New to the HDL is the finding that estrogen may affect BDNF levels because estrogen affects the desire to exercise. Here is a good referenced review of how exercise affects us all. --Jerry

Exercise: a behavioral intervention to enhance brain health and plasticity Extensive research on humans suggests that exercise could have benefits for overall health and cognitive function, particularly in later life.

Recent studies using animal models have been directed towards understanding the neurobiological bases of these benefits. It is now clear that voluntary exercise can increase levels of brain-derived neurotrophic factor (BDNF) and other growth factors, stimulate neurogenesis, increase resistance to brain insult and improve learning and mental performance. Recently, high-density oligonucleotide microarray analysis has demonstrated that, in addition to increasing levels of BDNF, exercise mobilizes gene expression profiles that would be predicted to benefit brain plasticity processes. Thus, exercise could provide a simple means to maintain brain function and promote brain plasticity.

In 1890, William James first recognized that one of the most important features of human behavior is the ability to carry out meaningful change [1]. He broadly defined this under the rubric of 'behavioral plasticity'. Since then, this concept of plasticity has been further developed to include structural change in the brain at the cellular, molecular, and system levels, with the convergence of these mechanisms ultimately supporting behavioral plasticity.

Maintaining brain health and plasticity throughout life is an important public health goal, and it is increasingly clear that behavioral stimulation and exercise can help us to achieve it. Such intervention is particularly crucial from middle age onwards, when the brain faces a series of challenges that can include the pathogenesis of neurodegenerative diseases like Alzheimer's disease (AD). Over the past decade, a number of studies on humans have shown the benefits of exercise on brain health and function, particularly in aging populations. Exercise participation has consistently emerged as a key indicator of improved cognitive function [2–5] . Recently, a large, five-year prospective study revealed that physical activity was associated with lower risks of cognitive impairment, AD and dementia in general [6]. Furthermore, a retrospective analysis found that behavioral stimulation and physical activity reduced the risk of developing AD [7]. These data from humans are supported by animal research demonstrating that exercise and/or behavioral enrichment can increase neuronal survival and resistance to brain insult [8,9] , promote brain vascularization [10,11] , stimulate neurogenesis [12], enhance learning [12,13] and contribute to maintenance of cognitive function during aging [14].

Exercise and neurotrophic factors

It is possible that some of the beneficial aspects of exercise act directly on the molecular machinery of the brain itself, rather than on general health (as was widely assumed in the early 1990s). To explore this hypothesis, we sought a protocol for an animal study in which exercise would be isolated as the central variable, and that would parallel aspects of human exercise studies. Voluntary wheel-running was selected because it allows rats or mice to choose how much to run (i.e. it avoids confounding variables associated with the stress of forced treadmill running and investigator handling) and it is quantifiable.

Several molecular systems could potentially participate in the benefits of exercise on the brain. Neurotrophic factors have most of the properties that could underlie such beneficial effects. We chose to focus initially on brain-derived neurotrophic factor (BDNF) because it supports the survival and growth of many neuronal subtypes, including glutamatergic neurons [15,16] . Subsequently, as the neurotrophin field evolved, BDNF emerged as a key mediator of synaptic efficacy, neuronal connectivity and use-dependent plasticity.

We predicted that a neurotrophin-mediated response to exercise would probably be restricted to motor–sensory systems of the brain, such as the cerebellum, primary cortical areas or basal ganglia. The findings were surprising: several days of voluntary wheel-running increased levels of BDNF mRNA in the hippocampus [21], a highly plastic structure that is normally associated with higher cognitive function rather than motor activity. The changes in mRNA levels were found in neurons, particularly those of the dentate gyrus (DG), hilus and CA3 region. They appeared within days in both male [22] and female [23] rats, were sustained even after several weeks of exercise [24], and were paralleled by increased amounts of BDNF protein ( Fig. 2). In addition to the hippocampus, running activity increased levels of BDNF mRNA in the lumbar spinal cord [25], cerebellum and cortex [22], but not in the striatum [22]. Although other trophic factors, including nerve growth factor (NGF) [22] and fibroblast growth factor 2 (FGF-2) [26], were also induced in the hippocampus in response to exercise, their upregulation was transient and less robust than that of BDNF, suggesting that BDNF is a better candidate for mediating the long-term benefits of exercise on the brain.

