Intrauterine complications (i.e, perinatal asphyxia, prenatal immune activation and cesarean delivery) are a recognized risk factor for the emergence of later neuropsychiatric disorders. These disorders are characterized by hyperdopaminergic function, and include schizophrenia, autism, Attention Deficit Hyperactivity Disorder (ADHD), Tourette's Syndrome (TS) and Obsessive Compulsive Disorder (OCD). However, intrauterine complications are difficult to quantify, and there presently exist no biomarkers for identification of individuals with increased vulnerability for developing neuropsychiatric disorders due to intrauterine complications. To establish important new biomarkers, we will combine non-invasive longitudinal in vivo 1H Magnetic Resonance Imaging (MRI) and MR Spectroscopy (MRS), in vitro 1H Nuclear Magnetic Resonance (NMR) Spectroscopy, immunohistochemistry and behavioral studies of postnatal rats following exposure to controlled perinatal asphyxia. Using a longitudinal approach, neurometabolic spectra will be acquired and analyzed in the striatum, hippocampus and prefrontal cortex of single subjects by applying MRS at three key postnatal ages (1,4 and 8 weeks). Results will be analyzed in relation to predicted postnatal neural and behavioral changes associated with intrauterine complications, including Tyrosine Hydroxylase (TH), a major metabolite in the dopamine (DA) pathway, and cognitive, emotional and social behaviors implicated in hyperdopaminergic states. In cross- sectional studies, we will perform correlative in vivo MRS and in vitro NMR studies. Pharmacological manipulations will be performed to alter neurometabolites, and the resulting spectra compared for the two technique. These integrative studies will break new ground by providing important, necessary validation and extension of non-invasive MRS applications to small animal imaging studies involving intrauterine complications. The results will establish a solid basis for important new studies of developmental pathways leading to the emergence of neuropsychiatric dysfunction, and are vital for identification of non-invasive biomarkers that will lead to early diagnosis and the development of intervention strategies. This proposal addresses issues that are globally relevant to vital problems of child health and welfare with important pediatric and neuropsychiatric implications. Our long-term goal is to identify the mechanisms linking intrauterine events and the emergence of neurodevelopmental disorders. The experiments proposed in this integrative application combining imaging, molecular, neurochemical, physiological and behavioral approaches will lay important groundwork for identification of biomarkers of neuropsychiatric dysfunction and help specify translational goals for prenatal diagnosis and intervention, postnatal care and the establishment of developmental programs.
|Morgan, Jonathan J; Kleven, Gale A; Tulbert, Christina D et al. (2013) Longitudinal 1H MRS of rat forebrain from infancy to adulthood reveals adolescence as a distinctive phase of neurometabolite development. NMR Biomed 26:683-91|