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. 2012 Sep 5;3(4):451–457. doi: 10.1016/j.nurx.2006.07.010

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

Larry B Goldstein 1,2,
PMCID: PMC3593407  PMID: 17012058

Summary

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

References

  • 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. doi: 10.1016/0166-4328(93)90025-L. [DOI] [PubMed] [Google Scholar]
  • 2.Kolb B, Forgie M, Gibb R, Gorny G, Rowntree S. Age, experience and the changing brain. Neurosci Biobehav Rev. 1998;22:143–159. doi: 10.1016/S0149-7634(97)00008-0. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1002/cne.902740305. [DOI] [PubMed] [Google Scholar]
  • 4.Johansson BB. Functional outcome in rats transferred to an enriched environment 15 days after focal brain ischemia. Stroke. 1996;27:324–326. doi: 10.1161/01.STR.27.2.324. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1089/neu.1996.13.41. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1093/ilar.44.2.130. [DOI] [PubMed] [Google Scholar]
  • 7.Cotman CW, Berchtold NC. Exercise: a behavioral intervention to enhance brain health and plasticity. Trends Neurosci. 2002;25:295–301. doi: 10.1016/S0166-2236(02)02143-4. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1023/A:1026025408742. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/0165-0270(90)90154-8. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.3233/RNN-1990-1501. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1126/science.272.5269.1791. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1523/JNEUROSCI.21-14-05272.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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. doi: 10.1523/JNEUROSCI.3834-03.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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. doi: 10.1523/JNEUROSCI.19-22-10153.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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. doi: 10.1177/154596830001400304. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1006/exnr.1999.7061. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1161/01.STR.31.5.1144. [DOI] [PubMed] [Google Scholar]
  • 18.Kozlowski DA, James DC, Schallert T. Use-dependent exaggeration of neuronal injury after unilateral sensorimotor cortex lesions. J Neurosci. 1996;16:4776–4786. doi: 10.1523/JNEUROSCI.16-15-04776.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/S0006-8993(97)01356-5. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1097/00004647-199909000-00007. [DOI] [PubMed] [Google Scholar]
  • 21.Leasure JL, Schallert T. Consequences of forced disuse of the impaired forelimb after unilateral cortical injury. Behav Brain Res. 2004;150:83–91. doi: 10.1016/S0166-4328(03)00254-7. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1093/ilar.44.2.144. [DOI] [PubMed] [Google Scholar]
  • 23.Kasamatsu T, Pettigrew JD, Ary M. Restoration of visual cortical plasticity by local microperfusion of norepinephrine. J Comp Neurol. 1979;185:163–182. doi: 10.1002/cne.901850110. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1161/01.STR.29.11.2381. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1126/science.7100929. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/0006-8993(84)91437-9. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1037/0735-7044.103.4.837. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/0006-8993(85)91135-7. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1037/0735-7044.103.3.574. [DOI] [PubMed] [Google Scholar]
  • 30.Boyeson MG, Feeney DM. Intraventricular norepinephrine facilitates motor recovery following sensorimotor cortex injury. Pharmacol Biochem Behav. 1990;35:497–501. doi: 10.1016/0091-3057(90)90279-Q. [DOI] [PubMed] [Google Scholar]
  • 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. pp. 303–308. [Google Scholar]
  • 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;26:157–157. doi: 10.1002/ana.410260410. [DOI] [Google Scholar]
  • 33.Goldstein LB, Davis JN. Clonidine impairs recovery of beam-walking in rats. Brain Res. 1990;508:305–309. doi: 10.1016/0006-8993(90)90413-6. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.3233/RNN-1992-4101. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1037/h0084243. [DOI] [PubMed] [Google Scholar]
  • 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;9:1002–1002. [Google Scholar]
  • 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. [PubMed] [Google Scholar]
  • 38.van Hasselt P. Effect of butyrophenones on motor function in rats after recovery from brain damage. Neuropharmacology. 1973;12:245–247. doi: 10.1016/0028-3908(73)90109-3. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1177/154596830201600402. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.3233/RNN-1991-3105. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1037/0735-7044.106.6.964. [DOI] [PubMed] [Google Scholar]
