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Principal Investigator: Cameron S. Carter
Organization: UNIVERSITY OF CALIFORNIA AT DAVIS
Fiscal Year: 2024
Award: $530,926
Funding agency: National Institute of Mental Health
PROJECT SUMMARY – PROJECT 5
Evidence from epidemiology implicates gestational maternal immune activation (MIA) in the pathophysiology of
schizophrenia (SZ). These data, together with recent advances in our understanding of the role of immune
molecules in normal brain development, have led to the overarching hypothesis of this Conte Center: 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. Our initial pilot studies of a unique nonhuman primate (NHP) MIA model
found evidence of altered social, repetitive, and self-injurious behaviors that emerged during adolescence and
were associated with increased striatal dopamine (DA). During the previous funding cycle, we found decreases
in frontal cortical volumes and increases in extracellular free water (FW), a putative measure of
neuroinflammation, measured using diffusion weighted MRI (DWI), in cingulate cortex gray matter (GM) in
male MIA NHPs. These changes in the developing NHP brain were present as early as 6 months postnatally,
prior to the emergence of any behavioral abnormalities, and highlight the importance of the postnatal period for
understanding the effects of MIA on brain development. In a parallel study in patients with SZ, we showed
increased GM FW, with maximal differences present in anterior cingulate, supporting the clinical relevance of
the NHP MIA model. In the present project, we propose to focus on the effects of MIA in the postnatal period
and on brain development in female NHPs, scanning both males and females at 6 and 18 months of age. To
obtain an integrated cross-species understanding of the effects of MIA and SZ on the development of cortico-
striatal functional circuitry, we will pursue the following three aims: (i) Longitudinal imaging studies of
phenotypic heterogeneity in MIA NHPs, (ii) Computational model–based analysis of frontal-striatal circuitry
associated with motivation and cognitive control in SZ, and (iii) Mechanisms underlying sex-related phenotypic
heterogeneity in SZ. Interpretation of the results of these imaging studies will be enhanced by tissue analyses
in the NHPs (Project 4) at age 18 months and measurement of the BIR and immunoreactivity of the mothers
(Project 1) of the offspring we plan to image. Finally, in addition to the above study in MIA NHPs, and in line
with our center’s expanded focus on MIA effects and of SZ on cortico-striatal circuitry, we will use a novel
computational model–based fMRI analysis to dissect the neural circuitry underlying motivation and cognitive
control deficits as well as their relationship to cortical FW and midbrain neuromelanin (NM), a novel proxy for
hyperdopaminergic activity in SZ. This computational model will allow cross-species comparisons of the role
for cortico-striatal circuitry in similar behavioral assays in the mouse MIA model and the MIA NHP. Finally, we
will also examine the role of sex in the phenotypic heterogeneity in humans with SZ at the neural systems level
and in relationship to symptoms and clinical outcomes.
Terms: <12-20 years old><Address><Adolescence><Age><Age Months><Anatomic Sites><Anatomic structures><Anatomy><Animals><Anterior><Behavior><Behavioral><Behavioral Assay><Biological Markers><Body Tissues><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><Clinical><Computer Models><Computerized Models><Corpus Striatum><Corpus striatum structure><DWI (diffusion weighted imaging)><DWI-MRI><Data><Data Analyses><Data Analysis><Deliberate Self-Harm><Detection><Development><Differences between sexes><Differs between sexes><Diffusion MRI><Diffusion Magnetic Resonance Imaging><Diffusion Weighted MRI><Diffusion weighted imaging><Diffusion-weighted Magnetic Resonance Imaging><Dopamine><Dysfunction><Encephalon><Epidemiologic Research><Epidemiologic Studies><Epidemiological Studies><Epidemiology><Epidemiology Research><Female><Functional MRI><Functional Magnetic Resonance Imaging><Functional disorder><Funding><Gestation><Heterogeneity><Human><Hydrogen Oxide><Hydroxytyramine><Image><Immune><Immune Cell Activation><Immune response><Immunes><Immunological response><Incentives><Individual><Link><MR Imaging><MR Tomography><MRI><MRIs><Magnetic Resonance Imaging><Measurement><Measures><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Mental disorders><Mental health disorders><Mesencephalon><Mice><Mice Mammals><Mid-brain><Midbrain><Midbrain structure><Modeling><Modern Man><Molecular><Mothers><Motivation><Murine><Mus><NMR Imaging><NMR Tomography><Neural Development><Neurodevelopmental Disorder><Neuroimmune><Neuroimmune Mechanisms><Neuroimmune Processes><Neuroimmunomodulation><Neurological Development Disorder><Nuclear Magnetic Resonance Imaging><Outcome><Patients><Phenotype><Physiopathology><Pilot Projects><Pregnancy><Proxy><Psychiatric Disease><Psychiatric Disorder><Psychopathology><Resolution><Risk><Role><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><Sampling><Scanning><Schizophrenia><Schizophrenic Disorders><Self-Injurious Behavior><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><Striate Body><Striatum><Symptoms><System><Testing><Thick><Thickness><Time><Tissues><Water><Zeugmatography><abnormal psychology><adolescence (12-20)><adult youth><ages><anatomic imaging><anatomical imaging><behavior study><behavioral study><bio-markers><biologic marker><biomarker><brain circuitry><cingulate cortex><clinical relevance><clinically relevant><cognitive control><computational modeling><computational models><computer based models><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><data interpretation><deliberate self harm><dementia praecox><developmental><diffusion tensor imaging><early adolescence><epidemiologic><epidemiologic investigation><epidemiological><epidemiology study><extracellular><fMRI><female outcomes><frontal cortex><frontal lobe><gray matter><host response><imaging><imaging study><immune activation><immune system response><immunoreactivity><immunoresponse><insight><intentional self harm><intentional self injury><longitudinal imaging><male><maternal immune system><mental illness><mother immune system><mouse model><murine model><neural><neural circuit><neural circuitry><neural imaging><neural inflammation><neuro-imaging><neurocircuitry><neurodevelopment><neurodevelopmental disease><neuroimaging><neuroinflammation><neuroinflammatory><neurological imaging><neuromelanin><non-human primate><nonhuman primate><novel><offspring><outcomes among females><outcomes among women><outcomes in females><outcomes in women><pathophysiology><pilot study><post-natal period><postnatal><postnatal period><psychiatric illness><psychological disorder><recruit><resilience><resilient><resolutions><schizophrenic><self harm><self injury><serial imaging><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><social><social role><striatal><substantia grisea><synapse function><synaptic circuit><synaptic circuitry><synaptic function><women's outcomes><young adult><young adulthood>