Candidate Review:

Neuroprotection by Physical Activity

Amanda C Mitchell

Neuroscience Graduate Program, Vanderbilt University School of Medicine, U1205 Medical Center North, Nashville, TN 37232, USA.
Correspondence e-mail:

Abstract | Full Text | PDF

Abstract | Physical activity is neuroprotective, lowering the risk of neurological diseases, increasing overall brain health, and leading to specific gene expression changes throughout the brain. In particular it upregulates growth factors, immediate early genes, immune genes, synaptic trafficking genes, neurotransmitter systems, and activates the extracellular signal-regulated kinases 1 and 2 (ERK1/2) and protein kinase B (PKB/AKT) signal transduction pathways. The beneficial effects of physical activity are supported in animal models of Parkinson’s disease (PD). The unilateral 6-hydroxydopamine (6-OHDA) rat and bilateral 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse PD models show behavioral and biochemical sparing in the striatum after forced limb use, and forced treadmill running.


A growing body of evidence suggests that mild1, moderate, and vigorous physical activity2 are neuroprotective, decreasing the risk of many brain disorders including ischemic stroke3,4, Alzheimer’s disease1,5, and Parkinson’s disease (PD)2. Many clinicians routinely recommend physical activity for those suffering from the effects of these diseases. In PD patients physical activity has been shown to improve gait, tremor, grip strength, balance, and motor coordination6,7. Regardless of disease presence physical activity can improve sleep8, cognition9,10, and decrease depression11-13. Supporting animal data show that exercise and environmental enrichment enhance learning and memory, increase neuronal survival, increase resistance to brain insults, trigger synaptogenesis, promote brain angiogenesis, and promote neurogenesis14,15. We believe physical activity affects the entire brain and have previously studied the effects of physical activity on the brain alone (unpublished) and in an Alzheimer’s disease model14.

Exercise gene expression changes have been studied largely in the hippocampus, a site of neurogenesis crucial in spatial learning and memory16-18. Initial examinations showed increases in nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) throughout the brain with the most dramatic increases in the hippocampus and posterior cortex16. In the hippocampus voluntary wheel running also increases the expression of phosphoinositide kinase 3 (PI3K), protein kinase B (PKB/AKT), BDNF, cAMP response element binding (CREB), and tyrosine kinase B (TrkB, the BDNF receptor)19. It is now understood that physical activity modulates the BDNF system through intracellular signaling systems such as AKT and extracellular signal-regulated kinases 1 and 2 (ERK1/2) with endpoint effects on the production, phosphorylation, and function of CREB20 (Figure 1). AKT also phosphorylates forkhead box O3 (FOXO3), a transcription factor, causing its retention in the cytoplasm. When in the nucleus, FOXO3 likely triggers apoptosis by inducing the expression of genes critical for cell death21. Keeping FOXO3 in the cytoplasm, therefore, may promote cell survival.

Two DNA microarray studies comparing voluntary running rats to their sedentary counterparts revealed the upregulation of genes involved in neuronal activity, synaptic structure, and neuronal plasticity in the hippocampus22, 23. These genes included: neurotrophins, immediate early genes (IEGs), immune genes, and trafficking proteins22. The second study also revealed the upregulation of neurotrophic factors (NGF, BDNF, and basic fibroblast growth factor, FGF-2) as well genes involved in synaptic trafficking (syntaxin, synapsin I, and synaptotagmin), neutrotransmitter systems (ionotropic glutamate receptor subunits NR2A and NR2B, excitatory amino-acid carrier 1 (EAAC1), γ-aminobutyric-acid receptor β3 (GABAA β3), and glutaminic acid decarboxylase (GAD65)), and signal transduction pathways (ERK1/2, and protein kinase C (PKC))23. They furthered showed that CaMKIIδ was more highly expressed during acute exercise (3 days) and that ERK1/2 was more highly expressed during chronic exercise (28 days)23. CaMKII is activated by increases in Ca2+ (Figure 1) and phosphorylates many substrates including components of the ERK1/2 signal transduction pathway. Figure 1 shows the BDNF – TrkB interaction, but most growth factors, including glial derived neurotrophic factor (GDNF), NGF, and FGF-2, activate the same signaling cascades24-26

Figure 1 | BDNF Signaling Pathways. BDNF activates the AKT and ERK1/2 pathways. PI3K indirectly causes the phosphorylation of AKT, which phosphorylates and inhibits death proteins (FOXO3 and BAD). ERK1/2 is phosphorylated by a kinase cascade (RAF to MEK to ERK1/2) that is activated by RAS, which is activated by RAS-GEF binding to Grb2 bound to phosphorylated TrkB dimers. This pathway also can be phosphorylated by CaMKII19, 21-23.

