# Neuroinflammation grading and adjusting of spinal sensorimotor circuitries in response to remote injuries in peripheral nerves

> **NIH NIH R01** · EMORY UNIVERSITY · 2021 · $362,753

## Abstract

Project Summary / Abstract
Nerve injury patients face life-long sensorimotor deficits despite continued improvements in microsurgical
techniques and nerve regeneration. These are usually believed to result from poor or unspecific regeneration
of the peripheral nerve. However, deficits are still present when experimental nerve injuries are designed in
animal models for rapid, specific and efficient nerve regeneration and muscle re-innervation. We have
proposed that structural remodeling of spinal cord circuitry after nerve lesions is in part responsible. Thus,
future advances in nerve regeneration will predictably be limited by deficits caused by this much less studied
central synaptic plasticity. Remarkably, the central synaptic branches of Ia afferent proprioceptive axons
injured in the periphery are removed from the spinal cord ventral horn after nerve injury resulting in dysfunction
of critical motor control circuits. We recently found that this synaptic plasticity is graded to the type of nerve
injury and correlated with the more or less target specificity obtained during muscle reinnervation. Our
preliminary data suggest that neuroinflammation occurring inside the otherwise intact spinal cord ventral horn,
is critical for grading circuit remodeling to the severity of the nerve injury. Ventral horn microglia are activated
after nerve injuries and although their capacity for synapse phagocytosis has been frequently proposed, their
function inside the spinal cord after a remote nerve injury continues to be debated. Moreover, we found that
microglia activation is followed by infiltration of cells from the adaptive and innate peripheral immune system,
but this is variable depending on injury type. When occurs, it correlates with maximal Ia synapse and axon
removal from the ventral horn. These cells, particularly monocyte/macrophages were missed in previous
studies because they share many markers with activated microglia, preventing their identification. Thus, their
function inside the spinal cord ventral horn after nerve injury is unexplored. We will use genetic approaches to
distinguish microglia from blood-derived immune cells and investigate their significance for Ia afferent removal.
In Aim 1 we will genetically label and manipulate each cell type to test their roles in Ia axon and synapse
deletions and probe cellular signaling mechanisms. In Aim 2 we will visualize with time-lapse two-photon
microscopy genetically labeled sensory afferents and microglia or monocyte-derived cells to directly observe
and analyze their interactions. Finally, in Aim 3 we will test the relevance of this mechanism for motor function,
whether is maladaptive, causing long-lasting motor deficits or adaptive, to preserve the best function possible
when peripheral connectivity becomes highly scrambled after regeneration. The new knowledge generated will
allow us to consider new methods for optimization of central circuitry function through modulation of central
neuroin...

## Key facts

- **NIH application ID:** 10129440
- **Project number:** 5R01NS111969-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** FRANCISCO J ALVAREZ
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $362,753
- **Award type:** 5
- **Project period:** 2020-04-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10129440

## Citation

> US National Institutes of Health, RePORTER application 10129440, Neuroinflammation grading and adjusting of spinal sensorimotor circuitries in response to remote injuries in peripheral nerves (5R01NS111969-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10129440. Licensed CC0.

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