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Principal Investigator: JUDY A. VAN DE WATER
Organization: UNIVERSITY OF CALIFORNIA AT DAVIS
Fiscal Year: 2024
Award: $512,130
Funding agency: National Institute of Mental Health
PROJECT SUMMARY – PROJECT 1
Maternal infection increases susceptibility of offspring to psychiatric and neurodevelopmental disorders,
including schizophrenia (SZ). Animal models of maternal immune activation (MIA) support this link, because
mid-gestational injection of poly(I:C) induces behavioral and neuropathological abnormalities in adult offspring
in domains similar to those affected in SZ. Thus, the poly(I:C) mouse model provides an opportunity to identify
the molecular and cellular underpinnings of susceptibility to MIA, which could lead to earlier diagnosis and
treatment of brain disease in humans. However, critical gaps in knowledge persist related to two of the most
important aspects of this risk factor for human disease: (i) most pregnancies are resilient to maternal infection
and (ii) susceptible pregnancies lead to multiple distinct disorders in offspring. We have recently discovered a
way to study both of these issues in the MIA mouse model. Results to date have revealed — for the first time
— an intrinsic factor, baseline immunoreactivity (BIR) of female mice before pregnancy, that, together with the
poly(I:C) dose used to induce MIA, predicts resilience as well susceptibility to neuropathology and aberrant
behaviors in offspring. These discoveries provide a unique opportunity to identify immune signatures before
and during pregnancy that underlie susceptibility and resilience to MIA, which can be used as biomarkers for
susceptible pregnancies. The central goal of this project is to identify the immune signaling pathways in
females before and during pregnancy that confer susceptibility or resilience to distinct subsets of MIA-induced
behavioral endophenotypes in offspring. We will address three specific aims: (i) identify immune biomarkers
and signaling pathways that underlie the range of BIR in female mice before pregnancy and that correlate with
susceptibility and resilience to MIA in offspring, (ii) identify how the progression of the maternal gestational
immune response in the mouse model dictates susceptibility or resilience to the effects of MIA in offspring, and
(iii) determine if BIR before pregnancy, and the maternal gestational immune response, correlate with
susceptibility or resilience to MIA in the non-human primate model. Project 1 directly addresses the central
hypothesis and all 3 aims of this Conte Center in a mechanistic manner by identifying immune signaling
pathways in females before and during pregnancy that confer susceptibility or resilience to distinct subsets of
MIA-induced neurodevelopmental and behavioral phenotypes in offspring. Results from this project are also
essential to the success of the other projects in the Center in revealing the immune signaling pathways that
drive susceptibility and resilience to sex-dependent changes in neural circuits (Projects 2, 4 and 5) and
neurodevelopmental and behavioral outcomes of offspring (Projects 2-5). Working closely with Project 2, we
will also test causality of two immune pathways for MIA-induced changes in striatal DA release and behaviors,
developing a pipeline for testing immune pathways (Projects 1, 4) across models (Projects 2, 3, and 5) for their
ability to ameliorate the effects of MIA, thereby enhancing the translational relevance of our Center.
Terms: <Address><Adult Children><Adult Daughters><Adult Offspring><Adult Sons><Affect><Animal Model><Animal Models and Related Studies><Automobile Driving><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><BCDF><BSF-2><BSF2><Behavior><Behavioral><Biological Markers><Blood Serum><Brain><Brain Diseases><Brain Disorders><Brain Nervous System><C57BL/6 Mouse><COVID crisis><COVID epidemic><COVID pandemic><COVID-19 crisis><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 period><COVID-19 public health crisis><COVID-19 years><Causality><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Chemotactic Cytokines><Corpus Striatum><Corpus striatum structure><Development><Disease><Disorder><Dopamine><Dose><Early Diagnosis><Early treatment><Encephalon><Encephalon Diseases><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Etiology><Exhibits><Female><Fever><Future><Gestation><Goals><HPGF><Hepatocyte-Stimulating Factor><High Risk Woman><Homologous Chemotactic Cytokines><Human><Hybridoma Growth Factor><Hydroxytyramine><IFN-beta 2><IFNB2><IL-6><IL6 Protein><Immune><Immune Cell Activation><Immune Markers><Immune response><Immune signaling><Immunes><Immunochemical Immunologic><Immunologic><Immunologic Factors><Immunologic Markers><Immunologic Tests><Immunological><Immunological Factors><Immunological Tests><Immunological response><Immunologically><Immunologics><Infection><Inflammatory><Injections><Intercrines><Interleukin-6><Intracellular Communication and Signaling><Intracranial CNS Disorders><Intracranial Central Nervous System Disorders><Intrinsic factor><Knowledge><Lead><Link><MGI-2><Maternal Immunity><Maternally-Acquired Immunity><Measures><Mediating><Mental disorders><Mental health disorders><Mice><Mice Mammals><Modeling><Modern Man><Modification><Molecular><Molecular Target><Monkeys><Murine><Mus><Myeloid Differentiation-Inducing Protein><Neural Development><Neurodevelopmental Disorder><Neuroimmune Mechanisms><Neuroimmune Processes><Neuroimmunomodulation><Neurological Development Disorder><Pathway interactions><Pb element><Peripheral><Plasmacytoma Growth Factor><Poly I-C><Polyinosinic-Polycytidylic Acid><Predisposition><Pregnancy><Production><Psychiatric Disease><Psychiatric Disorder><Pyrexia><Risk><Risk Factors><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SIS cytokines><Schizophrenia><Schizophrenic Disorders><Serum><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Striate Body><Striatum><Susceptibility><Testing><Time><Viral><Viral Diseases><Virus Diseases><at-risk females><at-risk women><behavior outcome><behavior phenotype><behavioral outcome><behavioral phenotyping><bio-markers><biologic marker><biological signal transduction><biomarker><biomarker identification><causation><chemoattractant cytokine><chemokine><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><cytokine><dementia praecox><developmental><disease causation><driving><early detection><early therapy><endophenotype><epigenetically><experiment><experimental research><experimental study><experiments><febrile><febris><females at high risk><heavy metal Pb><heavy metal lead><high risk females><host response><human disease><identification of biomarkers><identification of new biomarkers><immune activation><immune system response><immune-based biomarkers><immunologic substance><immunological biomarkers><immunological markers><immunological substance><immunoreactivity><immunoresponse><interest><interferon beta 2><marker identification><mental illness><model of animal><mouse model><murine model><neural circuit><neural circuitry><neurocircuitry><neurodevelopment><neurodevelopmental disease><neuropathologic><neuropathological><neuropathology><non-human primate><nonhuman primate><offspring><pathway><poly I:C><poly IC><poly(I:C)><predictive biomarkers><predictive marker><predictive molecular biomarker><prevent><preventing><psychiatric illness><psychological disorder><resilience><resilient><response><schizophrenic><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><sex><striatal><success><synaptic circuit><synaptic circuitry><viral infection><virus infection><virus-induced disease><women at high risk>