Immediately following both voluntary wheel running and treadmill running in rodents there is an increase of corticosterone (indicative of the stress response) along with a decrease in phosphorylated CREB (pCREB) with treadmill running animals displaying a higher elevation of corticosterone and decrease in pCREB27. Though of small effect, corticosterone is known to decrease the expression of BDNF in the dentate gyrus (DG) of the hippocampus28. If corticosterone is administered subcutaneously to adrenalectomized animals, there is a transient decrease in BDNF at 4 and 6 hours and an increase in its TrkB receptor at 6 and 12 hours29. This immediate stress response, however, is likely specific to acute exercise and may diminish with repeated exercise exposures27. Studies have shown that the increases in corticosterone do fall off over time30,31. After five weeks of wheel running, there is no difference in corticosteroid response in a 20 minute restraint stress test between exercised and sedentary animals31. Lastly, in a study that standardized the distance ran between rats, it was shown that voluntary exercisers ran more rapidly for a shorter time than forced exercisers and had less bromodeoxyuridine (BrdU) incorporation into the DNA of hippocampal slices (an indication of neurogenesis)32. These studies show that although forced exercise may transiently activate the stress response, long term forced exercise may be more beneficial.


After extensive investigation of the hippocampus our attention has turned to brain areas related to PD. PD is characterized by tremor at rest, muscle rigidity, postural instability, and a slowing of physical movement (bradykinesia) that can progress to a complete loss of movement (akinesia)33. As disabling motor symptoms are managed with medications (such as L-3, 4-dihydroxyphenylalanine, L-DOPA), other symptoms become more apparent. These include depression, high level cognitive dysfunction, and subtle language problems34,35. It is thought that symptoms emerge from the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). At the onset of motor symptoms dopaminergic neuron loss is already 60-80%. These neurons normally project to the striatum forming the nigrostriatal dopaminergic pathway33. Insufficient action of dopamine (DA) on the striatum is believed to lead to decreased stimulation of the motor cortex and PD symptoms34-38.

PD is also often characterized by the presence of Lewy bodies. These proteinaceous cytoplasmic inclusions composed of α-synuclein, are present in the locus ceruleus, nucleus basalis of Meynert, dorsal motor nucleus of the vagus, hypothalamus, and other sites of some PD patients, but 20-40% patients with neuronal loss in the SNpc have no Lewy bodies raising the question of whether Lewy bodies are markers of presymptomatic PD or a feature of normal aging39. Common treatments aim to replace and stabilize dopamine. The most common is L-DOPA, which crosses the blood brain barrier and is converted to DA. Neuroprotective strategies, such as physical activity, however, aim to slow dopaminergic neuron loss and lead to improved functioning of the remaining neurons33.

It is difficult to model the progressive nature of PD in animals, but two models, 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP), are able to model some of the pathology and symptoms. 6-OHDA causes the degeneration of catecholaminergic neurons (DA, norepinephrine, and epinephrine) when applied to the brain. For localized dopaminergic degeneration it is stereotactically injected into the SNpc, the nigrostriatal tract (medial forebrain bundle), or the striatum of one brain hemisphere33. Dopaminergic neurons start degenerating within 24 hours and striatal DA is depleted 80-90% 2-3 days later corresponding with bradykinesia, impairment of movement initiation, and skilled motor functions on the contralateral side of the body33,39. SNpc degeneration also causes the upregulation of post synaptic DA receptors in the striatum. In a unilateral model this upregulation causes contralateral rotations with administration of a DA receptor agonist, apomorphine36.

