Normal function within spinal circuits depends on precise regulation of baseline levels for neuron excitability. Perhaps the most important sources of this regulation are the monoaminergic tracts that originate in the brainstem and release either serotonin or norepinephrine in the cord. These two neuromodulators, which act via intracellular second messenger systems, have potent effects that can be either excitatory or inhibitory, depending on the receptor subtype of the target neuron. Our recent data suggest a new organizing principle for monoaminergic actions on spinal interneurons. We postulate that interneurons with narrow receptive fields receive monoaminergic excitation while those with broad receptive fields receive strong inhibition. We test this hypothesis for the interneurons that process information on muscle length, which is generated by muscle spindle group Ia and II afferents. The Ia interneurons mediate reciprocal inhibition between antagonist muscles and we hypothesize that these cells have narrow receptive fields and receive monoaminergic excitation. In contrast, the receptive fields of group II interneurons are hypothesized to be broad and their monoaminergic input to be inhibitory. Interneuron discharge patterns are recorded extracellularly in an in vivo preparation with tonic activity in monoaminergic fibers.
In aim I, systematic measurements of Ia and II interneuron receptive fields are obtained from controlled length changes of many different muscles and from precise joint rotations. These studies may show that II interneurons calculate net length changes for the whole limb, while Ia interneurons specify length only for rotation of individual joints. Because length feedback via these interneurons plays a fundamental role in controlling muscles, the monoaminergic system may exert differential control on mechanical properties of single joints versus the whole limb.
In aim 2, the effect of altering tonic monoaminergic drive is assessed, with increases achieved via stimulation of the brainstem and decreases via a reversible cold block. The results are especially important for understanding the spasticity and other deficits accompanying spinal injury. Injury mediated loss of excitation to Ia interneurons would suppress the normal reciprocal relations between antagonist muscles. At the same time, the debilitating spasms that afflict spinal cord injured patients may be caused by the loss of inhibition of group II interneurons. This mechanism would account for the tendency of these spasms to rapidly spread throughout an entire limb.
In aim 3, the specific receptor subtypes that mediate monoaminergic excitation of Ia interneurons and inhibition of II interneurons are evaluated. These studies are likely to lead to novel pharmacological strategies to help restore normal function in spinal cord injury and stroke.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS040862-04
Application #
6653158
Study Section
Special Emphasis Panel (ZNS1-SRB-L (01))
Program Officer
Pancrazio, Joseph J
Project Start
2000-09-28
Project End
2005-08-31
Budget Start
2003-09-01
Budget End
2004-08-31
Support Year
4
Fiscal Year
2003
Total Cost
$257,250
Indirect Cost
Name
Northwestern University at Chicago
Department
Physiology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611