The Role of Immune Cells within Maternal Immune Activation-Induced Behavioral Deficits

PROJECT SUMMARY
This NIH F30 application describes a three-year plan for mentored research and career development for the
PI, Jana Badrani. The scientific premise of this proposal is focused on the role of GR-1+ non-microglial myeloid
cells (NMCs) on brain development and adulthood behaviors under normal conditions and following maternal
immune activation (MIA). MIA encompasses any pro-inflammatory response within the mother during
pregnancy and can be caused by infectious and non-infectious stimuli. MIA is a known risk factor for
psychiatric and neurodevelopmental disorders, like schizophrenia and autism, in offspring. MIA is also
implicated in hematopoietic changes and disruptions in immune cell development and differentiation. Here, we
will elucidate the cellular and molecular mechanisms of meningeal and brain non-microglial immune cell
interactions with neurons during normal brain development and following a representative MIA model of
maternal systemic challenge with polyI:C (PIC). Our preliminary flow cytometric data identifies a prominent GR-
1+ NMC population that increases within the brains of male MIA offspring. scRNA-seq analysis identified GR-1+
neutrophil populations in the brain, with significant gene expression changes in PIC offspring compared to
vehicle offspring. Male MIA offspring also demonstrated behavioral deficits in the elevated plus maze (EPM).
Systemic depletion of GR-1+ cells improved the EPM behavioral deficits in PIC male offspring. Thus, our central
hypothesis is that GR-1+ neutrophils in the brain impair neuronal function and behaviors via MMP in male PIC
offspring. We will test this hypothesis through immunohistochemistry, flow cytometry, single-cell
transcriptomics, and a variety of in vivo experiments, including the use of anti-GR1 depleting antibodies and
MMP inhibitors. Understanding the involvement of GR-1+ non-microglial myeloid cells in brain development and
following MIA will have a significant impact on our understanding of immune-brain interactions underlying brain
homeostasis. The proposed training plan for the PI is sponsored by Dr. Shin-ichi Kano, MD, PhD, and Dr.
Farah Lubin, PhD. Included in the training plan are experiences that will help Jana develop in three major
areas: (1) rigorous neuroimmunological research in neuro-immune interactions, which includes developing
familiarity with existing literature, critical evaluation of data, and training in responsible conduct of research; (2)
rigorous training in advanced bioinformatics, high dimensional data analysis, and scRNA-sequencing analysis;
and (3) career and professional development, including grant and manuscript writing, scientific
communications, and the translation of research findings to clinical applications. This proposal drives the
development of skills required for rigorous scientific research in immunology, neuroscience, and bioinformatics
necessary for the PI’s future career as a clinician-scientist focused on neuropsychiatry and immunotherapy.

Grant Number: 1F30MH139313-01A1
NIH Institute/Center: NIH
Principal Investigator: Jana Badrani