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Project

Chemogenetic Silencing of Interneurons to Modulate Autonomic Dysreflexia

Funder: Craig H Neilsen Foundation

Funding period
USD 150 K
Funding amount
Abstract
Abstract:

Traumatic spinal cord injury (SCI) leads to both motor, sensory and autonomic dysfunction. Autonomic dysreflexia (AD) is a condition that manifests as acute, episodic hypertension with concurrent bradycardia that is elicited by noxious stimuli like bladder and bowel distention below the injury site. The blood pressure remains high until the precipitating stimulus is removed. The loss of supraspinal control following injury and reorganization of spinal circuitry are thought to be major contributors to the pathophysiology of AD. Our lab has reported that increased sprouting of both lumbosacral nociceptive afferents and ascending propriospinal neurons (APN) that relay noxious sensory information to the sympathetic preganglionic neurons (SPN) are associated with this condition. While earlier investigations show that inhibition of primary afferent sprouting reduces the severity of AD, it remains unknown whether a similar effect can be achieved by modulating APN. In order to address this issue, this fellowship proposal will combine novel intraspinal viral vector injection techniques with histology and cardiophysiology to reversibly silence APN by delivering designer receptors exclusively activated by designer drugs (DREADDs) during noxious colorectal distention (CRD) in rats with complete high thoracic SCI. After AAV viral vectors are injected into lumbosacral spinal cord that contains the rostral-projecting APN, inhibitory lentivirus hM4D(Gi)-mCherry DREADD is then transported retrogradely after injections into SPN injections to enable silencing of APN will mitigate AD in response to noxious CRD. (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