Control of Spinal Locomotor Activity by Monoamines

Project: Research project

Project Details

Description

Impaired locomotion is one of the many devastating consequences of spinal cord injury (SCI). The extent
of impairment depends on the level and magnitude of the injury and the neuronal pathways disrupted.
Research from our laboratory indicates that, in addition to reticulospinal pathways, brainstem
monoaminergic neurons, which are the sole source of the spinal monoamines serotonin and
norepinephrine, are also activated during deep brain stimulation (DBS) of the mesencephalic locomotor
region (MLR). The profound effects of monoaminergic drugs on locomotor function even when normal
brainstem sources of activation have been experimentally blocked suggests that these transmitters can be
used to facilitate locomotion in humans with SCI. Providing there are spared connections following SCI, this
method has the potential to facilitate locomotion by artificially maximizing endogenous transmitter release
in target areas of the spinal cord still innervated. As part of our long-term goal of developing and optimizing
treatments for SCI based on transmitter enhancement strategies, the objectives of this application are to
determine the therapeutic potential of DBS to improve locomotor function following partial SCI and to define
the precise role of monoamines in this recovery. The central hypothesis is that DBS of the MLR can be
used therapeutically to facilitate locomotion in chronic SCI. Preliminary data show significant improvements
in locomotor capabilities with DBS in animals with contusion injury. Our specific aims are: Aim 1. Delimit
the capabilities of spared pathways to facilitate locomotor recovery after SCI. To examine this, we shall
stimulate the MLR in animals with mild-to-severe contusion and other select thoracic injuries over acute
and chronic stages of injury. Motor recovery and the extent of injury will be assessed. Aim 2. Determine
the relationship between the amount of locomotor recovery with DBS and spinal monoaminergic
neurotransmission. Extracellular monoamine levels will be correlated with locomotor capabilities following
DBS. Monoaminergic receptor antagonists will be given to animals showing behavioral improvement in
order to further delineate this relationship.
StatusFinished
Effective start/end date7/1/116/30/13

Funding

  • National Institute of Neurological Disorders and Stroke: $382,500.00

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