# Inflammatory injury-mediated synaptic plasticity in the periaqueductal gray

> **NIH NIH F32** · STANFORD UNIVERSITY · 2022 · $41,845

## Abstract

PROJECT SUMMARY
Inflammatory injury can have substantial, lasting effects on nociceptive neurocircuits, and potentiates
peripheral sensory neuron synapses onto spinal neurons projecting to the midbrain periaqueductal gray (PAG).
Although these findings suggest that inflammation strengthens excitatory spinal input to the PAG, complex and
heterogenous neurocircuitry in the PAG differentially affects pain transmission. Rodent studies suggest GABA-
and glutamatergic PAG neurons facilitate nociception and analgesia, respectively. I propose to isolate spinal
input to the PAG using optogenetics and determine if ascending inputs to GABAergic PAG neurons are
strengthened, consequently reducing excitation of the glutamatergic PAG population. Furthermore,
cannabinoids may promote analgesia via presynaptic inhibition in the PAG, which could be reduced by
inflammation—a possibility tested in this proposal. Moreover, since inflammatory injury results in long-term
potentiation (LTP) of peripheral synapses onto spinal projection neurons, this proposal will test for LTP in the
spino-PAG circuit. Finally, I will use this optogenetic approach in vivo to determine if inhibiting and activating
spinal afferents in the PAG after can alleviate or worsen pain after inflammatory injury, respectively.
Aim 1: Ascertain if inflammatory injury strengthens spinal input to GABAergic PAG neurons, thereby reducing
input to glutamatergic PAG neurons. I will address this hypothesis using in vitro patch-clamp recordings in PAG
slices from formalin-injected (inflammatory injury) and control animals. Genetically modified mice expressing
channelrhodopsin (Chr2) in ascending spinal projections will allow for selective and temporally precise
stimulation of spinal afferents in the PAG. I will label GABA- and glutamatergic PAG neurons using promoter-
specific viruses. A) I will determine if inflammation affects the presynaptic strength (number of release sites
and probability of release), magnitude of feedforward inhibition, and cannabinoid sensitivity of spinal input to
GABA- and glutamatergic PAG neurons. B) I will determine if inflammatory injury potentiates spinal input to the
PAG using stimulation protocols and an adenylyl cyclase activator (forskolin) to generate LTP in control
animals and assess if this effect is occluded by inflammatory injury.
Aim 2: Determine if inhibiting spinal input to the PAG reduces inflammatory pain, and if activating these inputs
can exacerbate and/or replicate inflammatory pain. This aim will use optical implants over the PAG region of
genetically modified mice expressing opsins in ascending spinal afferents, while measuring pain behaviors. A)
Mice expressing halorhodopsin will be used to determine if inhibiting spinal afferents reduces formalin-evoked
inflammatory pain. B) Mice expressing the high-fidelity ChETA variant of Chr2 (to mimic the burst firing
patterns of spino-PAG projection neurons) will be used to determine if activating ascending spinal te...

## Key facts

- **NIH application ID:** 10490262
- **Project number:** 5F32NS123008-02
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Chelsie L Brewer
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $41,845
- **Award type:** 5
- **Project period:** 2021-09-30 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10490262

## Citation

> US National Institutes of Health, RePORTER application 10490262, Inflammatory injury-mediated synaptic plasticity in the periaqueductal gray (5F32NS123008-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10490262. Licensed CC0.

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