, Volume 3, Issue 4, pp 451–457 | Cite as

Neurotransmitters and motor activity: Effects on functional recovery after brain injury

  • Larry B. GoldsteinEmail author


There are complex relationships among behavioral experience, brain morphology, and functional recovery of an animal before and after brain injury. A large series of experimental studies have shown that exogenous manipulation of central neurotransmitter levels can directly affect plastic changes in the brain and can modulate the effects of experience and training. These complex relationships provide a formidable challenge for studies aimed at understanding neurotransmitter effects on the recovery process. Experiments delineating norepinephrine-modulated locomotor recovery after injury to the cerebral cortex illustrate the close relationships among neurotransmitter levels, brain plasticity, and behavioral recovery. Understanding the neurobiological processes underlying recovery, and how they might be manipulated, may lead to novel strategies for improving recovery from stroke-related gait impairment in humans.

Key Words

Stroke motor function brain injury norepinephrine recovery 


  1. 1.
    Rose FD, al-Khamees K, Davey MJ, Attree EA. Environmental enrichment following brain damage: an aid to recovery or compensation? Behav Brain Res 1993;5: 93–100.CrossRefGoogle Scholar
  2. 2.
    Kolb B, Forgie M, Gibb R, Gorny G, Rowntree S. Age, experience and the changing brain. Neurosci Biobehav Rev 1998;22: 143–159.PubMedCrossRefGoogle Scholar
  3. 3.
    Beaulieu C, Colonnier M. Richness of environment affects the numbers of contacts formed by boutons containing flat vesicles but does not alter the number of these boutons per neuron. J Comp Neurol 1988;274: 347–356.PubMedCrossRefGoogle Scholar
  4. 4.
    Johansson BB. Functional outcome in rats transferred to an enriched environment 15 days after focal brain ischemia. Stroke 1996;27: 324–326.PubMedCrossRefGoogle Scholar
  5. 5.
    Hamm RJ, Temple MD, O’Dell DM, Pike BR, Lyeth BG. Exposure to environmental complexity promotes recovery of cognitive function after traumatic brain injury. J Neurotrauma 1996;13: 41–47.PubMedCrossRefGoogle Scholar
  6. 6.
    Schallert T, Woodlee MT, Fleming SM. Experimental focal ischemic injury: behavior-brain interactions and issues of animal handling and housing. ILAR J 2003;44: 130–143.PubMedGoogle Scholar
  7. 7.
    Cotman CW, Berchtold NC. Exercise: a behavioral intervention to enhance brain health and plasticity. Trends Neurosci 2002;25: 295–301.PubMedCrossRefGoogle Scholar
  8. 8.
    Kleim JA, Jones TA, Schallert T. Motor enrichment and the induction of plasticity before or after brain injury. Neurochem Res 2003;28: 1757–1769.PubMedCrossRefGoogle Scholar
  9. 9.
    Goldstein LB, Davis JN. Beam-walking in rats: studies towards developing an animal model of functional recovery after brain injury. J Neurosci Methods 1990;31: 101–107.PubMedCrossRefGoogle Scholar
  10. 10.
    Goldstein LB, Davis JN. Post-lesion practice and amphetamine-facilitated recovery of beam-walking in the rat. Restor Neurol Neurosci 1990;1: 311–314.PubMedGoogle Scholar
  11. 11.
    Nudo RJ, Wise BM, SiFuentes F, Milliken GW. Neural substrates for the effects of rehabilitative training on motor recovery after ischemic infarct. Science 1996;272: 1791–1794.PubMedCrossRefGoogle Scholar
  12. 12.
