Exercise and Neurogenesis

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Regular exercise is integral in promoting neurogenesis, synaptic plasticity, and maintaining regular cognitive performance, allegedly through neuromodulator activity in highly plastic areas of the brain. This is emphasized by findings of increased hippocampal volume after persistent aerobic training in human studies[1]. Many of the neuromodulators involved in promoting synaptic plasticity such as dopamine and estrogen have also been implicated in peripheral physiological processes. After voluntary exertion, they work synergistically to promote the expression of neurotrophic factors, which then act on trk and p75 receptors to elicit these effects. Though some of the proteins associated with the neuroprotective effects of physical exercise are endogenous to the CNS, others act through peripheral mechanisms[2]—such as Irisin, which is secreted from muscle. Selective lesions as well as disruptions of neurotransmitter signaling in the brain have proven to be detrimental in actuating neurogenesis and memory formation associated with regular exercise. Aerobic workouts are therefore contiguous with public health efforts to curb neurodegenerative diseases such a Parkinson’s and Alzheimer’s.

1. Erickson KI, Voss MW, Prakash RS, Basak C, Szabo A, Chaddock L, et al. Exercise training increases size of hippocampus and improves memory. Proc Natl Acad Sci USA. 2011;108(7): 3017-11.
2. Cotman CW, Berchtold NC. Exercise: a behavioural intervention to enhance brain health and plasticity. Trends Neurosci. 2002;25(6): 295-301.
3. Image source: Kevin Deeth. http://kevindeeth.wordpress.com/tag/cardio/

Brain-Derived Neurotrophic Factor

main article: Brain-Derived Neurotrophic Factor
author: Maxim Onichtchouk
BDNF was the second neurotrophin to be discovered and has since been implicated as an important factor in neurogenesis and synaptic plasticity. Upregulation of BDNF in the hippocampus has been found to be more potent and sustained than that of other neurotrophins after several weeks of aerobic exercise. This evidence privileges BDNF in effectuating the benefits of voluntary physical activity in the brain. Furthermore, a strong correlation has been established between learning and BDNF gene expression—suggesting that activities which modulate BDNF, such as aerobic exercise, are beneficial to cognitive performance[1]. BDNF promotes growth and survival of neurons throughout the Central Nervous System—particularly in hippocampal and cortical neurons—by allegedly strengthening excitatory synapses. However, recent evidence also suggests that it plays an important role in peripheral sensory neurons and skeletal muscle[2]. Because of increasing evidence affirming its role in synaptic plasticity and neurogenesis, understanding the action of BDNF is vital to the creation of novel therapies for patients with neurodegenerative disorders. In such a way, it is perhaps possible to find a comprehensive link between exercise as a facilitator of physical health and mental health.

