be on par with serotonin-targeting medications [36].

3.2 The role of hippocampal neurogenesis in depression

Diverse streams of evidence—ranging from imaging studies to animal research and psychopharmacology—have converged on the finding that hippocampal neurogenesis plays an important role in depression. In fact, the adult neurogenesis hypothesis of depression implicates reduced levels of hippocampal neurogenesis in the pathogenesis of depression (Figure 4) [37].

Figure 4. The adult neurogenesis hypothesis of depression
Image Unavailable
Chronic stress may inhibit neurogenesis and lead to the development of depression. Exercise and
antidepressants may help rescue neurogenesis in depression by stimulating similar neurotrophic mechanisms
at the molecular level. Adapted from Figure 1 in [48].

Brain imaging studies in humans have consistently found a decreased hippocampal volume in depressed individuals [38], believed to be the result of reduced hippocampal neurogenesis [39]. Similarly, rodent models of depression tend to show significantly reduced cell proliferation in the hippocampus [40]. At the same time, several antidepressants appear to act in the brain by either stimulating neurogenesis in the dentate gyrus of the hippocampus [41] or inhibiting cell apoptosis [42] in this brain region. For example, fluoxetine, a commonly prescribed selective serotonin reuptake inhibitor (SSRI), was found to increase the proliferation of a particular class of early progenitor cells in the hippocampus [43]. An easy-to-read research brief on the neurogenic effects of antidepressants can be found here.

Altogether, these findings suggest that hippocampal neurogenesis is a common target in the brain for both exercise and antidepressants. One implication is that hippocampal neurogenesis may serve as the common physiological mechanism underlying the therapeutic effects of exercise and antidepressants.

3.2.1 A common therapeutic mechanism for exercise and antidepressants?

Huang et al. (2012) [4] recently provided strong evidence in favour of a common therapeutic mechanism between exercise and antidepressants in the amelioration of depression. Moreover, the authors hypothesized that the common underlying factor contributing to improvements in depressive-like behaviour in rodents following each of these two interventions may be adult hippocampal neurogenesis [4].

Figure 5. Exercise and antidepressants both stimulate neurogenesis
Image Unavailable
Exercise and chronic fluoxetine (a SSRI) both produced
significantly greater numbers of newly-born neurons
in the dentate gyrus. Adapted from Figure 2 in [4].

To investigate whether any such shared molecular or neuronal mechanisms exist, the authors compared changes in neurogenesis, synaptic plasticity, and gene expression in the hippocampus of mice under three conditions: exercise, environmental enrichment, and chronic fluoxetine. Indeed, the results of the study suggested that antidepressant drugs (i.e. fluoxetine treatment) and exercise may share a common therapeutic mechanism [4]. First, fluoxetine treatment and voluntary exercise (but not environmental enrichment) both produced significant increases in hippocampal neurogenesis after 28 days. The two conditions also resulted in similar gene expression profiles, further supporting the hypothesis of commonalities in their molecular mechanism. Importantly, similarities were not only observed at the genetic level, but were also replicated at the behavioural level of analysis. Exercise reduced depressive-like behaviours in mice similar to chronic fluoxetine treatment across several behavioural tests [4].

Taken together, these results suggest that exercise and the antidepressant drug fluoxetine may share a common underlying antidepressant mechanism, and in particular, that this mechanism may be mediated through the stimulation of hippocampal neurogenesis [4].

3.3 Exercise and neurogenesis in the Flinders Sensitive Line (FSL) rodent model of depression

While antidepressant treatment and exercise interventions have been shown to effectively increase hippocampal neurogenesis in healthy rodent models, it is important to investigate whether these effects are true in a more clinically-relevant animal model. Bjornebekk and colleagues (2005; 2006) have reported some evidence along this line of research, investigating the effects of exercise in the Flinders Sensitive Line (FSL) model of depression [40], [44].

3.3.1 The Flinders Sensitive Line (FSL) model validity

The Flinders Sensitive Line (FSL) is a rodent model commonly used in the study of depression. The FSL line has high face validity as a model for human depression. That is, FSL rats show numerous behavioural characteristics and associated problems that are consistent with the symptoms of depression in humans [45]. For example, FSL rats have been shown to display poor motor activation and motivation, diminished appetite, and sleep disturbances [45].

Recently, studies attempting to characterize the FSL line at the cellular or molecular level have found support for the construct validity of this model. This suggests that some of the same underlying brain mechanisms may be responsible for depressive symptoms in rats and the human disorder [44]. Importantly, the ameliorating effects of exercise appear to hold true in animal models of depression [46], including the FSL line specifically [44], lending greater predictive validity to these models.

3.3.2 Exercise-induced neurogenesis in the FSL model

In 2005, Bjornebekk and colleagues conducted an interesting study in the FSL model, the results of which suggested an important role for exercise-induced hippocampal neurogenesis in the amelioration of depression [40]. First, the authors characterized the baseline cell proliferation in the hippocampus of FSL rats versus Flinders Resistant Line (FRL) controls. It was found that FSL rats showed a significantly lower cell proliferation than controls [40], as might be predicted from human studies. After 5 weeks of voluntary access to running wheels, hippocampal cell proliferation levels increased approximately 450% in FSL rats, normalizing to proliferation levels in controls [40].

This research demonstrates that exercise has a potent antidepressant effect, and that its impact on mood and behaviour may be mediated through the promotion of hippocampal neurogenesis. The study is particularly important given that it demonstrated the antidepressant effect of exercise in the Flinders Sensitive Line (FSL). This rodent model has already proven effective in the identification of pharmacological antidepressants for human use [45]. Thus, the antidepressant effects of free running reported in this research suggest that exercise therapy may also constitute a valid treatment option in human depression.

See also

Exercise and Cognition
Stress Induced Depression
The Effects of Exercise on Stress

External links

Bibliography
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