    Biernaskie J, Corbett D. Enriched rehabilitative training promotes improved forelimb motor function and enhanced dendritic growth after focal ischemic injury. J Neurosci 2001;21: 5272–5280.PubMedGoogle Scholar
  13. 13.
    Biemaskie J, Chemenko G, Corbett D. Efficacy of rehabilitative experience declines with time after focal ischemic brain injury. J Neurosci 2004;24: 1245–1254.CrossRefGoogle Scholar
  14. 14.
    Jones TA, Chu CJ, Grande LA, Gregory AD. Motor skills training enhances lesion-induced structural plasticity in the motor cortex of adult rats. J Neurosci 1999;19: 10153–10163.PubMedGoogle Scholar
  15. 15.
    Friel KM, Heddings AA, Nudo RJ. Effects of postlesion experience on behavioral recovery and neurophysiologic reorganization after cortical injury in primates. Neurorehabil Neural Repair 2000;14: 187–198.PubMedGoogle Scholar
  16. 16.
    Humm JL, Kozlowski DA, Bland ST, James DC, Schallert T. Use-dependent exaggeration of brain injury: is glutamate involved? Exp Neurol 1999;157: 349–358.PubMedCrossRefGoogle Scholar
  17. 17.
    Bland ST, Schallert T, Strong R, Aronowski J, Grotta JC. Early exclusive use of the affected forelimb after moderate transient focal ischemia in rats: functional and anatomic outcome. Stroke 2000;31: 1144–1151.PubMedCrossRefGoogle Scholar
  18. 18.
    Kozlowski DA, James DC, Schallert T. Use-dependent exaggeration of neuronal injury after unilateral sensorimotor cortex lesions. J Neurosci 1996;16: 4776–4786.PubMedGoogle Scholar
  19. 19.
    Humm JL, Kozlowski DA, James DC, Gotts JE, Schallert T. Use-dependent exacerbation of brain damage occurs during an early post-lesion vulnerable period. Brain Res 1998;783: 286–292.PubMedCrossRefGoogle Scholar
  20. 20.
    Risedal A, Zeng J, Johansson BB. Early training may exacerbate brain damage after focal brain ischemia in the rat. J Cereb Blood Flow Metab 1999;19: 997–1003.PubMedCrossRefGoogle Scholar
  21. 21.
    Leasure JL, Schallert T. Consequences of forced disuse of the impaired forelimb after unilateral cortical injury. Behav Brain Res 2004;150: 83–91.PubMedCrossRefGoogle Scholar
  22. 22.
    Jones TA, Bury SD, Adkins-Muir DL, Luke LM, Allred RP, Sakata JT. Importance of behavioral manipulations and measures in rat models of brain damage and brain repair. ILAR J 2003;44: 144–152.PubMedGoogle Scholar
  23. 23.
    Kasamatsu T, Pettigrew JD, Ary M. Restoration of visual cortical plasticity by local microperfusion of norepinephrine. J Comp Neurol 1979;185: 163–182.PubMedCrossRefGoogle Scholar
  24. 24.
    Stroemer RP, Kent TA, Hulsebosch CE. Enhanced neocortical neural sprouting, synaptogenesis, and behavioral recovery with d-amphetamine therapy after neocortical infarction in rats. Stroke 1998;29: 2381–2395.PubMedCrossRefGoogle Scholar
  25. 25.
    Feeney DM, Gonzalez A, Law WA. Amphetamine, haloperidol, and experience interact to affect the rate of recovery after motor cortex injury. Science 1982;217: 855–857.PubMedCrossRefGoogle Scholar
  26. 26.
    Hovda DA, Feeney DM. Amphetamine with experience promotes recovery of locomotor function after unilateral frontal cortex injury in the cat. Brain Res 1984;298: 358–361.PubMedCrossRefGoogle Scholar
  27. 27.
    Sutton RL, Hovda DA, Feeney DM. Amphetamine accelerates recovery of locomotor function following bilateral frontal cortex ablation in cats. Behav Neurosci 1989;103: 837–841.PubMedCrossRefGoogle Scholar
  28. 28.
    Feeney DM, Hovda DA. Reinstatement of binocular depth perception by amphetamine and visual experience after visual cortex ablation. Brain Res 1985;342: 352–356.PubMedCrossRefGoogle Scholar
