Neurotransmitters and Motor Activity: Effects on Functional
Recovery after Brain Injury
Larry B. Goldstein
Department of Medicine (Neurology), Duke Center for Cerebrovascular Disease, Duke University, Durham, North Carolina; and
Durham Department of Veterans Affairs Medical Center, Durham, North Carolina
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 experi-
mental 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 nore-
pinephrine-modulated locomotor recovery after injury to the
cerebral cortex illustrate the close relationships among neuro-
transmitter levels, brain plasticity, and behavioral recovery.
Understanding the neurobiological processes underlying recov-
ery, and how they might be manipulated, may lead to novel
strategies for improving recovery from stroke-related gait im-
pairment in humans. Key Words: Stroke, motor function, brain
injury, norepinephrine, recovery.
Impaired walking after stroke is associated both with
higher levels of disability and with compromised levels
of social functioning. Depending on the level of assis-
tance required, this particular deficit can lead to great
increases in caregiver burden and so may necessitate the
patient’s residence in a formal assisted-living environ-
ment. Effective strategies aimed at improving poststroke
gait impairments would help mitigate its functional and
Much has been learned about the immediate response
of the brain to stroke-related injury, as well as its poten-
tial for plasticity during the recovery period. Understand-
ing the roles of specific neurotransmitters as modulators
of the recovery process could lead to effective poststroke
EFFECT OF EXPERIENCE AND TRAINING
ON FUNCTIONAL LOCOMOTOR RECOVERY
IN ANIMAL MODELS
Numerous studies in laboratory animals show that en-
vironmental complexity can have a direct impact on an-
atomical brain plasticity.1Housing in complex environ-
ments is associated with overall and regionally specific
increases in brain weight, cortical depth, hippocampal
thickness, callosal size, and cortical glial density1and
has effects on both neuronal morphology1,2and connec-
tivity.3It has also long been recognized that housing
animals in complex environments (as opposed to a stan-
dard cage), either before or after brain injury, can lead to
less severe neurological deficits and more favorable out-
comes,4–6although some debate remains as to whether
this represents true recovery or enhancement of compen-
satory behavioral strategies.1
In addition to general environmental factors, a large
number of laboratory studies also show the importance
of training after brain injury for functional motor recov-
ery.2,7,8As summarized in these detailed reviews, exer-
cise can increase levels of neurotrophic factors such as
brain-derived neurotrophic factor (BDNF), enhance neu-
rogenesis, and improve learning. Rehabilitative training
is associated with specific improvements in motor func-
tion after cortex injury in several behavioral para-
digms,9–14particularly when this training is coupled with
housing in complex environments.12,13
Experimental studies in squirrel monkeys suggest that
repetitive use of the impaired hand is required for main-
tenance of the spared portion of the hand representation
after motor cortex infarction.15Overuse of the affected
limb during vulnerable periods after experimental brain
Address correspondence and reprint requests to: Larry B. Goldstein,
M.D., Director, Duke Center for Cerebrovascular Disease, Box 3651,
Duke University Medical Center, Durham, NC 27710. E-mail:
NeuroRx?: The Journal of the American Society for Experimental NeuroTherapeutics
Vol. 3, 451–457, October 2006 © The American Society for Experimental NeuroTherapeutics, Inc.
61. Hopkins WF, Johnston D. Frequency-dependent noradrenergic
modulation of long-term potentiation in the hippocampus. Science
62. Wigstrom H, Gustafsson B. Facilitation of hippocampal long-last-
ing potentiation by GABA antagonists. Acta Physiol Scand Suppl
63. Douglas RM, Goddard GV, Riives M. Inhibitory modulation of
long-term potentiation: evidence for a postsynaptic locus of con-
trol. Brain Res 1982;240:259–272.
64. Olpe HR, Karlsson G. The effects of baclofen and two GABA
Schmiedebergs Arch Pharmacol 1990;342:194–197.
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.
66. Williams S, Johnston D. Muscarinic depression of long-term po-
tentiation in CA3 hippocampal neurons. Science 1988;242:84–87.
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.
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.
69. Feeney DM, Sutton RL. Pharmacotherapy for recovery of function
after brain injury. Crit Rev Neurobiol 1987;3:135–197.
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;
71. Kuhar MJ, Atweh SF, Bird SJ. Studies of cholinergic-monoamin-
ergic interactions in rat brain. In: Butcher LL, editor. Cholinergic–
monoaminergic interactions in the brain. New York: Academic
Press; 1978. p. 211–227.
72. Douglas RM, McNaughton BL, Goddard GV. Commissural inhi-
bition and facilitation of granule cell discharge in fascia dentata.
J Comp Neurol 1983;219:285–294.
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. ?-Aminobutyric acid-in-
duced potentiation of cortical hemiplegia. Brain Res 1986;362:
75. Schallert T, Hernandez TD, Barth TM. Recovery of function after
brain damage: severe and chronic disruption by diazepam. Brain
76. Bourdelais A, Kalivas PW. Amphetamine lowers extracellular
GABA concentration in the ventral pallidum. Brain Res 1990;516:
77. Windle V, Corbett D. Fluoxetine and recovery of motor function
after focal ischemia in rats. Brain Res 2005;1044:25–32.
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