Plasticity of spinal cord function after injury: Autonomic dysreflexia

The injured spinal cord often becomes hyper-responsive resulting in autonomic dysfunction and devastating chronic pain syndromes. Spinal preganglionic sympathetic neurons (SPNs) are the sympathetic output neurons of the CNS and are located in thoracic and upper lumbar spinal segments. Loss of brain controls to SPNs after spinal injury leads to an unregulated circuitry strongly influenced by afferent input from pain systems, which can produce autonomic dysreflexia. We hypothesize that excitatory nociceptive input converts and traps SPNs into an up-state in excitability (plateau potentials) and so generating continuous SPN firing to produce potentially life-threatening hypertensive crisis. Using an adult spinal slice preparation and recording SPN firing properties changes after cord injury, we predict the up-state is maintained by constitutively-active monoamine receptors, and will focus on the actions of inverse agonists as prospective therapeutics.

Neuromodulatory control of spinal sympathetic autonomic function

Spinal preganglionic sympathetic neurons represent the final common output of the CNS sympathetic nervous system. These neurons are located in thoracic and upper lumbar spinal segments. Loss of descending controls to this system after spinal injury leads to an unregulated circuitry that is strongly influenced by input from pain systems. One result is excess sympathetic drive which can produce autonomic dysreflexia. We have begun to characterize the properties of sympathetic preganglionic neurons (Zimmerman and Hochman 2010) and study the actions of neuromodulatory transmitters that regulate their function and to assess their plasticity after spinal cord injury.

5ht2a in SPNs

5HT2A receptors in HB9-GFP+ SPNs. Images of 5HT2A receptor (left), SPNs (middle) and merged image (right).

Studies on visceral afferent evoked responses on sympathetic efferents

While many studies have shown that visceral afferents project to DRGs several segments away from their spinal nerves, few have suggested they reach the appropriate DRGs by traveling within the sympathetic chain. We therefore sought to confirm the presence of afferents in the sympathetic chain and major splanchnic nerve in the neonatal mouse model system, using immunohistochemistry on fixed tissue of dissected whole mounts of the major splanchnic nerve and sympathetic chain.

Axon fiber composition in paravertebral ganglia. Section in central region of ganglia shows that, while sympathetic preganglionics appear to form basket-like synapses around postganglionics, CGRP+ visceral afferents do not project through this region. Image is a collapsed stack of 11 consecutive confocal images (4.18 micron total). Scale bar is 20 microns.

Plasticity of inhibitory circuit function after cord injury

Using GAD67-EGFP transgenic mice, we studied the properties of visually-identified GABAergic neurons in lamina I of the spinal cord (Dougherty et al 2005) (Dougherty et al 2008) (Dougherty et al 2009). This region is involved in spinal pain processing and modification in the lamina I inhibitory apparatus may contribute significantly to the high incidence of chronic pain syndromes following cord injury.

 

GAD67 and GABA

Comparison of endogenous GFP to GABA-IR in P0, P7, P14, and adult mice (from Dougherty et al 2009)

 

SCI firing props

A subpopulation of GABAergic interneurons become more excitable after spinal cord injury (from Dougherty et al 2008)

 

Gene expression changes after spinal cord injury

In collaboration with Deb Baro, we have used DNA microarrays in conjunction with laser-capture microdissection (LCM) to provide a comprehensive dissection of gene expression changes in motoneurons and sympathetic preganglionic neurons following chronic spinal injury (Cui et al 2006). Our goal is to identify expression changes in important cell populations to direct novel approaches for spinal cord repair.
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