  29. 29.
    Hovda DA, Sutton RL, Feeney DM. Amphetamine-induced recovery of visual cliff performance after bilateral visual cortex ablation in cats: measurements of depth perception thresholds. Behav Neurosci 1989;103: 574–584.PubMedCrossRefGoogle Scholar
  30. 30.
    Boyeson MG, Feeney DM. Intraventricular norepinephrine facilitates motor recovery following sensorimotor cortex injury. Pharmacol Biochem Behav 1990;35: 497–501.PubMedCrossRefGoogle Scholar
  31. 31.
    Goldstein LB. Amphetamine-facilitated functional recovery after stroke. In: Ginsberg MD, Dietrich WD, editors. Cerebrovascular diseases. 16th Research (Princeton) Conference. New York: Raven Press; 1989. p. 303–308.Google Scholar
  32. 32.
    Goldstein LB, Poe HV, Davis JN. An animal model of recovery of function after stroke: facilitation of recovery by an α2-adrenergic receptor antagonist. Ann Neurol 1989;26: 157.CrossRefGoogle Scholar
  33. 33.
    Goldstein LB, Davis JN. Clonidine impairs recovery of beam-walking in rats. Brain Res 1990;508: 305–309.PubMedCrossRefGoogle Scholar
  34. 34.
    Sutton RL, Feeney DM. α-Noradrenergic agonists and antagonists affect recovery and maintenance of beam-walking ability after sensorimotor cortex ablation in the rat. Restor Neurol Neurosci 1992;4: 1–11.PubMedGoogle Scholar
  35. 35.
    Feeney DM, Westerberg VS. Norepinephrine and brain damage: α-noradrenergic pharmacology alters functional recovery after cortical trauma. Can J Psychol 1990;44: 233–252.PubMedCrossRefGoogle Scholar
  36. 36.
    Hovda DA, Feeney DM, Salo AA, Boyeson MG. Phenoxyben-zamine but not haloperidol reinstates all motor and sensory deficits in cats fully recovered from sensorimotor cortex ablations. Abstr Soc Neurosci 1983;9: 1002.Google Scholar
  37. 37.
    Hovda DA, Feeney DM. Haloperidol blocks amphetamine induced recovery of binocular depth perception after bilateral visual cortex ablation in the cat. Proc West Pharmacol Soc 1985;28: 209–211.PubMedGoogle Scholar
  38. 38.
    van Hasselt P. Effect of butyrophenones on motor function in rats after recovery from brain damage. Neuropharmacology 1973;12: 245–247.PubMedCrossRefGoogle Scholar
  39. 39.
    Goldstein LB, Bullman S. Differential effects of haloperidol and clozapine on motor recovery after sensorimotor cortex injury in the rat. Neurorehabil Neural Repair 2002;16: 321–325.PubMedCrossRefGoogle Scholar
  40. 40.
    Goldstein LB, Coviello A, Miller GD, Davis JN. Norepinephrine depletion impairs motor recovery following sensorimotor cortex injury in the rat. Restor Neurol Neurosci 1991;3: 41–47.PubMedGoogle Scholar
  41. 41.
    Boyeson MG, Callister TR, Cavazos JE. Biochemical and behavioral effects of a sensorimotor cortex injury in rats pretreated with the noradrenergic neurotoxin DSP-4. Behav Neurosci 1992; 106: 964–973.PubMedCrossRefGoogle Scholar
  42. 42.
    Ungerstedt U. Stereotaxic mapping of the monoamine pathways in rat brain. Acta Physiol Scand Suppl 1971;367: 1–48.PubMedGoogle Scholar
  43. 43.
    Pickel VM, Segal M, Bloom F. A radioautographic study of the efferent pathways of the nucleus locus coeruleus. J Comp Neurol 1974;155: 15–42.PubMedCrossRefGoogle Scholar
  44. 44.
    Harik SI. Locus ceruleus lesion by local 6-hydroxydopamine infusion causes marked and specific destruction of noradrenergic neurons, long-term depletion of norepinephrine and the enzymes that synthesize it, and enhanced dopaminergic mechanisms in the ipsilateral cerebral cortex. J Neurosci 1984;4: 699–707.PubMedGoogle Scholar
