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Principal Investigator: Melissa Dawn Bauman
Organization: UNIVERSITY OF CALIFORNIA AT DAVIS
Fiscal Year: 2024
Award: $3,124,965
Funding agency: National Institute of Mental Health
PROJECT SUMMARY - OVERALL
Psychiatric illnesses, including schizophrenia, affect a significant proportion of the population, yet current
treatments are only partially effective for many individuals and, in the case of SZ, do little to address disabling
cognitive and negative symptoms. Thus, there is a pressing need to develop biomarkers to identify at-risk
individuals for early intervention and new molecular pathways to target for development of novel therapies. An
increasingly compelling pathway associated with SZ is immune dysregulation. This proposed renewal of the
UC Davis Conte Center brings together investigators with a unique combination and wide range of
complementary expertise to address a critical gap in knowledge related to the potential links between immune
dysregulation and psychiatric illness. During the previous funding period, we took a multi-pronged approach to
test our Center hypothesis that early activation of the maternal immune system alters brain development
in offspring leading to structural and functional changes in connectivity that are associated with the
emergence of psychopathology in adolescence and young adulthood. Four important findings emerged
from those studies that serve as the premise for this renewal application. First, we discovered two factors in the
mouse model that predict susceptibility and resilience of offspring to MIA, allowing us to study why MIA causes
aberrant outcomes in only a subset of pregnancies and how it can lead to diverse phenotypes in offspring.
Second, we found signatures of abnormal brain development in our male MIA NHP offspring as early as 6
months of age, indicating that the early postnatal period is critical for understanding the impact of MIA on brain
development. Third, combined results from NHP and mouse models point to cortico-striatal circuitry as central
to behavioral outcomes in MIA offspring. Finally, convergence between MIA NHP imaging findings and recent
onset SZ support the clinical relevance of the MIA models. In this renewal, we will continue to test our original
Center hypothesis across species (mouse and NHP MIA models and humans with SZ), through three specific
aims: (i) Identify immune signaling pathways in females before and during pregnancy that confer susceptibility
or resilience to distinct subsets of MIA-induced behavioral phenotypes in offspring, (ii) Determine the
contribution of cortico-striatal circuits to susceptibility, resilience and phenotypic heterogeneity in MIA mouse
and NHP offspring and in individuals with SZ, and (iii) Determine how sex contributes to susceptibility,
resilience and phenotypic heterogeneity in MIA offspring and individuals with SZ. Successful completion of
these Aims, which could only be accomplished in a highly integrated interdisciplinary Center as proposed, will
identify causal molecular pathways in specific neural circuits critical for guiding the development of
interventions optimized for the developmental age and sex of at-risk offspring following MIA. They will also
reveal new immune signaling pathways that can be targeted for the development of biomarkers to identify at-
risk pregnancies, and a new class of much-needed therapeutic interventions to prevent SZ and other NDDs.
Terms: <12-20 years old><Address><Adolescence><Affect><Age><Age Months><Behavioral><Biological Markers><Brain><Brain Nervous System><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><Computer Models><Computerized Models><Corpus Striatum><Corpus striatum structure><Coupled><DWI (diffusion weighted imaging)><DWI-MRI><Development><Differences between sexes><Differs between sexes><Diffusion MRI><Diffusion Magnetic Resonance Imaging><Diffusion Weighted MRI><Diffusion weighted imaging><Diffusion-weighted Magnetic Resonance Imaging><Disease><Disorder><Dopamine><Early Intervention><Encephalon><Female><Functional MRI><Functional Magnetic Resonance Imaging><Funding><Gene Expression><Gestation><Heterogeneity><Human><Hydroxytyramine><Image><Immune><Immune Cell Activation><Immune response><Immune signaling><Immunes><Immunological response><Incidence><Individual><Infection><Intervention><Intervention Strategies><Investigators><Knowledge><Lead><Link><MR Spectroscopy><Magnetic Resonance Spectroscopy><Maternal Immunity><Maternally-Acquired Immunity><Measures><Mediating><Mental disorders><Mental health disorders><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Mothers><Motivation><Murine><Mus><Neuranatomies><Neuranatomy><Neuroanatomies><Neuroanatomy><Neurodevelopmental Disorder><Neuroimmune><Neuroimmune Mechanisms><Neuroimmune Processes><Neuroimmunomodulation><Neurological Development Disorder><Outcome><Pathway interactions><Patients><Pb element><Phenotype><Poly I-C><Polyinosinic-Polycytidylic Acid><Population><Predisposition><Pregnancy><Psychiatric Disease><Psychiatric Disorder><Psychopathology><Research><Research Personnel><Researchers><Risk><Risk Factors><Rodent Model><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><Schizophrenia><Schizophrenic Disorders><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><Sex Differences><Sexual differences><Signal Pathway><Striate Body><Striatum><Susceptibility><Symptoms><Testing><Therapeutic Intervention><Time><abnormal psychology><adolescence (12-20)><adult youth><ages><at-risk pregnancies><behavior outcome><behavior phenotype><behavioral outcome><behavioral phenotyping><bio-markers><biologic marker><biological sex><biomarker><biomarker development><brain abnormalities><clinical relevance><clinically relevant><cognitive control><cognitive disability><cognitively disabled><computational modeling><computational models><computer based models><computer based prediction><computerized modeling><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><dMRI><dementia praecox><develop therapy><developmental><diffusion tensor imaging><fMRI><heavy metal Pb><heavy metal lead><host response><imaging><immune activation><immune system response><immunoreactivity><immunoresponse><in vivo><intervention development><intervention therapy><interventional strategy><male><maternal immune system><mental illness><mother immune system><mouse model><murine model><neural><neural circuit><neural circuitry><neural imaging><neuro-imaging><neurocircuitry><neurodevelopmental disease><neuroimaging><neurological imaging><neuromelanin><neuropsychiatric disease><neuropsychiatric disorder><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><non-genetic><non-human primate><nongenetic><nonhuman primate><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><offspring><optogenetics><outcome prediction><pathway><poly I:C><poly IC><poly(I:C)><post-natal period><postnatal period><predictive modeling><prevent><preventing><psychiatric illness><psychological disorder><resilience><resilient><response><schizophrenia risk><schizophrenic><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><sex><sex based differences><sex-dependent differences><sex-related differences><sex-specific differences><single cell genomics><sober><sobriety><striatal><synaptic circuit><synaptic circuitry><therapy development><transcriptomics><treatment development><young adult><young adulthood>