# Post-SCI effects of BDNF and epidural stimulation on inhibitory RORb interneurons

> **NIH NIH F31** · DREXEL UNIVERSITY · 2022 · $46,752

## Abstract

ABSTRACT
The number of individuals living with a spinal cord injury (SCI) continues to rise but rehabilitative strategies for
functional locomotor recovery remain inadequate. Spinal circuits remain intact and functional even in the
absence of descending control and serve as therapeutic targets. Neurotrophic factors have been shown to
enhance neuronal plasticity and experimental viral overexpression of brain-derived neurotrophic factor (AAV-
BDNF) is sufficient activate locomotor circuits to elicit alternating plantar stepping of hindlimbs after complete
SCI in rodents. However, viral BDNF effects also induce a hyperreflexive state and hindlimb spasms. Sub-motor
threshold epidural stimulation (ES) can reduce hyperreflexia in individuals living with SCI but the mechanism of
action underlying this effect remains elusive. We have recently combined viral BDNF treatment with daily ES in
a mouse model of complete SCI to identify synergistic effects between these two potentially complementary
therapeutic strategies and our preliminary findings suggest a possible role for ES in mitigating BDNF-induced
hyperreflexia while maintaining locomotor improvements. In addition to chronic disability, a large number of
individuals living with SCI also suffer from hyperreflexia and our approach allows for exploration of treatment and
mechanism in parallel. Spinal interneurons are the primary source of inhibitory control below the level of injury,
and we will use precise physiological and genetic methods to identify the neural components subject to plasticity
after SCI and subsequent intervention with viral BDNF, with or without ES. In this proposal, we focus on a
population of inhibitory interneurons (INs) expressing the retinoid orphan nuclear receptor (RORb) which has
recently been shown to gate low threshold sensory afferent signals via primary afferent depolarization (PAD), a
spinal mechanism of presynaptic inhibition. RORb INs are likely to be affected by our combinatorial approach as
they express TrkB receptors, the cognate receptor for BDNF, and are recruited upon activation of proprioceptive
fibers, potential effector neurons of low intensity ES. Our central hypotheses are that: 1) BDNF increases the
cellular excitability of RORb INs and enhances PAD pathway activity but this is insufficient to counteract other
actions of BDNF leading to hyperreflexia, 2) the RORb-mediated PAD pathway is acutely enhanced during
concurrent ES to limit BDNF-induced hyperreflexia and promote improvements in hindlimb stepping after
complete SCI. We will investigate changes in the excitability of RORb INs at the presynaptic inhibitory circuit,
together with behavior to determine the effects of SCI and treatment with BDNF alone and in combination with
ES. This proposal will provide mechanistic insight into SCI-induced plasticity and identify therapeutic interactions
that are associated with functional motor recovery as well as those underlying loss of function, both of which will
b...

## Key facts

- **NIH application ID:** 10536779
- **Project number:** 1F31NS127584-01A1
- **Recipient organization:** DREXEL UNIVERSITY
- **Principal Investigator:** Nicholas Stachowski
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $46,752
- **Award type:** 1
- **Project period:** 2022-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10536779

## Citation

> US National Institutes of Health, RePORTER application 10536779, Post-SCI effects of BDNF and epidural stimulation on inhibitory RORb interneurons (1F31NS127584-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10536779. Licensed CC0.

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