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Project

Property of vasoconstrictor thoracic sympathetic postganglionic neurons after SCI

Funder: Craig H Neilsen Foundation

Funding period
USD 150 K
Funding amount
Abstract
High-thoracic and cervical spinal cord injury (high SCI) commonly causes autonomic dysreflexia (AD), an episodic uncontrolled crisis of hypertension in response to a nociceptive stimuli. Sympathetic postganglionic neurons (SPNs) receive convergent input from preganglionic motoneurons in the spinal cord and provide the dominant sympathetic output controlling of vasculature. Vasomotor thoracic SPNs (tSPNs) are deeply embedded within brown adipose tissue adjacent to the vertebral column and are physically inaccessible for in vivo studies. Thus little is known about the normative electrophysiological properties of tSPNs. Most critically there has been no study of changes in tSPN cellular or synaptic properties following SCI and thus the contribution of tSPN plasticity to dysregulated vasomotor function following high SCI is not known. Preliminary data provided by the Hochman lab suggest that tSPNs become hyper-excitable after high SCI supporting a causal contribution of tSPN dysregulation to AD. The cellular mechanisms underlying this hyper-excitability however are not known. In Aim 1 I will study the intrinsic properties of tSPNs that exclusively project to vasculature by using the NPY::Tdtomato mouse in concert with a newly-developed ex vivo whole cell recording model in adult naive and high-thoracic transected spinal mice. I will characterize both passive electrical and active firing properties of NPY-positive tSPNs to determine its intrinsic properties, and will test its plasticity of persistent inward current (PIC) as an important mechanism for hyper-excitability after SCI. In addition, I will use sparse-labeling method in NPY line to determine whether there are anatomical changes to NPY-tSPNs after SCI that correlate with PICs plasticity and other intrinsic cellular changes. In Aim 2 I will study tSPN synaptic properties by using the ChAT::ChR2 mouse that allows for selective activation of preganglionic axons while simultaneously recording tSPN intracellular properties. In this model I will study preganglionic convergence in both naive and high SCI mice and determine the duration and distribution of evoked EPSPs in tSPNs. In addition, I will quantify amplitude and frequency of spontaneous EPSPs. Studies in Aim 2 will demonstrate whether tSPNs respond more strongly to synaptic input after SCI. I hypothesize that tSPN intrinsic properties will change after SCI, including increased PICs that amplify preganglionic input. Additionally, I hypothesize that high SCI will lead to increased divergence and strength of preganglionic input to tSPNs. I thus expect that changes in both intrinsic and synaptic mechanisms will contribute to tSPN hyperexcitability post-SCI. I believe that elucidation of the intrinsic and synaptic mechanisms underlying increased excitability of tSPNs after high SCI will lead to the development of evidence-based therapies for prevention and treatment of AD . (CHN: SCIRTS chn:wdg)
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System

Categories
  • FOR (ANZSRC)

    1109 Neurosciences

  • RCDC

    Injury (total) Accidents/Adverse Effects

  • RCDC

    Injury - Trauma - (Head and Spine)

  • RCDC

    Neurosciences

  • RCDC

    Spinal Cord Injury

  • RCDC

    Neurodegenerative

  • HRCS HC

    Neurological

  • HRCS RAC

    2.1 Biological and endogenous factors

  • Health Research Areas

    Biomedical

  • Broad Research Areas

    Basic Science