MPTP crosses the blood brain barrier and is metabolized by monoamine oxidase B (MAO-B) to 1-methyl-4-phenyl-2, 3-dihydropyridinium ion (MPP+). MPP+ is selectively taken up by the DA transporter (DAT) where it inhibits complex I of the mitochondrial electron transport chain, which mirrors the 30-40% decrease in mitochondrial electron chain complex I activity in the SNpc of PD patients33. Increased reactive oxygen species (hydrogen peroxide, superoxide, peroxyl radicals, nitric oxide, and hydroxyl radicals) caused by a dysfunctional complex I react with nucleic acids, proteins, lipids, and other molecules altering their structure, causing damage, and eventually leading to axon degeneration and neuron loss40.

Acute bilateral MPTP exposure leads to 50-93% loss of cells in the SNpc and more than 99% loss of DA in the striatum leading to akinesia, rigidity, and in some species tremor33. A stable early stage unilateral model of PD (MPTP) was developed in middle-aged monkeys41. The most pronounced difference from acute bilateral models is the preservation of dopaminergic fiber projections to the caudate nucleus and putamen. Other studies support the concept that cell bodies of DA neurons can be maintained in the substantia nigra for long periods following axonal loss in the striatum42. The early stage model with greater preservation of nigrostriatal projections could be useful for testing neuroprotective strategies, such as exercise, to preserve and restore dopaminergic innervation to the striatum.


Increases in dendritic arborization and synapse number in the cortex have been associated with motor training43-45. Hence, Tillerson et al hypothesized that motor training might retard the loss of dopaminergic neuron projections from the SNpc to the striatum in a unilateral 6-OHDA rat model. After infusing 6-OHDA into the medial forebrain bundle (MFB), they forced the use of the impaired limb by casting the unimpaired limb on days 1-7, 3-9, or 7-13 after lesioning. Apomorphine-induced contralateral rotations and DA levels were used as a measure of SNpc dopaminergic neuron loss. Animals receiving a cast on days 1-7 and 3-9 did not show step or forelimb asymmetry, rotated significantly different from sham animals in response to apomorphine, and had significantly different levels of DA, DOPAC, or HVA from sham animals. Timing of exercise matters; early forced use (days 1-7 and 3-9), but not late forced use (days 7-13), of the impaired limb attenuated movement asymmetry and dopamine loss45.

Tillerson switched to a forced treadmill running paradigm, as unilateral forced use is an exercise modality not commonly practiced in humans. They believed that treadmill running, like forced use, would attenuate DA loss and behavior. Rats were given either 6-OHDA and mice were given MPTP and forced to run until day 12 or 30 for behavioral tests and sacrificed for biochemical analysis. Moderate forced treadmill running reversed 6-OHDA movement impairments in rats after one day with 450 m/day of treadmill running, reversed MPTP movement impairments in mice after three days with 50 m/day, and attenuated striatal DA loss and DA terminal marker loss (DAT, VMAT, tyrosine hydroxylase (TH)) in both models46. Treadmill running, like forced use, attenuated both movement impairments and dopamine loss. 

It is believed that mild stress can cancel the effect of neuroprotection. Both voluntary and forced exercise have been associated with mild stress. Howell et al addressed this issue by looking at the effect of stress on voluntary exercise. Animals were placed into three groups: runners allowed access to a running wheel, stressed runners allowed access to a running wheel (stressed with one hour of wheel immobilization a day, food deprivation, and a shift in the light dark cycle), and nonrunners. Both stressed runners and nonrunners had significantly more apomorphine rotations than runners alone with no difference in TH staining suggesting that mild stress can cancel the affect of exercise47. Earlier studies indicate that corticosterone, produced immediately following exercise, may diminish neuroprotection; these effects, however, wear off after five weeks30-31. Numerous other studies demonstrate that voluntary and forced exercise can ameliorate the behavioral and biochemical consequences of 6-OHDA and MPTP PD models47-52 though the time, amount, method of exercise, and type of lesion do affect the behavioral and biochemical outcome.

Figure 2 | Sparing with Exercise. Exercise results in an increase of neurotrophic factors and their receptors. Both BDNF and GDNF are increased with exercise. In the striatum we believe cortical BDNF increases the survival of striatal spines, while GDNF increases the survival of both SN terminals and striatal spines.

