Neuroimmune Mechanisms of Psychiatric Disorders

Project: Research project

Description

? DESCRIPTION (provided by applicant): Growing evidence from epidemiology, genetics and clinical neuroscience implicates neuroimmune mechanisms in the pathophysiology of schizophrenia (SZ) and other developmental psychiatric disorders. A new class of animal models of maternal immune activation (MIA), expressing developmentally phenotypic features related to SZ, has been developed; however, little is known about the mechanisms by which MIA results in changes to brain development, connectivity and behavior. The UC Davis Conte Center seeks to bridge that gap. Supported by pilot funding for the past three years, this team has worked together to develop hypotheses, design experiments and collect preliminary data to develop the present application. The Center comprises an accomplished group of investigators from molecular and cell biology, systems and behavioral neuroscience, biomedical engineering, neuroimaging, and clinical neuroscience and a highly integrated set of studies conducted across species and scale to test the hypothesis that MIA contributes to SZ by altering immune molecules in the brains of offspring, which, in turn, alters cortical connectivity, function and behavior during development. Synaptic changes, gene expression, structural and functional connectivity, neural inflammation and behavior will be measured in mouse and non-human primate (NHP) models at multiple ages to determine the timing and hierarchy of the effects of MIA. When possible, parallel studies in humans will be conducted to establish the clinical relevance of the MIA animal models. The Center will pursue two Specific Aims to determine: 1) if MIA increases risk for neurodevelopmental psychiatric disorders in offspring by altering neural circuitry through dysregulated signaling of immune molecules and gene networks throughout development; 2) the timing of the appearance and progression of structural and functional changes in the brains of MIA offspring relative to the onset of dopamine dysregulation, neural inflammation, and SZ-related behavioral disturbances in the MIA NHP and compare these data to those seen in first-episode SZ. The projects will measure changes in synaptic connectivity, gene expression, structural and functional connectivity, neural inflammation, and behavior in parallel mouse and NHP MIA models at multiple ages to determine the relative timing and hierarchy of these changes and understand the underlying mechanisms. These studies in the mouse and NHP model will be complemented by novel analyses of synaptic connectivity and gene expression in post mortem human tissue from SZ.
StatusActive
Effective start/end date4/1/153/31/20

Funding

  • National Institutes of Health
  • National Institutes of Health: $2,000,000.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $2,000,000.00
  • National Institutes of Health

Fingerprint

Schizophrenia
Mothers
Primates
Neuroimmunomodulation
Brain
Psychiatry
Neuroimaging
Inflammation
Dopamine
Animal Models
Corpus Striatum
Macaca mulatta
Positron-Emission Tomography
Haplorhini
Rodentia
Neurosciences
Macaca
Pregnancy
Psychotic Disorders
Cognition

ASJC

  • Medicine(all)