# Brainstem Cholinergic Circuitries in the Inflammatory Reflex during Sepsis

> **NIH NIH R01** · FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH · 2020 · $176,754

## Abstract

Abstract: The objective of this proposal is to elucidate brainstem regulatory cholinergic circuitries involved in
the vagus nerve-based inflammatory reflex during sepsis. Sepsis is a complex lethal condition defined as “life-
threatening organ dysfunction caused by a dysregulated host response to infection”. The incidence of sepsis is
increasing and costs approx $17B per year. Moreover, many “sepsis survivors” develop immune dysfunction,
chronic illness, and severe functional disabilities, which may result in death. An essential understudied aspect
of sepsis is the involvement of the nervous system. We have pioneered studies on the role of the nervous
system and the inflammatory reflex and have provided important insight related to the role of this neural
immunomodulatory mechanism in sepsis and other conditions characterized by immune dysfunction. These
preclinical findings recently led to successful clinical exploration of the inflammatory reflex via vagus nerve
stimulation in patients with rheumatoid arthritis. Despite this progress, there are major gaps in our
understanding of the vagus nerve-based inflammatory reflex and its relevance to sepsis. Efferent vagus nerve
fibers originate in two brainstem nuclei, the dorsal motor nucleus of the vagus (DMN) and nucleus ambiguus
(NA). Experimental evidence supports that efferent vagus nerve fibers interact with the splenic nerve in ganglia
of the celiac (solar) plexus within the inflammatory reflex. However, the brainstem origin of the efferent vagus
nerve fibers critical to the inflammatory reflex and the specific role(s) of these circuitries in regulating immune
and metabolic indices during sepsis are presently unknown. We hypothesize that brainstem DMN and NA
efferent cholinergic fibers have differential roles in the inflammatory reflex during sepsis. This hypothesis will
be tested by the following Specific Aims:
Specific Aim 1. Elucidate the specific role of brainstem cholinergic circuitries in the vagus nerve-based
inflammatory reflex. Working hypothesis: Efferent vagus nerve fibers originating in the brainstem DMN and
NA differentially contribute to the vagus nerve-based inflammatory reflex to the spleen. We will utilize: 1)
recombinant adeno-associated viruses transcriptionally activated by Cre recombinase (Cre-on) to achieve
precise molecular mapping of brainstem cholinergic circuitries in mice; 2) selective optogenetic cholinergic
stimulation of brainstem circuitries to examine acetylcholine release in the spleen and anti-inflammatory effects
in endotoxemic mice; and 3) selective vagotomies to confirm the role of the vagus nerve.
Specific Aim 2. Evaluate the effects of selective cholinergic activation of brainstem nuclei on
inflammatory and metabolic markers and survival following sepsis. Working hypothesis: Selective
cholinergic optogenetic stimulation of DMN and NA differentially alleviates sepsis derangements. We will
perform experiments using selective optogenetic stimulation of brainst...

## Key facts

- **NIH application ID:** 10225663
- **Project number:** 3R01GM128008-03S1
- **Recipient organization:** FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
- **Principal Investigator:** VALENTIN Atanassov PAVLOV
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $176,754
- **Award type:** 3
- **Project period:** 2018-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10225663

## Citation

> US National Institutes of Health, RePORTER application 10225663, Brainstem Cholinergic Circuitries in the Inflammatory Reflex during Sepsis (3R01GM128008-03S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10225663. Licensed CC0.

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