In all of the studies the number of SNpc cells did not change with exercise47-52; rather, we believe behavioral and biochemical sparing comes from sparing of SNpc axons and terminals projecting to the striatum51. It has been hypothesized that forced use ameliorates the behavioral and biochemical effects of 6-OHDA and MPTP through a cascade of events that involves GDNF53, a potent survival factor for DA neurons54. There is a significant increase of striatal GDNF 24 and 72 hours after using a non-impaired limb55. In the striatum ERK1/2 activation by GDNF remains elevated up to 1 month afterwards55,56. The medium spiny neurons of the striatum receive BDNF from cortical input. They receive and produce GDNF. GDNF homodimers bind two GFRα1 receptors, which then bind two RET (Rearranged during Transfection) receptors, which cross phosphorylate each other in the striatum and SNpc. BDNF increases the survival of striatal spines, while GDNF increases the survival of both SNpc terminals and striatal spines (Figure 2). Exercise affects the entire brain with the upregulation of growth factors16, and it seems most probable that the effects of exercise in PD would emerge at the intersection of the SNpc and motor cortex in the striatum.


Physical activity in PD has been investigated over the past decades. The 6-OHDA rat and MPTP mouse Parkinson’s disease models show behavioral and biochemical sparing in the striatum after voluntary wheel running, forced limb use, and forced treadmill running though the most beneficial time (before or after lesioning), amount,  and method (voluntary versus forced) of exercise for neuroprotection are still under investigation. Evidence suggests that reduced nigrostriatal degeneration is due in part to the upregulation of neurotrophic factors, one of the many affects of exercise, acting at the striatum.


1.   Yaffe K, Barnes D, Nevitt M, Lui LY and Covinsky K (2001). A Prospective Study of Physical and Cognitive Decline in Elderly Women: Women Who Walk. Archives of Internal Medicine. 161 (14): 1703-1708.

2.   Thacker EL, Chen H, Patel AV, McCullough ML, Calle EL, Thun MJ, Schwarzschild MA and Ascherio A (2008). Recreational Physical Activity and Risk of Parkinson’s Disease. Mov Disord. 23 (1):69-74.        

3.   Hu FB, Stampfer MJ, Colditz GA, Ascherio A, Rexrode KM, Willett WC and Manson JE (2000). Physical Activity and Risk of Stroke in Women. JAMA. 283:2961-2967.

4.   Lee IM and Paffenbarger RS (1998). Physical Activity and Stroke Incidence. The Harvard Alumni Health Study. Stroke. 29: 2049–2054.

5.   Larson EB, Wang L, Bowen JD, McCormick WC, Teri L, Crane P and Kukull W  (2006). Exercise is Associated with Reduced Risk for Incident Dementia Among Persons 65 Years of Age and Older. Ann Intern Med. 144 (2):73-81.

6.   Hirsch MA, Toole T, Maitland CG and Rider RA (2003). The Effects of Balance Training and High-Intensity Resistance Training on Persons with Idiopathic Parkinson's Disease. Arch Phys Med Rehabil. 84:1109-1117.

7.   Palmer SS, Mortimer JA, Webster DD, Bistevins R and Dickinson GL (1986). Exercise Therapy for Parkinson's Disease. Archives of Physical Medicine & Rehabilitation. 67:741-745.

8.   Driver HS and Taylor SR (2000). Exercise and Sleep. Sleep Med Rev. 4 (4):387-402.

9.   Colcome S and Kramer AF (2003). Fitness Effects on the Cognitive Function of Older Adults: A Meta-Analytic Study. Psychol Sci. 14 (2):125-130.

10. Weuve J, Kang JH, Manson JE, Breteler MM, Ware JH and Grodstein F (2004). Physical Activity, Including Walking, and Cognitive Function in Older Women. JAMA. 292 (12):1454-1461.

11. Dunn AL, Trivedi MH, Kampert JB, Clark CG and Chambliss HO (2005). Exercise Treatment for Depression: Efficacy and Dose Response. Am J Prev Med. 28 (1): 1-8.

