The present project explores a barely studied and poorly-understood area of vertebrate autonomic neuroscience: the recruitment properties of thoracic paravertebral sympathetic postganglionic neurons (tSPNs). The prominent role of thoracic paravertebral sympathetic chain ganglia is as the final neural control element regulating vasomotor tone. Given their strategic nodal site in autonomic signaling to body, any plasticity in tSPNs is likely to be of high significance. Unfortunately, tSPNs are largely inaccessible for in vivo study, so operational principles are inferred from studies in cervical and lumbar chain ganglia. Only 3 in vitro studies have revealed tSPN electrophysiological properties: none accurately measure cellular integrative properties or underlying recruitment principles due to electrode impalement injury. We undertook the first physiological studies on caudal thoracic chain ganglia in the adult mouse by developing an ex vivo preparation with intact segmental preganglionic and rostrocaudal interganglionic connections. We obtained the first whole- cell patch clamp recordings of tSPNs and observed fundamentally different integrative and firing properties are than previously observed. This reliable data set is a critical prerequisite to realistic computational simulation. We propose to interleave experimental testing with modeling to understand tSPN recruitment principles and their integrative properties. [SA1] We will test the hypothesis that tSPNs have heterogeneous synaptic, cellular, and network properties, and are active participants in input-output recruitment strategies. Higher thoracic spinal cord injuries (SCI) disrupt the brainstem pathways that regulate tSPN excitability via spinal preganglionic loops. Such disruption can lead to sudden life-threatening tSPN mediated hypertensive crises (autonomic dysreflexia). Whether paravertebral sympathetic chain ganglia dysfunction contributes to amplification in a vasomotor response is unknown. To fill this significant gap in knowledge, experimental studies will disclose plasticity in the cellular and synaptic organizational rules serving tSPN recruitment. [SA2] We will test the hypothesis that tSPNs increased their intrinsic excitability and convert from linear to non-linear gain amplifiers after SCI. Computational simulation will construct a database amenable to realistic modeling of recruitment principles of potential clinical relevance that could be transformative to the field. The relative simplicity of the organization makes discovery of principles through modeling more assured than in more complex systems. Realistic simulation of the neural bases of tSPN function and emergent dysfunction could catalyze predictive drug discovery-based high throughput simulations that normalize function for rapid preclinical testing. Significance:
we aim to uncover the operational principles governing the final neural command pathways regulating vascular tone. As sympathetic hyperactivity is implicated in various autonomic disorders, a database amenable to realistic modeling studies will be of broad predictive use in preclinical and translational studies.
This project addresses a poorly understood and barely investigated area of neuroscience: the properties of thoracic paravertebral sympathetic ganglia that regulate vascular tone, and whose dysfunction in spinal cord injury may be causal to the threatening episodes of autonomic dysreflexia. Proposed is a combined physiological and computational simulation study on these ganglia. Discovery of the neural bases of dysfunction after cord injury could leverage computer simulation to catalyze high throughput drug discovery for preclinical experimental tests of potential clinical relevance.