Research on humans suggests that exercise and behavioral stimulation can maintain or improve brain plasticity. Learning, a high-order of brain plasticity, increases BDNF gene expression [27], and BDNF, in turn, facilitates learning [28]. This predicts that mechanisms that induce BDNF gene expression, such as exercise, can enhance learning. Indeed, running enhances LTP in the DG and improves spatial learning in the water-maze task [12].

Roles of neuronal activity and neurotransmitters

Neuronal activity and neurotransmitter interactions control BDNF gene expression patterns in the hippocampus, with glutamate-mediated signaling being the likely central convergence point. Several modulatory neurotransmitters that converge on glutamatergic neurons, including ACh, GABA and monoamines, could affect BDNF expression.

The medial septum, being a source of cholinergic and GABAergic afferents to the hippocampus, might participate in the upregulation of BDNF in response to exercise. As first reported by Vanderwolf in 1969 [29], voluntary wheel-running activates a persistent firing pattern (known as theta-rhythm) in the rat hippocampus, and this firing pattern is dependent on medial septal cholinergic and GABAergic neurons [29–32] . Extensive literature supports the idea that an ACh-mediated mechanism also regulates BDNF gene expression in the hippocampus, particularly in the basal state [33–35] . This suggests that ACh-mediated activation of the hippocampus could underlie the regulation of BDNF by exercise.

Surprisingly, although septal ACh-mediated input provides tonic regulation of baseline hippocampal BDNF gene expression, it is not a key regulator in the activity-dependent state. Despite causing complete loss of septo–hippocampal cholinergic afferents and a reduction in basal BDNF gene expression, selective lesions of medial septal cholinergic neurons did not impair exercise-induced BDNF gene expression in the hippocampus [36]. By contrast, when partial loss of septal cholinergic afferents was combined with loss of medial septal GABAergic neurons, exercise-dependent BDNF regulation was disrupted, notably in the DG and hilus. Thus, there is a strong involvement of the medial septum in activity-dependent regulation of BDNF gene expression, and it appears to involve either non-ACh-mediated signaling or a combination of neurotransmitter systems [36].

Monoamine-mediated signaling also contributes to BDNF gene regulation. Several antidepressants that increase transmission at monoaminergic synapses also increase BDNF gene expression in the hippocampus [37,38] . Interestingly, antidepressant treatment in combination with exercise enhances exercise-dependent BDNF upregulation in the hippocampus [24]. Noradrenaline-mediated signaling might be particularly important in the modulation of BDNF gene expression by exercise [39].

Regulation by peripheral as well as central mechanisms

Although CNS activity-dependent mechanisms are pivotal in driving exercise-induced changes in levels of BDNF mRNA in the brain, it is now emerging that peripheral mechanisms are also important. Components contributing to this peripheral control include estrogen, corticosterone and insulin-like growth factor-1 (IGF-1).

Estrogen-dependent upregulation of BDNF gene expression
Steroid hormones such as estrogen influence brain aging, particularly in post-menopausal women. Estrogen replacement (ER) after menopause appears to slow age-related cognitive decline and to delay the onset of AD in human subjects [40]. Conversely, reduced levels of estrogen compromise neuronal function, survival and synaptogenesis in animal models [41], and decrease hippocampal availability of BDNF [23,42] .

In females, the benefits of exercise appear to depend on the presence of estrogen [23]. After two months of estrogen-deprivation, exercise no longer increased either BDNF mRNA or protein levels in the female rat hippocampus. By contrast, when exercise was combined with long-term ER, BDNF protein levels showed a greater increase than in response to ER alone ( Fig. 3a) [23]. Thus, the presence of estrogen in females might be a permissive factor necessary for exercise-induced regulation of BDNF availability.

Interestingly, levels of voluntary physical activity also depend on estrogen status. Animals were less active in the absence of estrogen, and ER restored activity to normal levels ( Fig. 3b) [23]. This effect of estrogen raises the interesting possibility that some of the health benefits associated with hormone replacement in women could be related to increased exercise participation.

Exercise and stress: antagonistic regulators of BDNF levels
Prolonged exposure to stress hormones (e.g. corticosteroids) is harmful for neuronal health and survival, particularly in the hippocampus [43]. In response to acute and chronic stress, neurons undergo morphological changes, including dendritic atrophy and spine reduction, which have a negative impact on brain plasticity [44–46] . Exercise is commonly believed to be a behavioral strategy to relieve stress, and can reduce depression and anxiety in humans [47]. Animal studies demonstrate that corticosteroids decrease BDNF availability in the hippocampus [48], although exercise before a stressful event can counteract this downregulation. For example, one week of voluntary wheel-running exercise before forced swimming prevents downregulation of hippocampal BDNF mRNA and improves behavioral measures of stress [49]. The molecular mechanism(s) responsible for the ability of exercise to counteract stress is an exciting field for future research with clear human relevance.