  45. 45.
    Gonzalez-Pina R, Bueno-Nava A, Montes S, et al. Pontine norepinephrine content after motor cortical ablation in rats. Proc West Pharmacol Soc 2005;48: 73–76.PubMedGoogle Scholar
  46. 46.
    Goldstein LB. Effects of bilateral and unilateral locus coeruleus lesions on beam-walking recovery after subsequent unilateral sensorimotor cortex suction-ablation in the rat. Restor Neurol Neurosci 1997;11: 55–63.PubMedGoogle Scholar
  47. 47.
    Kobayashi RM, Palkovitz M, Kopin IJ, Jacobowitz DM. Biochemical mapping of noradrenergic nerves arising from the rat locus coeruleus. Brain Res 1974;77: 269–279.PubMedCrossRefGoogle Scholar
  48. 48.
    Room P, Postema F, Korf J. Divergent axon collaterals of rat locus coeruleus neurons: demonstration by a fluorescent double labeling technique. Brain Res 1981;221: 219–230.PubMedCrossRefGoogle Scholar
  49. 49.
    Everitt BJ, Robbins TW, Gaskin M. The effects of lesions to ascending noradrenergic neurons on discrimination learning and performance in the rat. Neuroscience 1983;10: 397–410.PubMedCrossRefGoogle Scholar
  50. 50.
    Goldstein LB, Bullman S. Effects of dorsal noradrenergic bundle lesions on recovery after sensorimotor cortex injury. Pharmacol Biochem Behav 1997;58: 1151–1157.PubMedCrossRefGoogle Scholar
  51. 51.
    Schallert T, Leasure JL, Kolb B. Experience-associated structural events, subependymal cellular proliferative activity, and functional recovery after injury to the central nervous system. J Cereb Blood Flow Metab 2000;20: 1513–1528.PubMedCrossRefGoogle Scholar
  52. 52.
    Schallert T, Kozlowski DA, Humm JL, Cocke RR. Use-dependent structural events in recovery of function. Adv Neurol 1997;73: 229–238.PubMedGoogle Scholar
  53. 53.
    Jones TA, Schallert T. Overgrowth and pruning of dendrites in adult rats recovering from neocortical damage. Brain Res 1992; 581: 156–160.PubMedCrossRefGoogle Scholar
  54. 54.
    Schallert T, Jones TA. “Exuberant” neuronal growth after brain damage in adult rats: the essential role of behavioral experience. J Neural Transplant Plast 1993;4: 193–198.PubMedCrossRefGoogle Scholar
  55. 55.
    Jones TA, Schallert T. Use-dependent growth of pyramidal neurons after neocortical damage. J Neurosci 1994;14: 2140–2152.PubMedGoogle Scholar
  56. 56.
    Bliss TVP, Dolphin AC. What is the mechanism of long-term potentiation in the hippocampus? Trends Neurosci 1982;5: 289–290.CrossRefGoogle Scholar
  57. 57.
    Collingridge GL, Bliss TVP. NMDA receptors-their role in long-term potentiation. Trends Neurosci 1987;10: 288–293.CrossRefGoogle Scholar
  58. 58.
    Stanton PK, Sarvey JM. Blockade of norepinephrine-induced long-lasting potentiation in the hippocampal dentate gyrus by an inhibitor of protein synthesis. Brain Res 1985;361: 276–283.PubMedCrossRefGoogle Scholar
  59. 59.
    Dahl D, Sarvey JM. Norepinephrine induces pathway-specific long-lasting potentiation and depression in the hippocampal dentate gyrus. Proc Natl Acad Sci U S A 1989;86: 4776–4780.PubMedCrossRefGoogle Scholar
  60. 60.
    Swanson LW, Teyler TJ, Thompson RF. Hippocampal long-term potentiation: mechanisms and implications for memory. Neurosci Res Program Bull 1982;20: 601–769.Google Scholar
  61. 61.