12. Lawlor DA and Hopker SW (2001). The Effectiveness of Exercise as an Intervention in the Management of Depression: Systematic Review and Meta-Regression Analysis of Randomised Controlled Trials. BMJ. 322 (7289):763-767.

13. Reuter I, Engelhardt M, Stecker K and Baas H (1999). Therapeutic Value of Exercise Training in Parkinson's Disease. Medicine & Science in Sports & Exercise. 31:1544-1549.

14. Lazarov O, Robinson J, Tang YP, Hairston IS, Korade-Mirnics Z, Lee VM, Hersh LB, Sapolsky RM, Mirnics K and Sisodia SS (2005). Environmental Enrichment Reduces Aβ levels and Amyloid Deposition in Transgenic Mice. Cell. 120:701-713.

15. van Praag H, Shubert T, Zhao C and Gage FH (2005). Exercise Enhances Learning and Hippocampal Neurogenesis in Aged Mice. J. Neurosci. 25 (38):8680-8685.

16. Neeper SA, Gomez-Pinilla F, Choi J and Cotman CW (1996). Physical Activity Increases mRNA for Brain-Derived Neurotrophic Factor and Nerve Growth Factor in Rat Brain. Brain Res. 726 (1-2):49-56.

17. van Praag H, Kempermann G and Gage FH (2000). Neural Consequences of Environmental Enrichment. Nature Neuroscience. 1:191-198.

18. Li Y, Mu Y and Gage FH (2009). Development of Neural Circuits in the Adult Hippocampus. Current Topics in Developmental Biology. 87: 149-174.

19. Chen MJ and Russ-Neustadt AA (2005). Exercise Activates the Phosphatidylinositol 3-Kinase Pathway. Brain Res Mol Brain Res. 135 (1-2): 181-193.

20. Vaynman S, Ying Z and Gomez-Pinilla F (2004). Hippocampal BDNF Mediates the Efficacy of Exercise on Synaptic Plasticity and Cognition.  Eur J Neurosci. 20 (10):2580-2590.

21. Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J and Greenberg ME (1999). Akt Promotes Cell Survival by Phosphorylating and Inhibiting a Forkhead Transcription Factor. Cell. 96: 857-868.

22. Tong L, Shen H, Perreau VM, Balazs R and Cotman CW (2001). Effects of Exercise on Gene-Expression Profile in the Rat Hippocampus. Neurobiol Dis. 8 (6): 1046-1056.

23. Molteni R, Ying Z and Gómez-Pinilla F (2002). Differential Effects of Acute and Chronic Exercise on Plasticity-Related Genes in the Rat Hippocampus Revealed by Microarray. Eur J Neurosci. 16 (6):1107-1116.

This study explores gene expression changes in the hippocampus of rats after physical activity.

24. Hauck SM, Kinkl N, Deeg CA, Swiatek-de Lange M, Schoffmann S and Ueffing M (2006). GDNF Family Ligands Trigger Indirect Neuroprotective Signaling in Retinal Glial Cells. Molecular and Cellular Biology. 26 (7): 2746-2757.

25. Tsang M and Dawid (2004). Promotion and Attenuation of FGF Signaling Through the Ras-MAPK Pathway. Sci. STKE. 228:17.

26. Yuan J and Yankner BA (2000). Neuronal Survival Pathways Induced by the Binding of NGF to its Receptor TrkA. Nature. 407:802-809.

27. Ploughman M, Granter-Button S, Chernenko G, Attwood Z, Tucker BA, Mearow KM and Corbett D (2007). Exercise Intensity Influences the Temporal Profile of Growth Factors Involved in Neuronal Plasticity Following Focal Ischemia. Brain Res. 1150: 207–216.

28. Smith MA, Makino S, Kvetnansky R and Post RM (1995). Stress and Glucocorticoids Affect the Expression of Brain Derived Neurotrophic Factor and Neurotrophin 3 mRNAs in the Hippocampus. J of Neuroscience. 15: 1768-1777.

29. Schaaf M, de Jong J, de Kloet E and Vreugdenhil E (1998). Downregulation of BDNF mRNA and Protein in the Rat Hippocampus by Corticosterone. Brain Res.  813: 112–120.

