Engrailed2 regulates forebrain monoamines and behavior

Principal Investigators:  Jacqueline Crawley, Ph.D. and Emanuel DiCicco-Bloom, M.D., UMDNJ-Robert Wood Johnson Medical School

Engrailed2 is a homeodomain transcription factor that regulates embryonic hindbrain development. Single nucleotide polymorphisms in EN2, the gene coding for Engrailed2, have been associated with autism in five independent genetic studies, implicated EN2 genetic variants as a likely autism susceptibility gene. This project investigates monoamine levels and behavioral phenotypes relevant to the symptoms of autism in En2 knockout mice. We are conducting behavioral assays relevant to sociability, cognition, and depression. Pharmacological treatments that reverse the noradrenergic abnormalities discovered by our collaborator Manny DiCicco-Bloom are being evaluated for reversal of behavioral phenotypes in En2 knockout mice.

Genetics and physiology of emotion in Fragile X syndrome

Principal Investigator:   David Hessl, Ph.D.

This research investigates genetic, physiological, and environmental factors that contribute to emotional problems in individuals with Fragile X syndrome, and in carriers of the Fragile X mental retardation 1 (FMR1) gene.  In addition to cognitive impairment, children and adults with Fragile X syndrome demonstrate a characteristic behavioral phenotype that includes prominent social anxiety and avoidance.  Using psychophysiological measures including potentiated startle reflex, electrodermal response, and cardiovascular reactivity, we are examining the biological basis of these difficulties.  Given that many individuals with Fragile X also have autism, we are especially interested in knowing whether physiological reactivity contributes to deficits in reciprocal social interaction in these individuals.  In addition, in collaboration with other member of the Fragile X team at U.C. Davis, we are studying variation in other genes including the monoamine oxydase A and serotonin transporter polymorphisms as well as environmental factors that may explain variation in the severity of the behavioral phenotype.  Finally, related work in the laboratory focuses on limbic system function in adult premutation carriers in collaboration with Drs. Rivera, Tassone, and Hagerman.  We have recently established that male carriers with abnormal elevation of FMR1 mRNA report higher rates of psychological symptoms.  We are seeking to understand the brain basis of these symptoms, and the relevance of these findings to the Fragile X-Associated Tremor Ataxia Syndrome, which occurs in older male and rare female carriers.

Immune system regulation of neural stem cells in the prenatal brain

Principal Investigator:  Stephen C. Noctor, Ph.D.

Recent studies show that microglia, the immune cell component of the central nervous system, colonize neural stem cell niches and regulate cell production in proliferative regions of the prenatal brain. The goal of this project is to identify the signaling pathways that regulate interactions between microglia and neural stem cells in the developing brain under normal and pathological conditions. This project will contribute to our understanding of the etiology of neurodevelopmental disorders, such as schizophrenia and autism, in which immune system activation during gestation has been implicated.