# Chemogenetic afferent modulation to understand spinal cord circuit function and plasticity post injury

> **NIH NIH R01** · TEMPLE UNIV OF THE COMMONWEALTH · 2022 · $391,984

## Abstract

PROJECT SUMMARY
Spinal cord injury (SCI) causes life-long neurological impairment, and there is currently no
effective treatment. The premise of this proposal is recent work demonstrating that afferent
stimulation paired with treadmill training can enhance standing, stepping, and volitional control
in humans and animal models. Therefore, it is critically important to understand the mechanisms
by which afferent stimulation drives motor improvement. Tools that can identify which afferents
are necessary and sufficient to enhance recovery, and that can facilitate characterization of the
helpful neural plasticity, are urgently needed. Our long-term goal is to develop approaches for
selective afferent modulation, and apply them to the dissection of the mechanisms underlying
recovery from SCI. The objective of this grant is to identify which sets of afferents are important
for recovery and how spinal circuits change to facilitate it. To achieve selective modulation of
afferents and enable genetic tracing we will use Designer Receptors Exclusively Activated by
Designer Drugs (DREADDs) that can modulate excitability in specific populations of neurons. To
accurately quantify improvement, we will use Deep Learning to analyze large kinematic data
sets. Our preliminary data shows strong expression of DREADDs in large diameter DRG
neurons, that their activation by CNO can excite or inhibit the H-reflex, and that activation of
excitatory DREADDs during treadmill training post-SCI improves stepping. Our main hypothesis
is that activation of large afferents by the excitatory DREADD (hM3Dq) during treadmill training
will enhance recovery, whereas inhibitory DREADDs (hM4Di) will suppress recovery. Four sub-
hypotheses will test whether recovery is mediated by increased afferent projection onto 1) motor
neurons, or 2) inhibitory interneurons; or by sprouting of 3) reticulospinal and 4) propriospinal
circuits. Our Specific Aims are to determine whether selective expression of DREADDs in (Aim
1) all large diameter (proprioceptive and tactile) neurons and (Aim 2) large proprioceptive
afferents only can enhance recovery. The rationale for these aims is that afferent stimulation is
hypothesized to work through selective excitation of large diameter sensory afferents (LDSA)
that both drive motor pools locally and facilitate proprio- and surpraspinal input. To date, it has
not been possible to definitively determine which afferents were recruited after electrical
stimulation, or to select between afferents of similar diameter. The significance of this work lies
in determining whether recovery is mediated exclusively by proprioceptive axons or a
combination of proprioceptive and tactile afferents, and uncovering the mechanisms of
functional plasticity in the spinal cord.

## Key facts

- **NIH application ID:** 10468315
- **Project number:** 5R01NS114007-03
- **Recipient organization:** TEMPLE UNIV OF THE COMMONWEALTH
- **Principal Investigator:** Andrew Spence
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $391,984
- **Award type:** 5
- **Project period:** 2020-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10468315

## Citation

> US National Institutes of Health, RePORTER application 10468315, Chemogenetic afferent modulation to understand spinal cord circuit function and plasticity post injury (5R01NS114007-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10468315. Licensed CC0.

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