IGF-1 as a mediator of the effects of exercise
IGF-1, a growth factor structurally related to pro-insulin, is a potent survival factor for neurons and oligodendrocytes and participates in neuronal growth and differentiation in the brain [50,51] . In addition, IGF-1 might be an upstream mediator of BDNF gene regulation, neurogenesis and the ability of exercise to protect the brain from injury [9,52] . IGF-1 levels increase in both the periphery [53] and brain [52] after exercise, and at least part of the increase in the brain reflects increased transport from the periphery across the blood–brain barrier [54]. Interestingly, peripheral IGF-1 appears to participate in the neuroprotective effect of exercise, as peripheral infusion of IGF-1-blocking antibodies before an injury reduces the protection [9]. Because peripheral administration of IGF-1 induces BDNF mRNA in the brain [52], BDNF is potentially a downstream target that mediates some of the protective effects of IGF-1. These data suggest that peripheral IGF-1 initiates growth-factor cascades in the brain that can alter ongoing plasticity mechanisms.

Promotion of neurogenesis
The effect of exercise on genes encoding neurotrophins and other proteins predicts that exercise could regulate downstream anatomical changes that support brain plasticity. Recently, it has been demonstrated that exercise increases the number of new neurons in the DG of adult animals [56]. Trophic factors, such as BDNF, IGF-1 and FGF-2, might mediate this effect. Exercise increases levels of BDNF in the DG (the progenitor-cell layer of the hippocampus) and BDNF promotes the survival of newly differentiated neurons [50]. Support for the idea that BDNF is a key variable comes from the observation that estrogen [57], corticosteroids [58,59] and neuronal activity [60] each regulate both BDNF gene expression and neurogenesis. Exercise increases brain uptake of circulating IGF-1, a factor that promotes neuronal differentiation of progenitor cells [50,61] and increases hippocampal BDNF gene expression [52]. In addition, levels of FGF-2, a molecule that stimulates proliferation and differentiation of hippocampal neuroprogenitor cells [62,63] , are increased in hippocampal astrocytes after exercise. Finally, microarray analysis reveals increased expression of additional neurogenesis-related genes (e.g. those encoding Krox-24 and VGF) [55] that are likely to act in concert with IGF-1, BDNF and FGF-2 to modulate neurogenesis. Thus, exercise activates a number of factors that converge on neurogenesis.

Common mechanisms underlying plasticity induced by exercise, behavioral enrichment and learning
A robust literature documents that experience and behavior activate brain plasticity mechanisms and remodel neuronal circuitry in the brain. Exercise and behavioral enrichment paradigms, such as environmental enrichment [64], rehabilitation training [65,66] and learning [67,68] , affect common endpoints in the brain, including regulation of growth factors, neurogenesis and structural changes. The similarities between the effects of exercise and these well-established paradigms support the hypothesis that there are common mechanisms regulating behavioral plasticity.

Conclusion
Exercise is a simple and widely practised behavior that activates molecular and cellular cascades that support and maintain brain plasticity. It induces expression of genes associated with plasticity, such as that encoding BDNF, and in addition promotes brain vascularization, neurogenesis, functional changes in neuronal structure and neuronal resistance to injury. Significantly, these effects occur in the hippocampus, a brain region central to learning and memory. BDNF availability could be crucial for these mechanisms. Exercise-driven increases in the level of hippocampal BDNF are controlled by neuronal activity, neurotransmitters and interactions with peripheral factors that include estrogen, corticosterone and possibly IGF-1. The peripheral influence illustrates how exercise can relate overall body status to brain function. Exercise recruits use-dependent plasticity mechanisms that prepare the brain to encode meaningful information from the environment and, at the same time, activates mechanisms that protect the brain from damage. By inducing BDNF and other molecules, exercise strengthens neuronal structure and facilitates synaptic transmission, thus, priming activated cells for encoding.

The clinical literature has recognized for years that exercise affects overall health and brain function. Scientific studies are now strengthening the premise that exercise can benefit brain function and are encouraging additional clinical research in this area.

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Source: Adapted from: Trends in Neurosciences 2002, 25:295-301 Carl W. Cotman et al.
Institute for Brain Aging and Dementia, Dept of Neurobiology and Behavior and Dept of Neurology, University of California, Irvine, CA

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