Fetal neuroinflammation

1. The cholinergic anti-inflammatory pathway is one of the major discoveries in the last 15 years of neuroimmunology. It establishes connection between brain and innate immune system via the vagus nerve. I became interested in its relevance to fetal physiology and brain development. I was the first to provide evidence that fetal cholinergic activity is mature enough in pre-term fetal sheep and inhibits systemic and brain inflammation near term. This opens new diagnostic and treatment options for neuroinflammatory disorders in fetuses, neonates and adults.

a. Frasch, M et al. (2009). Cholinergic anti-inflammatory pathway mechanisms may be active in the pre-term ovine fetus. Reproductive Sciences 16(3 Suppl): 137A.

b. Frasch, M et al. (2009). Repetitive umbilical cord occlusions with worsening acidemia in the ovine fetus near term may activate cholinergic anti-inflammatory pathway mechanisms. Reproductive Sciences 16(3 (Suppl): 243A.

c. LD Durosier et al. Neural signature of cerebral activity of the fetal cholinergic anti-inflammatory pathway derived from heart rate variability. FASEB J April 9, 2013 27:926.11

d. Garzoni, L., Faure, C., Frasch, MG. Fetal cholinergic anti-inflammatory pathway and necrotizing enterocolitis: the brain-gut connection begins in utero. Front Integr Neurosci. 2013 (8)7:57. doi: 10.3389/fnint.2013.00057

e. Frasch, MG et al. (2016). Decreased neuroinflammation correlates to higher vagus nerve activity fluctuations in near-term ovine fetuses: a case for the afferent cholinergic anti-inflammatory pathway? J of Neuroinflammation 10;13(1):103. doi: 10.1186/s12974-016-0567-x.

f. Harwood Kwan, Luca Garzoni, Hai Lun Liu, Mingju Cao, Andre Desrochers, Gilles Fecteau, Patrick Burns, Martin G Frasch. VNS in inflammation: systematic review of animal models and clinical studies. Bioelectronic Medicine. 2016; 1-6. DOI: 10.15424/bioelectronmed.2016.00005.

2. My lab has been investigating the mechanisms of the fetal cholinergic brain anti-inflammatory pathway. Our team has established a unique in vivo/in vitro model of double-hit exposure of fetal microglia to an inflammatory stimulus, lipopolysaccharide (LPS). We showed that the inflammatory phenotype of fetal microglia is maintained after the transition into primary culture and is further amplified by re-exposure to LPS in vitro. This has consequences for understanding how perinatal inflammation affects brain function and development. We established the RNAseq pipeline in the ovine fetal brain’s primary microglia cultures and found intriguing links between the iron homeostasis and cholinergic modulation of microglial response to LPS-induced inflammation.

a. Burns P, Liu HL, Kuthiala S, Fecteau G, Desrochers A, Durosier LD, Cao M, Frasch MG. Instrumentation of Near-term Fetal Sheep for Multivariate Chronic Non-anesthetized Recordings. J Vis Exp. 2015(105). PMID: 26555084.

b. Cao M, Cortes M, Moore CS, Leong SY, Durosier LD, Burns P, Fecteau G, Desrochers A, Auer RN, Barreiro LB, Antel JP, Frasch MG. Fetal microglial phenotype in vitro carries memory of prior in vivo exposure to inflammation. Front Cell Neurosci. 2015;9:294. PMID: 26300730.

c. Cortes M, Cao M, Liu H.L. , Burns P, Moore C., Fecteau G, Desrochers A, Barreiro LB, Antel JP, Frasch MG. RNAseq profiling of primary microglia and astrocyte cultures in near-term ovine fetus: A glial in vivo-in vitro multi-hit paradigm in large mammalian brain. J Neurosci Methods. 2017. 276:23-32.

d. Marina Cortes, Mingju Cao, Hai Lun Liu, Craig S Moore, Lucien Daniel Durosier, Patrick Burns, Gilles Fecteau, Andre Desrochers, Luis B Barreiro, Jack Antel, Martin G Frasch. alpha7 nicotinic acetylcholine receptor signaling modulates the inflammatory and iron homeostasis in fetal brain microglia. bioRxiv. Preprint. doi: https://doi.org/10.1101/097295. Scientific Reports 2017. In press.

e. Mingju Cao, Marina Cortes, Hai Lun Liu, Martin G. Frasch. Manipulation of α7 nicotinic acetylcholine receptor signaling in primary ovine fetal microglia cultures. Protocol Exchange. 2018. doi:10.1038/protex.2018.013.