1. Cotman CW, Berchtold NC. Exercise: a behavioural intervention to enhance brain health and plasticity. Trends Neurosci. 2002;25(6): 295-301.
2. Binder DK, Scharfman HE. Brain-derived neurotrophic factor. Growth Factors 2004;22(3): 123-31.
3. Marosi K, Mattson MP. BDNF mediates adaptive brain and body responses to energetic challenges. Trends Endocrinol Metab. 2014 Feb;25(2): 89-98.
4. Robinson RC, Radziejewski C, Spraggon G, Greenwald J, Kostura MR, Burtnick LD, Stuart DI, Choe S, Jones EY. The structures of the neurotrophin-4 homodimer and the brain-derived neurotrophic factor/neurotrophin-4 heterodimer reveal a common Trk-binding site. Protein Sci. 1999;8: 2589–2597.
5. Robinson RC, Radziejewski C, Stuart DI, Jones EY. Structure of brain-derived neurotrophic factor/neurotrophin-3 heterodimer. Biochemistry. 1995;34: 4139–4146.
6. Andero R, Choi DC, Ressler KJ. BDNF–TrkB Receptor Regulation of Distributed Adult Neural Plasticity, Memory Formation, and Psychiatric Disorders. Prog Mol Biol Transl Sci. 2014;122: 169-92.
7. Pencea V, Bingaman KD, Wiegand SJ, Luskin MB. Infusion of brain-derived neurotrophic factor into the lateral ventricle of the adult rat leads to new neurons in the parenchyma of the striatum, septum, thalamus, and hypothalamus. J Neurosci. 2001 Sep 1;21(17): 6706-17.
8. Berchtold NC, Kesslak JP, Cotman CW. Hippocampal brain-derived neurotrophic factor gene regulation by exercise and the medial septum. J Neurosci Res. 2002 Jun 1;68(5): 511-21.
9. Vigers AJ, Amin DS, Talley-Farnham T, Gorski JA, Xu B, Jones KR. Sustained expression of brain-derived neurotrophic factor is required for maintenance of dendritic spines and normal behavior. Neuroscience. 2012 Jun 14;212: 1-18.
10. Bekinschtein P, Cammarota M, Katche C, Slipczuk L, Rossato JI, Goldin A, Izquierdo I, Medina JH. BDNF is essential to promote persistence of long-term memory storage. Proc Natl Acad Sci USA. 2008 Feb 19;105(7): 2711-6.
11. Erickson KI, Voss MW, Prakash RS, Basak C, Szabo A, Chaddock L, Kim JS, Heo S, Alves H, White SM, Wojcicki TR, Mailey E, Vieira VJ, Martin SA, Pence BD, Woods JA, McAuley E, Kramer AF. Exercise training increases size of hippocampus and improves memory. Proc Natl Acad Sci USA. 2011 Feb 15;108(7): 3017-22.
12. van Praag H, Christie BR, Sejnowski TJ, Gage FH. Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc Natl Acad Sci USA. 1999 Nov 9;96(23): 13427-31.
13. Pedersen BK, Febbraio MA. Muscles, exercise and obesity: skeletal muscle as a secretory organ. Nat Rev Endocrinol. 2012 Apr 3;8(8):457-65.
14. Gómez-Pinilla F, Ying Z, Roy RR, Molteni R, Edgerton VR. Voluntary exercise induces a BDNF-mediated mechanism that promotes neuroplasticity. J Neurophysiol. 2002 Nov;88(5):2187-95.
15. Acheson A, Conover JC, Fandl JP, DeChiara TM, Russell M, Thadani A, Squinto SP, Yancopoulos GD, Lindsay RM. A BDNF autocrine loop in adult sensory neurons prevents cell death. Nature. 1995 Mar 30;374(6521): 450-3.
16. Ozawa T, Yamada K, Ichitani Y. Hippocampal BDNF treatment facilitates consolidation of spatial memory in spontaneous place recognition in rats. Behav Brain Res. 2014 Apr 15;263: 210-6.
17. Vaughan S, Wallis M, Polit D, Steele M, Shum D, Morris N. The effects of multimodal exercise on cognitive and physical functioning and brain-derived neurotrophic factor in older women: a randomised controlled trial. [published online ahead of print February 23, 2014]. Age Ageing. doi: 10.1093/ageing/afu010

Dopamine, BDNF and Neuroplasticity

main article: Dopamine, BDNF and Neuroplasticity
author: Sasha_A

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Fig1. Adapted from MedicalHandbook.org[2014].Parkinson's disease

The monoamine neurotransmitter dopamine is best known for its connections with reward and motivation. However, it plays a large role in movement and learning. Dopamine levels are consistently seen to be raised by regular exercise. This is possibly mediated by neurotrophic factors, such as BDNF[7]. BDNF’s relationship with dopamine has implications for the method of action of antidepressants as well as pharmacotherapy for Parkinson's disease[5].

1. Foley, T. E., Fleshner, M. Neuroplasticity of dopamine circuits after exercise: implications for central fatigue. Neuromolecular Medicine. 10, 67-80 (2008).
2. Klingberg, T. Training and plasticity of working memory. Trends in Cognitive Sciences. 14, 317-324 (2010).
3. Savitz, J., Solms, M., Ramesar, R. The molecular genetics of cognition: dopamine, COMT and BDNF. Genes, Brain and Behaviour. 5, 311-328 (2006).
4. Molina-Luna, K. et al. Dopamine in motor cortex is necessary for skill learning and synaptic plasticity. Public Library of Science. 4(9), e7082 (2009).
5. Fumagalli, F., Racagni, G., Riva, M. A. Shedding light into the role of BDNF in the pharmacotherapy of Parkinson's disease. The Pharmacogenomics Journal. 6, 95-104 (2006).
6. Real, C. C., et al. BDNF receptor blockade hinders the beneficial effects of exercise in a rat model of Parkinson’s disease. Neuroscience. 237, 118-129 (2013).
7. Zigmond, M. J. et al. Triggering endogenous neuroprotective processes through exercise in models of dopamine deficiency. Parkinsonism and Related Disorders 15S3, 242-245 (2009).

