# Enhancing Respiratory Motor Function after Spinal Cord Injury

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2020 · $578,205

## Abstract

ABSTRACT
The proposed studies exploit exciting new developments in neuroplasticity to enhance recovery of ventilatory-
related diaphragm muscle (DIAm) activity following cervical spinal cord injury. There are nearly 17,000 new
cases of spinal cord injury in the United States each year, with around 282,000 people affected. The majority of
these injuries involve the cervical spinal cord and result in significant impairment of ventilatory-related DIAm
activity and an inability to maintain adequate ventilation. Long-term dependence on mechanical ventilation is
associated with significant morbidity and mortality. Thus, enhancing recovery of ventilatory-related DIAm
activity following cervical spinal cord injury is highly significant. Upper-cervical (C1-C3) spinal cord injury
disrupts direct excitatory descending bulbospinal glutamatergic (Glu) input to phrenic motor neurons (PhMNs).
Importantly, most spinal cord injuries are incomplete, thus spared descending pathways to PhMNs are an
extant substrate for neuroplasticity to restore DIAm activity, either by increasing excitatory (Glu) nerve terminal
density and/or by altering postsynaptic Glu receptor (NMDA NR1) expression. In the proposed studies, we will
employ a well-established C2 spinal hemisection (C2SH) model of incomplete spinal cord injury in rats, in
which spontaneous recovery of ventilatory-related DIAm activity occurs in a BDNF/TrkB signaling-dependent
fashion. Previously, we found that C2SH impairs ventilatory-related DIAm behaviors, which require recruitment
of smaller (more excitable) PhMNs comprising fatigue resistant motor units. These ventilatory-related
behaviors only partially recover over time, whereas, surprisingly, there is near full recovery of higher force
airway clearance behaviors, which require recruitment of larger (less excitable) PhMNs comprising more
fatigable motor units. The overall hypothesis of the proposed research is that the mechanisms underlying
neuroplasticity and recovery of ventilatory-related DIAm activity after C2SH depend on PhMN size (more
pronounced in smaller PhMNs), are mediated by NMDA Glu neurotransmission, and are promoted by
BDNF/TrkB signaling. Three specific aims are proposed: 1) To determine the effect of BDNF/TrkB signaling on
Glu presynaptic terminal density at PhMNs of differing size after C2SH; 2) To determine the effect of
BDNF/TrkB signaling on NMDAR expression at PhMNs of differing size after C2SH; and 3) To determine
whether NMDARs underlie the effects of BDNF/TrkB signaling on recovery of ventilatory-related DIAm activity
after C2SH. The results of the proposed studies will guide development of effective therapeutic approaches to
enhance recovery of respiratory function in patients with incomplete spinal cord injury.

## Key facts

- **NIH application ID:** 9843736
- **Project number:** 5R01HL146114-02
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Carlos B Mantilla
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $578,205
- **Award type:** 5
- **Project period:** 2019-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9843736

## Citation

> US National Institutes of Health, RePORTER application 9843736, Enhancing Respiratory Motor Function after Spinal Cord Injury (5R01HL146114-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9843736. Licensed CC0.

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