This project is aims to understand the cellular and molecular mechanisms that support emotional processing in adults. In this application, the investigators will explore a novel hypothesis that suggests early neonatal experience contributes to the shaping of neuronal circuits that govern emotional responses. It has long been known that interactions between an individual and the environment can contribute to brain development. Therefore, it is not surprising that events early on in childhood can impact one's ability to respond to emotionally relevant environmental cues as an adult. The investigators propose that social experiences in neonates trigger neuronal activity that refine circuits that project from, or innervate directly, various nuclei within the amygdala. They arrived at the hypothesis in response to preliminary studies indicating that an NMDAR-interacting protein, SynGAP, is necessary for proper responses to fear and anxiety in adult mice. Published studies indicate that this protein can regulate signaling pathways downstream of NMDARs. Because these receptors are essential for activity-dependent refinement of cortical areas that control sensory processes, it is conceivable that SynGAP mice express abnormal fear and anxiety because of improper wiring among brain regions that govern emotional processing. Importantly, SynGAP has been implicated as a cause of nonsyndromic mental retardation, supporting the investigators'hypothesis that this protein contributes importantly to brain development. To directly test this idea, they will generate a mouse line that will provide temporal control over SynGAP expression in the nervous system. The investigators will compare fear and anxiety from fully developed adult mice with reduced SynGAP expression to the phenotype of adult mice with SynGAP protein reduced before neonatal development. The outcome of these experiments will definitively determine the role NMDAR-SynGAP signaling serves in the maturation of emotional circuitry. In addition, they will also measure the possibility that reduced SynGAP expression during development promotes abnormal cell death in brain areas that govern emotion. Overall, the investigators are optimistic that these studies will provide initial insight into the molecular and cellular mechanisms that contribute to circuits required for emotional preservation. This application has a high probability of maturing into a more substantial research program targeted at understanding the details of how early childhood experience may shape behavior as adults.
Overall, this application explores an innovative hypothesis aimed at evaluating the effects of signaling through NMDARs on the postnatal development of circuits governing emotion. Understanding the molecular mechanisms that trigger the maturation of emotional responses may give us novel insights into the causes of childhood psychiatric conditions.
| Clement, James P; Aceti, Massimiliano; Creson, Thomas K et al. (2012) Pathogenic SYNGAP1 mutations impair cognitive development by disrupting maturation of dendritic spine synapses. Cell 151:709-723 |