30. Ploughman M, Granter-Button S, Chernenko G, Tucker BA, Mearow KM and Corbett  D (2005). Endurance Exercise Regimens Induce Differential Effects on Brain-Derived Neurotrophic Factor, Synapsin-I and Insulin-like Growth Factor I After Focal Ischemia. Neuroscience. 136: 991–1001.

31. Fediuc S, Campbell JE and Riddel MC (2006). Effect of Voluntary Wheel Running on Circadian Corticosterone Release and on HPA Axis Responsiveness to Restraint Stress in Spague-Dawley Rats. J Appl Physiol. 100: 1867-1875.

32. Leasure JL and Jones M (2008). Forced and Voluntary Exercise Differentially Affect Brain and Behavior. Neuroscience. 156 (3):456-465.

33. Betarbet R, Sherrer TB and Greenamyre JT (2002). Animal Models of Parkinson’s Disease. BioEssays. 24:308-318

34. Brown JA, Lutsep HL, Weinand M and Cramer SC (2006). Motor Cortex Stimulation for the Enhancement of Recovery from Stroke: A Prospective, Multicenter Safety Study. Neurosurgery. 58 (3):464-473.

35. Dagher A, Owen AM, Boecker H and Brooks DJ (2001). The Role of the Striatum and Hippocampus in Planning: A PET Activation Study in Parkinson’s Disease. Brain. 124 (5): 1020-1032.

36. Burke RE, Cadet JL, Kent JD, Karanas AL and Jackson-Lewis V (1990). An Assessment of the Validity of Densitometric Measures of Striatal Tyrosine Hydroxylase-Positive Fibers: Relationship to Apomorphine-Induced Rotations in 6-Hydroxydopamine Lesioned Rats. J. Neurosci Methods. 35 (1):63-73.

37. Cioni B (2007). Motor Stimulation for Parkinson’s Disease. Acta Neurochir Suppl. 97:233-238.

38. Rowe J, Klaas ES, Friston K, Frackowiak R, Lees A and Passingham R (2002). Attention to Action in Parkinson’s Disease: Impaired Effective Connectivity Among Frontal Cortical Region. Brain. 125 (2): 276-289.

39. Gelb DJ, Oliver E and Gilman S (1999). Diagnostic Criteria for Parkinson’s Disease. Arch Neurol. 56 (1): 33-39.

40. Mann VM, Cooper JM, Krige D, Daniel SE, Schapira AH and Marsden CD (1992). Brain, Skeletal Muscle and Platelet Homogenate Mitochondrial Function in Parkinson Disease. Brain. 115: 333–342.

41. Ding F, Luan L, Ai Y, Walton A, Gerhardt GA, Gash DM, Grondin R and Zhang Z (2008). Development of a Stable, Early Stage Unilateral Model of Parkinson’s disease in Middle-Aged Rhesus Monkeys. Exp Neurol. 212 (2): 421-439

We are using the early stage unilateral model of Parkinson’s disease in Middle-Aged Rhesus Monkeys.

42. Kirik D, Rosenblad C and Bjorklun A (2000). Preservation of a Functional nigrostriatal Dopamine Pathway by GDNF in the Intrastriatal 6-OHDA Lesion Model Depends on the Site of Administration of the Trophic Factor. Eur J. Neurosci. 12 (11): 3871-3882.

43. Jones TA and Schallert T (1992). Overgrowth and Pruning of Dendrites in Adult Rats Recovering from Neocortical Damage. Brain Res. 581:156-160.

44. Kleim JA, Lussnig E, Schwarz ER, Comery TA and Greenough WT (1996). Synaptogenesis and Fos Expression in the Motor Cortex of the Adult Rat After Motor Skill Learning. J Neurosci. 16 (14):4529-35.

45. Tillerson JL, Cohen AD, Philhower J, Miller GW, Zigmond MJ and Schallert T (2001). Forced Limb-Use Effects on the Behavioral and Neurochemical Effects of 6-Hydroxydopamine. J Neurosci. 21 (12):4427-4435.

46. Tillerson JL, Caudle MW, Reverόn ME and Miller GW (2003). Exercise Induces Behavioral Recovery and Attenuates Neurochemical Deficits in Rodent Models of Parkinson’s Disease. Neuroscience. 119 (3): 899-911.