    Hopkins WF, Johnston D. Frequency-dependent noradrenergic modulation of long-term potentiation in the hippocampus. Science 1984;226: 350–352.PubMedCrossRefGoogle Scholar
  62. 62.
    Wigstrom H, Gustafsson B. Facilitation of hippocampal long-lasting potentiation by GABA antagonists. Acta Physiol Scand Suppl 1985;125: 159–172.CrossRefGoogle Scholar
  63. 63.
    Douglas RM, Goddard GV, Riives M. Inhibitory modulation of long-term potentiation: evidence for a postsynaptic locus of control. Brain Res 1982;240: 259–272.PubMedCrossRefGoogle Scholar
  64. 64.
    Olpe HR, Karlsson G. The effects of baclofen and two GABA B-receptor antagonists on long-term potentiation. Naunyn Schmiedebergs Arch Pharmacol 1990;342: 194–197.PubMedCrossRefGoogle Scholar
  65. 65.
    Ito T, Miura Y, Kadokawa T. Effects of physostigmine and sco-polamine on long-term potentiation of hippocampal population spikes in rats. Can J Physiol Pharmacol 1988;66: 1010–1016.PubMedCrossRefGoogle Scholar
  66. 66.
    Williams S, Johnston D. Muscarinic depression of long-term potentiation in CA3 hippocampal neurons. Science 1988;242: 84–87.PubMedCrossRefGoogle Scholar
  67. 67.
    Burgard EC, Sarvey JM. Muscarinic receptor activation facilitates the induction of long-term potentiation (LTP) in the rat dentate gyrus. Neurosci Lett 1990;116: 34–39.PubMedCrossRefGoogle Scholar
  68. 68.
    De Ryck M, Duytschaever H, Janssen PAJ. Ionic channels, cho-linergic mechanisms, and recovery of sensorimotor function after neocortical infarcts in rats. Stroke 1990;21: S58-S63.Google Scholar
  69. 69.
    Feeney DM, Sutton RL. Pharmacotherapy for recovery of function after brain injury. Crit Rev Neurobiol 1987;3: 135–197.PubMedGoogle Scholar
  70. 70.
    Cheney DL, LeFevre HF, Racagni G. Choline acetyltransferase activity and mass fragmentographic measurement of acetylcholine in specific nuclei and tracts of rat brain. Neuropharmacology 1975; 14: 801–809.PubMedCrossRefGoogle Scholar
  71. 71.
    Kuhar MJ, Atweh SF, Bird SJ. Studies of cholinergic-monoaminergic interactions in rat brain. In: Butcher LL, editor. Cholinergic-monoaminergic interactions in the brain. New York: Academic Press; 1978. p. 211–227.CrossRefGoogle Scholar
  72. 72.
    Douglas RM, McNaughton BL, Goddard GV. Commissural inhibition and facilitation of granule cell discharge in fascia dentata. J Comp Neurol 1983;219: 285–294.PubMedCrossRefGoogle Scholar
  73. 73.
    Riches IP, Brown MW. The effect of lorazepam upon hippocampal long-term potentiation Neurosci Lett 1986:S42. [Abstract].Google Scholar
  74. 74.
    Brailowsky S, Knight RT, Blood K. γ-Aminobutyric acid-induced potentiation of cortical hemiplegia. Brain Res 1986;362: 322–330.PubMedCrossRefGoogle Scholar
  75. 75.
    Schallert T, Hernandez TD, Barth TM. Recovery of function after brain damage: severe and chronic disruption by diazepam. Brain Res 1986;379: 104–111.PubMedCrossRefGoogle Scholar
  76. 76.
    Bourdelais A, Kalivas PW. Amphetamine lowers extracellular GABA concentration in the ventral pallidum. Brain Res 1990;516: 132–136.PubMedCrossRefGoogle Scholar
  77. 77.
    Windle V, Corbett D. Fluoxetine and recovery of motor function after focal ischemia in rats. Brain Res 2005;1044: 25–32.PubMedCrossRefGoogle Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2006

Authors and Affiliations

  1. 1.Department of Medicine (Neurology), Duke Center for Cerebrovascular DiseaseDuke UniversityDurham
  2. 2.Durham Department of Veterans Affairs Medical CenterDurham

Personalised recommendations