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

• Cholinergic anti-inflammatory pathway — Nature Neuroscience
• 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
• 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
• Instrumentation of near-term fetal sheep for multivariate chronic non-invasive monitoring — JoVE
• Cao et al. (2015) — Fetal microglial inflammatory responses. Frontiers in Cellular Neuroscience
• RNAseq analysis of fetal microglia — PMC article
• Alpha-7 nicotinic acetylcholine receptor modulation of inflammation — bioRxiv preprint
• Cao et al. (2018) — Protocol for fetal microglial culture. Protocol Exchange
• SfN 2018 abstract: Cholinergic modulation of neuroinflammation
• Neuroinflammation and cholinergic signaling preprint — arXiv preprint
• Fetal cholinergic anti-inflammatory pathway — Frontiers in Immunology

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