Modifiability of Conduction Across Preganglionic Axonal Branch Points

项目总结

PROJECT SUMMARY Spinal cord sympathetic preganglionic neurons (SPNs) are found in the thoracic and lumbar spinal cord. They are the final arbiters of CNS sympathetic output. SPN axons branch to issue highly divergent multisegmental projections on paravertebral sympathetic chain ganglia postganglionic neurons (PNs). Divergence provides a mechanism for amplification of CNS sympathetic commands to the numerically much greater PNs. It is assumed that spike conduction is reliable across multisegmental branch points. This was based on ex vivo recordings from the sympathetic chain at room temperature (T°) where large increases in spike amplitude and width ensure a high safety factor for branch point conduction. As increasing T° promotes conduction failures, it is likely that SPN branch point conduction is also T°-sensitive. In somatosensory systems, branch points provide an important site for control of axonal conduction and extrasynaptic α5-containing GABAA receptors (GABAARs) are implicated. SPNs also express α5-GABAARs, and their expression at presynaptic axonal branch points may similarly control divergence and hence response amplification to PNs. We recorded from SPN axons diverging across ganglia in the adult mouse ex vivo thoracic paravertebral chain following stimulation of attached ventral roots. Initial experiments observed that conduction block was dependent on; number of traversed chain ganglia, T°, frequency, and GABAAR antagonists. Results support axonal divergence as a modifiable output stage in sympathetic gain control. [SA1] We hypothesize that preganglionic axonal conduction block across branch points is under neuromodulatory control by constitutively active, α5-containing GABAAR. We undertake experiments to aess axonal recruitment changes following application of GABAAR agonists, antagonists and endogenous neurosteroid allosteric modulators and tested across the physiological range of firing frequencies. [SA2] Many spinal cord injured (SCI) individuals have thermoregulatory dysfunction. As even small elevations in body T° can compromise spike conduction, SPN axonal function in the SCI population may be particularly vulnerable. We hypothesize that conduction across branch points is sensitive to the broader changes in T°core and will test the effect of T° on conduction block over a range of T° consistent with hypo- or hyperthermia. [SA3] We hypothesize that SCI leads to changes that promote conduction across branch points, including (a) increased GABAAR activity and (b) spike width broadening. Results above will be compared to those seen after T2 thoracic SCI at early (1-3 days) and chronic (4-6 weeks) time points. Exploring mechanisms that promote or prevent conduction across branch points is critical to understanding whether SPN signal amplification is hard-wired or physiologically modifiable (e.g. behavioral state dependent) and whether plasticity after SCI alters function at this important sympathetic output stage.