This study shows behavioral and biochemical sparing after forced physical activity in both the 6-OHDA rat and MPTP mouse Parkinson’s disease models.

47. Howell FM, Russell VA, Mabandla MV and Kellaway LA (2005). Stress Reduces the Neuroprotective Effect of Exercise in a Rat Model for Parkinson’s Disease. Behav Brain Res. 165 (2):210-20.

48. Caudle MW, Tillerson JL, Reverόn ME and Miller GW (2006). Use-Dependent Behavioral and Neurochemical Asymmetry in MPTP Mice. Neuroscience Letters. 418 (3); 211-212

49. Mabandla M, Kellaway L, St Clair Gibson A, Russell VA (2004). Voluntary Running Provides Neuroprotection in Rats after 6-Hydroxydopamine Injection into the Medial Forebrain Bundle. Metab Brain Dis 19:43-50.

50. O'Dell SJ, Gross NB, Fricks AN, Casiano BD, Nguyen TB and Marshall JF (2007). Running Wheel Exercise Enhances Recovery from Nigrostriatal Dopamine Injury Without Inducing Neuroprotection. Neuroscience. 144:1141-1151.

51. Petzinger GM, Walsh JP, Akopian G, Hogg E, Abernathy A, Arevalo P, Turnquist P, Vuckovic M, Fisher BE, Togasaki DM, and Jakowec MW. Effects of Treadmill Exercise on Dopaminergic Transmission in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Lesioned Mouse Model of Basal Ganglia Injury. Neurobiology of Disease. 27 (20):5291-5300.

52. Poulton NP and Muir GD (2005). Treadmill Training Ameliorates Dopamine Loss but not Behavioral Deficits in hemi-Parkinsonian Rats. Exp Neurol. 193:181-197.

53. Ries V, Cheng HC, Baohan A, Kareva T, Oo TF, Rzhetskaya M, Bland RJ, During MJ, Kholodilov R and Burke RE (2009). Regulation of the Postnatal Development of Dopamine Neurons of the Substantia Nigra In Vivo by Akt/Protein Kinase B. J. Neurochem. 110 (1): 22-33.

54. Cohen AD, Tillerson JL, Smith AD, Schallert T, and Zigmond MJ (2003). Neuroprotective Effects of Prior Limb Use in 6-Hydroxydopamine-Treated Rats: Possible Role of GDNF. Journal of Neurochemistry. 85: 299-305.

This study shows GDNF increases affect limb use in rats.

55. Lin E, Cavanaugh JE, Leak RK, Perez RK and Zigmond MJ (2007). Rapid Activation of ERK by 6-Hydroxydropamine Promotes Survival of Dopaminergic Cells. J Neuroscience Research.  86:108-117.

56. Lindgren N, Leak RK, Carlson KM, Smith AD and Zigmond MJ (2008). Activation of the Extracellular Signal-regulated Kinases 1 and 2 by Glial Cell Line-Derived Neurotrophic Factor and its Relation to Neuroprotection in a Mouse Model of Parkinson's Disease. J Neuroscience Research. 86 (9):2039-2049.

57. Shen H, Tong L, Balazs R and Cotman CW (2001). Physical Activity Elicits Sustained Activation of Cyclic AMP Response Element-binding Protein and Mitogen-Activated Protein Kinase in the Rat Hippocampus. Neuroscience. 107 (2):219-229.

58. Benjamini Y and Hochberg Y (1995). Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing, J. R. Stat. Soc., B. 57: 289–300.

59. Mirnics K (2001). Microarrays in Brain Research: The Good, the Bad and the Ugly. Nature Reviews Neuroscience. 2 (6):444-447.

60. Karssen AM, Li JZ, Her S, Patel PD, Meng F, Evans SJ, Vawter MP, Tomita H, Choudary PV, Bunney WE, Jones EG, Watson SJ, Akil H, Myers RM, Schatzberg AF and Lyons DM (2006). Application of Microarray Technology in Primate Behavioral Neuroscience Research. Methods.   38 (3): 227-234.


Karoly Mirnics’ Lab