Acute intermittent hypoxia elicits sympathetic neuroplasticity independent of peripheral chemoreflex activation and spinal cord tissue hypoxia in a rodent model of high-thoracic spinal cord injury

Mehdi Ahmadian; Erin Erskine; Liisa Wainman; Oliver H Wearing; Jennifer S Duffy; Liam C Stewart; Ryan L Hoiland; Alissa Taki; Raphael R Perim; Gordon S Mitchell; Jonathan P Little; Patrick J Mueller; Glen E Foster; Christopher R West

doi:10.1016/j.expneurol.2024.115054

Acute intermittent hypoxia elicits sympathetic neuroplasticity independent of peripheral chemoreflex activation and spinal cord tissue hypoxia in a rodent model of high-thoracic spinal cord injury

Exp Neurol. 2024 Nov 13:115054. doi: 10.1016/j.expneurol.2024.115054. Online ahead of print.

Affiliations

¹ School of Kinesiology, Faculty of Education, University of British Columbia, Vancouver, BC, Canada; International Collaboration on Repair Discoveries, University of British Columbia, Vancouver, BC, Canada; Centre for Chronic Disease Prevention and Management, University of British Columbia, Kelowna, BC, Canada; Department of Cellular and Physiological Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
² International Collaboration on Repair Discoveries, University of British Columbia, Vancouver, BC, Canada; Centre for Chronic Disease Prevention and Management, University of British Columbia, Kelowna, BC, Canada; Department of Cellular and Physiological Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
³ Department of Physiology and Pharmacology, College of Osteopathic Medicine, Marian University, Indianapolis, IN, USA.
⁴ Breathing Research and Therapeutics Centre, Department of Physical Therapy and McKnight Brain Institute, University of Florida, Gainesville, FL, USA.
⁵ School of Health and Exercise Sciences, University of British Columbia, Kelowna, BC, Canada.
⁶ Department of Physiology, Wayne State University School of Medicine, Detroit, MI, United States.
⁷ International Collaboration on Repair Discoveries, University of British Columbia, Vancouver, BC, Canada; Centre for Chronic Disease Prevention and Management, University of British Columbia, Kelowna, BC, Canada; Department of Cellular and Physiological Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada. Electronic address: [email protected].

PMID: 39547501
DOI: 10.1016/j.expneurol.2024.115054

Abstract

The loss of medullary control of spinal circuits controlling the heart and blood vessels is a unifying mechanism linking both hemodynamic instability and the risk for cardiovascular diseases (CVD) following spinal cord injury (SCI). As such, new avenues to regulate sympathetic activity are essential to mitigate CVD in this population. Acute intermittent hypoxia (AIH) induces a type of neuroplasticity known as long-term facilitation (LTF), a persistent increase in nerve activity post-AIH in spinal motor circuits. Whether LTF occurs within the sympathetic circuit following SCI is largely unknown. We aimed to test whether AIH elicits sympathetic LTF (i.e., sLTF) and attenuates hypoactivity in sub-lesional splanchnic sympathetic circuits in a male rat model of SCI. In 3 experimental series, we tested whether 1) high-thoracic contusion SCI induces hypoactivity in splanchnic sympathetic nerve activity, 2) AIH elicits sLTF following SCI, and 3) sLTF requires carotid chemoreflex or spinal cord tissue hypoxia. Our results indicate that a single-session of AIH therapy (10 × 1 min of F_iO₂ = 0.1, interspersed with 2 min of F_iO₂ = 1.0) delivered at 2 weeks following SCI attenuates SCI-induced sympathetic hypoactivity by eliciting sLTF 90 min post-treatment that is independent of peripheral chemoreflex activation and/or spinal cord hypoxia. These findings advance our mechanistic understanding of AIH in the field and yield new insights into factors underpinning AIH-induced sLTF following SCI in a rat model. Our findings also set the stage for the chronic application of AIH to alleviate secondary complications resulting from sympathetic hypoactivity following SCI.

Keywords: Carotid body; Neuroplasticity; Rat; Spinal cord injury; Spinal tissue oxygenation; Sympathetic; Therapeutic hypoxia.