Neuroinflammation

The Frasch Lab investigates mechanisms of fetal brain inflammation, with particular focus on the cholinergic anti-inflammatory pathway and its role in fetal development and neuroprotection.

Cholinergic Anti-Inflammatory Pathway

The connection between brain and innate immune system occurs via the vagus nerve. Our research demonstrates that fetal cholinergic activity in pre-term sheep can suppress both systemic and brain inflammation near term, offering potential diagnostic and treatment applications for neuroinflammatory disorders across fetal, neonatal, and adult populations.

Selected Publications

From the Frasch Lab

• Microglial and macrophage plasticity and regional cerebral blood flow in the prenatal brain and gut under vagus nerve stimulation — Methods in Molecular Biology, 2025
• The vagus nerve regulates immunometabolic homeostasis in the ovine fetus near term: the impact on terminal ileum — Biology, 2024
• Heart rate as a non-invasive biomarker of inflammation: implications for digital health — Frontiers in Immunology, 2022
• Factors determining the success of the chronically instrumented non-anesthetized fetal sheep model of human development — Cureus, 2022
• A review on the vagus nerve and autonomic nervous system during fetal development: searching for critical windows — Frontiers in Neuroscience, 2021
• Recording and manipulation of vagus nerve electrical activity in chronically instrumented unanesthetized near-term fetal sheep — Journal of Neuroscience Methods, 2021
• Fetal cholinergic anti-inflammatory pathway — Cao et al., Frontiers in Immunology, 2019
• Neuroinflammation and cholinergic signaling preprint — arXiv preprint, 2018
• SfN 2018 abstract: Cholinergic modulation of neuroinflammation
• Cao et al. (2018) — Protocol for fetal microglial culture. Protocol Exchange
• RNAseq analysis of fetal microglia — Cortes et al., J Neurosci Methods, 2017
• Alpha-7 nicotinic acetylcholine receptor modulation of inflammation — bioRxiv preprint (published as Cortes et al., Sci Rep, 2017)
• Frasch et al. (2016) — "Decreased neuroinflammation correlates to higher vagus nerve activity fluctuations" in near-term fetal sheep. Journal of Neuroinflammation
• Vagus nerve stimulation and bioelectronic medicine — Bioelectronic Medicine, 2016
• Cao et al. (2015) — Fetal microglial inflammatory responses. Frontiers in Cellular Neuroscience
• Instrumentation of near-term fetal sheep for multivariate chronic non-invasive monitoring — JoVE, 2015
• Durosier et al. (2013) — Documented "neural signature of cerebral activity" of the fetal cholinergic pathway using heart rate variability analysis
• Garzoni et al. (2013) — Explored the "brain-gut connection" in utero regarding necrotizing enterocolitis. Frontiers in Integrative Neuroscience

Supporting Research from the Field

• Cholinergic anti-inflammatory pathway — Pavlov & Tracey, Nature Neuroscience, 2017 (foundational review of the cholinergic anti-inflammatory pathway in the brain)

Microglial Inflammation Models

We developed a unique in vivo/in vitro model of double-hit exposure of fetal microglia to lipopolysaccharide (LPS). This demonstrates how inflammatory phenotypes persist during culture transition and amplify upon re-exposure, revealing critical mechanisms in perinatal inflammation affecting brain development.

Key Findings

• Fetal microglial cells retain inflammatory “memory of prior in vivo exposure”
• RNAseq analysis identified links between iron homeostasis and cholinergic modulation (PMC article)
• Alpha-7 nicotinic acetylcholine receptors modulate inflammatory responses and iron regulation (bioRxiv)

Laboratory Techniques

• Chronic fetal instrumentation and monitoring
• Primary microglia and astrocyte cultures
• RNAseq transcriptional profiling
• Nicotinic receptor signaling manipulation