  • 42.Ungerstedt U. Stereotaxic mapping of the monoamine pathways in rat brain. Acta Physiol Scand Suppl. 1971;367:1–48. doi: 10.1111/j.1365-201x.1971.tb10998.x. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1002/cne.901550103. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1523/JNEUROSCI.04-03-00699.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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. [PubMed] [Google Scholar]
  • 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. doi: 10.3233/RNN-1997-111206. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/0006-8993(74)90790-2. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/0006-8993(81)90773-3. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/0306-4522(83)90142-2. [DOI] [PubMed] [Google Scholar]
  • 50.Goldstein LB, Bullman S. Effects of dorsal noradrenergic bundle lesions on recovery after sensorimotor cortex injury. Pharmacol Biochem Behav. 1997;58:1151–1157. doi: 10.1016/S0091-3057(97)00324-9. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1097/00004647-200011000-00001. [DOI] [PubMed] [Google Scholar]
  • 52.Schallert T, Kozlowski DA, Humm JL, Cocke RR. Use-dependent structural events in recovery of function. Adv Neurol. 1997;73:229–238. [PubMed] [Google Scholar]
  • 53.Jones TA, Schallert T. Overgrowth and pruning of dendrites in adult rats recovering from neocortical damage. Brain Res. 1992;581:156–160. doi: 10.1016/0006-8993(92)90356-E. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1155/NP.1993.193. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Jones TA, Schallert T. Use-dependent growth of pyramidal neurons after neocortical damage. J Neurosci. 1994;14:2140–2152. doi: 10.1523/JNEUROSCI.14-04-02140.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Bliss TVP, Dolphin AC. What is the mechanism of long-term potentiation in the hippocampus? Trends Neurosci. 1982;5:289–290. doi: 10.1016/0166-2236(82)90181-3. [DOI] [Google Scholar]
  • 57.Collingridge GL, Bliss TVP. NMDA receptors-their role in long-term potentiation. Trends Neurosci. 1987;10:288–293. doi: 10.1016/0166-2236(87)90175-5. [DOI] [Google Scholar]
  • 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. doi: 10.1016/0006-8993(85)91299-5. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1073/pnas.86.12.4776. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60.Swanson LW, Teyler TJ, Thompson RF. Hippocampal long-term potentiation: mechanisms and implications for memory. Neurosci Res Program Bull. 1982;20:601–769. [PubMed] [Google Scholar]
  • 61.Hopkins WF, Johnston D. Frequency-dependent noradrenergic modulation of long-term potentiation in the hippocampus. Science. 1984;226:350–352. doi: 10.1126/science.6091272. [DOI] [PubMed] [Google Scholar]
  • 62.Wigstrom H, Gustafsson B. Facilitation of hippocampal long-lasting potentiation by GABA antagonists. Acta Physiol Scand Suppl. 1985;125:159–172. doi: 10.1111/j.1748-1716.1985.tb07703.x. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/0006-8993(82)90221-9. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1007/BF00166964. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1139/y88-165. [DOI] [PubMed] [Google Scholar]
  • 66.Williams S, Johnston D. Muscarinic depression of long-term potentiation in CA3 hippocampal neurons. Science. 1988;242:84–87. doi: 10.1126/science.2845578. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/0304-3940(90)90382-J. [DOI] [PubMed] [Google Scholar]
  • 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. [PubMed] [Google Scholar]
  • 69.Feeney DM, Sutton RL. Pharmacotherapy for recovery of function after brain injury. Crit Rev Neurobiol. 1987;3:135–197. [PubMed] [Google Scholar]
  • 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. doi: 10.1016/0028-3908(75)90107-0. [DOI] [PubMed] [Google Scholar]
  • 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. pp. 211–227. [Google Scholar]
  • 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. doi: 10.1002/cne.902190304. [DOI] [PubMed] [Google Scholar]
  • 73.Riches IP, Brown MW. The effect of lorazepam upon hippocampal long-term potentiation Neurosci Lett 1986:S42. [Abstract].
  • 74.Brailowsky S, Knight RT, Blood K. γ-Aminobutyric acid-induced potentiation of cortical hemiplegia. Brain Res. 1986;362:322–330. doi: 10.1016/0006-8993(86)90457-9. [DOI] [PubMed] [Google Scholar]
  • 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. doi: 10.1016/0006-8993(86)90261-1. [DOI] [PubMed] [Google Scholar]
  • 76.Bourdelais A, Kalivas PW. Amphetamine lowers extracellular GABA concentration in the ventral pallidum. Brain Res. 1990;516:132–136. doi: 10.1016/0006-8993(90)90907-S. [DOI] [PubMed] [Google Scholar]
  • 77.Windle V, Corbett D. Fluoxetine and recovery of motor function after focal ischemia in rats. Brain Res. 2005;1044:25–32. doi: 10.1016/j.brainres.2005.02.060. [DOI] [PubMed] [Google Scholar]

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