# Mechanisms of rhythm generation and recruitment in mammalian locomotor-related spinal interneurons

> **NIH NIH F31** · DREXEL UNIVERSITY · 2024 · $42,239

## Abstract

ABSTRACT
Rhythm is a critical feature of locomotion and is generated by interneurons in the spinal cord. The intrinsic and
local mechanisms employed by lumbar spinal rhythmogenic interneurons and how they are recruited by
supraspinal locomotor centers represent major gaps in our understanding of rhythmogenesis and locomotor
circuitry. This information is crucial in the pursuit of therapeutic targets to treat the leading causes of paralysis
including spinal cord injury, traumatic brain injury, and Parkinson’s Disease. Spinal interneurons expressing the
transcription factor Shox2 include a group of putatively rhythmogenic interneurons in the mouse. Shox2
interneurons in the adult lumbar spinal slice possess rhythmogenic ionic currents, including persistent inward
currents, and make functional excitatory connections to other Shox2 interneurons. We have found that a subset
of Shox2 interneurons in the adult lumbar spinal slice displays spontaneous rhythmic membrane potential
oscillations. Intrinsic and local network properties are essential for the initiation and maintenance of rhythmic
oscillations in other models of neuronal bursting and Shox2 interneurons in the spinal slice allow for the study of
the specific mechanisms involved in the adult mammalian locomotor circuitry. This proposal explores how
oscillations in Shox2 interneurons are generated and recruited using an innovative approach that combines
whole cell patch clamp electrophysiology, transsynaptic tract tracing, and optogenetics. With this combinatorial
approach, we will test the overarching hypothesis that Shox2 interneurons in the lumbar spinal cord of adult mice
display rhythmic firing that is critically mediated by persistent sodium current and local excitatory synaptic
connections and recruited by monosynaptic excitatory input from the lateral paragigantocellular nucleus in the
brainstem. In whole-cell patch clamp experiments, we will identify the voltage sensitive current(s) and underlying
voltage-gated ion channels critically involved in rhythmic oscillations in individual Shox2 interneurons.
Additionally, we will pharmacologically test the contributions of the local synaptic connections to oscillatory
properties in Shox2 INs in the lumbar spinal slice. Lastly, the supraspinal nuclei which monosynaptically project
to lumbar Shox2 interneurons will be identified by monosynaptic restricted transsynaptic tracing from Shox2
interneurons in the adult mouse. These anatomical projections will be functionally evaluated optogenetically in
the adult lumbar spinal slice. Together, this represents essential first steps in identifying and evaluating
mechanisms of rhythm generation in and recruitment of Shox2 interneurons which may serve as therapeutic
targets for the treatment of paralysis in which spinal locomotor circuits are left intact, but dormant.

## Key facts

- **NIH application ID:** 10933435
- **Project number:** 5F31NS132514-02
- **Recipient organization:** DREXEL UNIVERSITY
- **Principal Investigator:** Shayna Singh
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $42,239
- **Award type:** 5
- **Project period:** 2023-09-15 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10933435

## Citation

> US National Institutes of Health, RePORTER application 10933435, Mechanisms of rhythm generation and recruitment in mammalian locomotor-related spinal interneurons (5F31NS132514-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10933435. Licensed CC0.

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