Estrogen and BDNF Interactions

main article: Estrogen and BDNF Interactions
author: Vanessa Testaguzza

Estrogen and BDNF Interaction Pathways
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A: Induction; B: Convergence [1]

Brain-derived neurotrophic factor (BDNF) and estrogen are both important neuromodulators of synaptic plasticity which have been thoroughly studied individually. They have been shown to induce structural changes to and within neurons, as well as promote neuronal proliferation and differentiation within the hippocampus. Interestingly, they were found to be complimentarily expressed and to trigger similar cascading pathways, second messenger systems and have genomic effects in the hippocampus leading to dendritic growth. [1] These commonalities have led scientists to look further into estrogen-BDNF interactions. Possible direct and convergent pathways have been identified to address this link. An estrogen response element (ERE) identified on BDNF may serve to directly trigger its expression when estrogen bound; conversely, these two neuromodulators may work in concert to trigger the same intracellular transcription factors which eventually increase dendritic growth.[2] These dendritic changes equate to improvements in memory and learning tasks which represents the ultimate effect of estrogen and BDNF on individuals.

1. Luine V, Frankfurt M. Interactions between estradiol, BDNF and dendritic spines in promoting memory. Neuroscience. 2013; 34-45.
2. Scharfman HE, MacLusky NJ. Estrogen and brain-derived neurotrophic factor (BDNF) in hippocampus: Complexity of steroid hormone-growth factor interactions in the adult CNS. Frontiers in Neuroendocrinology. 2006; 27:415-435.

FNDC5 (Irisin)

main article: FNDC5 (Irisin)
author: Dimitar Krastev

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A ribbon model of cleaved irisin.

FNDC5 is a transmembrane protein present in cells both within and outside of the central nervous system, with PGC1a (an exercise dependent transcriptional coactivator) dependent expression[1]. It was discovered in 2012 by Bostrom et al.[2], and found to be cleaved into a water soluble protein called irisin which has been detected in both human plasma and CSF[3]. FNDC5 and Irisin have been linked to many peripheral phenomena including brown fat adipogenesis[2] and telomere length maintenance[4], as well as neurological effects such as hippocampal BDNF release.[1] This makes both FNDC5 and irisin key protein targets in future treatment plans for metabolic diseases like obesity, and neurodegenerative diseases such as Alzheimer's Disease. Potential irisin receptors, the downstream effects of irisin, and the effects of membrane bound FNDC5 all require further investigation.

1. Wrann, C. D., White, J. P., Salogiannnis, J., Laznik-Bogoslavski, D., Wu, J., Ma, D., e al. Spiegelman, B. M. (2013). Exercise induces hippocampal BDNF through a PGC-1alpha/FNDC5 pathway. Cell Metab, 18(5), 649-659.
2. Bostrom, P., Wu, J., Jedrychowski, M. P., Korde, A., Ye, L., Lo, J. C., et al. Spiegelman, B. M. (2012). A PGC1-alpha-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature, 481(7382), 463-468.
3. Piya, M. K., Harte, A. L., Sivakumar, K., Tripathi, G., Voyias, P. D., James, S., et al. McTernan, P. G. (2014). The Identification of Irisin in Human Cerebrospinal Fluid: Influence of Adiposity, Metabolic Markers and Gestational Diabetes. Am J Physiol Endocrinol Metab.
4. Rana, K. S., Arif, M., Hill, E. J., Aldred, S., Nagel, D. A., Nevill, A., … Brown, J. E. (2014). Plasma irisin levels predict telomere length in healthy adults. Age (Dordr), 36(2), 995-1001.
5. Image source: Weight Loss: A New Star is Irisin. https://www.caymanchem.com/app/template/Article.vm/article/2192

Vascular Endothelial Growth Factor (VEGF)

main article: Vascular Endothelial Growth Factor (VEGF)
author: ababuram

VEGF Family12
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Vascular endothelial growth factor (VEGF) has various different sub groups with a primary function of promoting angiogenesis as well as vascularogenesis. In addition to causing proliferation of blood cells in the body, VEGF also has effects on the brain particularly in the hippocampus where various studies have shown that overexpression of this molecule leads to neurogenesis1,11. In addition to promoting neuronal wellbeing, VEGF protects the brain from atrophic processes that occur during periods of extreme stress and depression7. This growth factor has been targeted for numerous therapeutic purposes where blockage and overexpression have proven effective in treating various ailments4. There are numerous pathways which VEGF works through and in turn illicits different responses within the individual. Although this molecule is an antagonist to stressors, stressful scenarios tend to repress the expression of VEGF and in some individuals this results in clinically diagnosed diseases and various stages of depression.

1. first full source reference
2. second full source reference

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