Project Summary/Abstract Patients with spinal cord injury (SCI) above spinal level T6 commonly have reduced basal sympathetic tone due to the loss of supraspinal sympathetic drive. Hypotension is common, but it is the profound nociceptor induced uncontrolled hypertensive crisis termed autonomic dysreflexia (AD) that is potentially life-threatening. Studies on AD mechanisms mostly focus on spinal cord where sprouting nociceptive afferents are thought to lead to exaggerated sympathetic preganglionic output. Nevertheless, missing from most studies is consideration of sympathetic post-ganglionic neurons (SPNs), the final neural step for sympathetic vasoconstriction. Conventionally considered simple relays, SPNs can integrate input from multiple preganglionic sources and so may substantially amplify CNS preganglionic drive post-SCI. Moreover, in contrast to paravertebral SPNs, prevertebral SPNs also receive direct input from afferent collaterals ascending through visceral nerves toward spinal cord. This feature makes prevertebral SPNs a peripheral sympathetic integration center. Prevertebral celiac ganglionic neurons (CGNs) innervate abdominal vascular beds that comprise ~1/3 of total body blood volume. This suggests that hyperresponsive CGN vasoconstrictor drive may be prominent in generating the observed hypertension in AD. In preliminary CGN whole cell recordings from the isolated adult mouse celiac ganglia, we observed that high thoracic SCI (SCIHT) had increased intrinsic and increased capability of repetitive firing. We also observe the substantially increased number of nociceptive afferent (CGRP+) synapses, that could further enhance CGNs excitability during AD. Thus, our first aim will test the hypothesis that SCIHT leads to intrinsic and synaptic modifications that promote exaggerated CGN output. We will use electrophysiological, optogenetic, pharmacological and anatomical approaches to determine pathophysiological and morphological modifications of CGNs after SCIHT in adult mice. Our second aim will test the hypothesis that CGN activity is both necessary and sufficient to generate hypertensive responses seen in mice with colon distention-induced AD. We will use implantable mini-pumps to deliver local infusions to the celiac ganglia that selectively block CGN activity while recording blood pressure during distention- induced AD (tests necessity) or selectively recruit CGNs while measuring blood pressure changes (sufficiency). These studies are expected to have broad impact on the field of autonomic dysfunction after SCI. First, if observed mechanisms of celiac ganglia dysfunction are associated with the expression of AD, the celiac ganglia would be an important site for subsequent therapeutic targeting. Secondly, as celiac ganglia have impact on multiple visceral organs (gastrointestinal tract, spleen kidney, liver) the identification of CGN circuit dysfunction may also contribute to various dysfunction in innervated organs (e.g. SCI -induced intestinal dysmotility).

Project Narrative This study explores physiological and anatomical plasticity of prevertebral celiac ganglion neurons after high thoracic spinal cord injury, including changes in their intrinsic properties and preganglionic and nociceptive inputs. Behavioral outcomes test the contribution of enhanced celiac ganglionic neuron activation to autonomic dysreflexia. This study may lead to new understanding of peripheral mechanisms of and therapeutic targets for autonomic dysreflexia.