Alexandre Bonnin, PhD

A. Main projects:
Research in the Bonnin’s lab focuses on understanding how maternal-fetal interactions shape fetal brain development during pregnancy; the goal is to identify molecular and cellular mechanism by which prenatal insults influence normal brain development leading to the emergence of mental disorders later in the offspring life.
Our two main projects aim at understanding the mechanisms by which prenatal stress and maternal immune activation (MIA), such as in response to viral infection, affect fetal brain development; two prenatal insults that are known risk factors for neurological disorders later in the offspring life.

A hallmark of gestational MIA is the chronic activation of microglial cells and neuroinflammation in the adult offspring brain. These are phenotypes also observed after blood-brain barrier (BBB) lesions in adults. We recently demonstrated that gestational MIA directly impacts BBB development in utero and BBB function across the lifespan, leading to chronic neuroinflammation and altered brain function (a). These observations support the idea that prenatal inflammation and subsequent activation of the microglia in early life disrupts BBB formation, leading to BBB breakdown across the lifespan. This self-perpetuating cycle of BBB breakdown and brain inflammation would ultimately promote increased risk for aging-related neuropathology later in life. We currently investigate this novel mechanism using pharmacological and genetic tools.
Our approaches explore vastly understudied life-long mechanisms involved in the etiology of vascular contributions to cognitive impairment and dementia, providing insights into the developmental origins of devastating diseases such as Alzheimer’s disease. Furthermore, the research will advance our understanding of the short- and long-term consequences of inflammation on the development and function of the BBB over the lifespan.

B. Collaborative studies of maternal vs placental influences on fetal brain development:
Our technological development of the ex vivo perfusion of the mouse placenta has led to numerous collaborative projects aiming at directly assessing the contributions of various maternally vs placentally-derived molecules to fetal brain development. For instance, this technology was applied in a collaborative project with Dr Karsenty (Columbia University) to demonstrate the maternal-fetal transfer of an important neurogenic molecule, osteocalcin, which is synthesized by maternal bone (b). It was also used in a collaboration with Dr Schwarcz (University of Maryland) to investigate the developmental sources of kynurenine and its metabolites (a branch of tryptophan metabolism, also involved in immune regulation of placental function) (c). It was also used in a collaboration with Dr Bale (University of Colorado) to study the effects of stress on maternally and placentally-derived steroid hormones reaching the developing fetus.

a. Zhao, Q., Dai, W., Chen, H. Y., Jacobs, R. E., Zlokovic, B. V., Lund, B. T., Montagne, A., and Bonnin, A. (2022). Prenatal disruption of blood-brain barrier formation via cyclooxygenase activation leads to lifelong brain inflammation. Proc Natl Acad Sci U S A 119, e2113310119.

b. Oury F, Khrimian L, Gardin A, Chamouni A, Goeden N, Huang Y, Srinivas P, Gao X, Suyama S, Mann JJ, Horvath T, Bonnin A, Karsenty G. (2013) Maternal and offspring-derived osteocalcin influences brain development and functions. Cell 155(1), 228-41. PMCID: PMC3864001

c. Goeden N, Notarangelo FM, Pocivavsek A, Beggiato S, Bonnin A, Schwarcz R (2017) Prenatal Dynamics of Kynurenine Pathway Metabolism in Mice: Focus on Kynurenic Acid. Dev Neurosci, 39:519–528.

• Brain & Behavior Research Foundation (NARSAD): Daniel X. Freedman Award for outstanding basic research achievement, 2011

• Prenatal inflammation disrupts blood-brain barrier development and long-term function.
  NIH · R01NS126981 · Jan 1, 2023 – Jan 1, 2027 · Role: Principal Investigator
• Prenatal inflammation disrupts blood-brain barrier development and long-term function
  NIH · R01NS126981 · Dec 1, 2022 – Nov 30, 2027 · Role: Principal Investigator
• Prenatal disruption of blood-placenta/brain barrier formation programs AD risk later in life.
  BrightFocus Foundation · Jul 1, 2019 – Jul 1, 2022 · Role: PI
• Prenatal stress and antidepressants effects on offspring brain development
  NIH · R01MH106806 · Jun 1, 2016 – May 31, 2021 · Role: Principal Investigator
• An ex-vivo placental perfusion system to study materno-fetal biology
  NIH · R21HD065287 · Sep 30, 2009 – Aug 31, 2012 · Role: Principal Investigator

• Levitt, Pat
• Zlokovic, Berislav
• Chmait, Ramen
• Peterson, Bradley
• Chatzi, Vaia
• Thompson, Paul