Lehtinen, Maria KLacey, Tiara2026-06-0920262026-06-052026Lacey, Tiara. 2026. Tracking choroid plexus-cerebrospinal fluid axis during development and inflammation in a mouse maternal immune activation model. Doctoral Dissertation, Harvard University Graduate School of Arts and Sciences.32700887https://p2p8-sa-zuvru-a9vusux.re-cotta.com/handle/1/42740445Brain barriers are critical neuroimmune interfaces that protect the brain from peripheral blood-borne challenges, such as inflammation. However, brain-body communication during development is understudied. The choroid plexus (ChP), a blood-cerebrospinal fluid (CSF) barrier present in each brain ventricle, is the primary producer of CSF, which is rich in spatiotemporally dynamic signaling molecules and cues critical for healthy brain development. Each of the ChP, lateral (LV), third (3V), and fourth (4V) ventricles, is morphologically distinct, transcriptionally heterogeneous, and comprises a diverse niche of cell types, including secretory epithelial cells and resident immune cells. Indeed, the LV and 4V ChP secrete distinct proteins into the CSF to specifically support the developmental needs of nearby CSF-contacting periventricular cells. Maternal immune activation (MIA) is an example of inflammation during brain development that increases the risk of several neurodevelopmental and neuropsychiatric disorders in offspring. Mouse MIA models exhibit embryonic parenchymal deficits and inflammation of the ChP-CSF axis. Still, the timeline of maternal inflammation transfer to embryonic ChP-CSF, the most vulnerable barrier site, and effects on ventricle-specific ChP secretion remain unclear. To address this gap, this study investigated the early acute-to-post-acute ChP-CSF immune responses to viral-mimetic polyinosinic: polycytidylic acid (poly(I:C))- induced MIA. We characterized baseline regional differences in LV and 4V ChP immunological milieu across age. Using previously described metrics of ChP-CSF MIA-induced inflammation, we tracked early acute and post-acute maternal and embryonic CSF inflammation and measured relative LV and 4V ChP secretion ex vivo using multiplex cytokine ELISAs. We showed regionally distinct ChP immune cell population fluxes via spectral flow cytometry and tight junction responses to MIA using histological analyses across acute and post-acute timepoints, suggesting differential inflammation vulnerability. Because sites of inflammation and immune cell activity can result in metabolic shifts, we generated a metabolomics resource from developing and inflamed embryonic CSF and uncovered age-dependent compositional changes. Our resource identified additional MIA-relevant metabolic pathways across the maternal-fetal axis for future investigation. Taken together, we propose a model of maternal to fetal MIA transfer where maternal inflammation induces early compositional shifts in embryonic CSF that perinatally return to baseline, influenced in part by the differential LV and 4V ChP responses to inflammation. Future studies will determine whether targeting ChP ventricle-specific signaling during the maternal-fetal inflammation transfer time window will lessen the severity of MIA neuropathology.application/pdfenCerebrospinal fluid (CSF)Choroid plexus (ChP)Maternal immune activation (MIA)Maternal-fetal interactionsNeurosciencesImmunologyThesis or Dissertation2026-06-090000-0001-8150-4224