THE CHILDREN'S HOSPITAL OF PHILADELPHIA
Grant: $474,466 - National Institutes of Health - Sep. 23, 2009
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Award Description: This application addresses broad Challenge Area (15) Translational Science, Gene x environment x development (GxExD) studies of brain function & mental disorders. Gene x environment epidemiology & psychiatry research studies have only recently been used & the findings of these studies have come into the limelight of the etiology of psychiatric disorders. Most research does not combine the examination of all three factors, i.e., genes, environment & development, but usually includes the examination of gene x environment, gene x development, or development x environment, often producing inconsistent findings. The challenge is to determine how the genetic predisposition, development of the relevant neural circuitry of the nervous system & the environment interact to alter brain function to produce the psychiatric disorder. Using an animal model, we propose to examine all three factors using genetic, behavioral, electrophysiological & morphological/anatomical techniques. The disorder under investigation is anxiety. Anxiety can be defined as a state of cognitive & behavioral preparedness that an organism mobilizes in response to a future or distant potential threat. In its non-pathological form anxiety can be divided into two categories: 1) state anxiety, which is an acute adaptive response of heightened vigilance & arousal that enables an organism to navigate an unfamiliar environment of unknown danger, & 2) trait anxiety which is a measure of an individual's baseline reactivity or tendency to generate anxious responses. In its pathological form, anxiety is a maladaptive state that impairs the ability of an organism to respond optimally to its environment. Anxiety disorders are highly prevalent & are associated with high levels of morbidity & mortality as well as high cost. It is estimated that anxiety disorders may affect up to 20% of the population at some point in their lifetime with an annual estimated cost of $44B in the US alone. The mean age is 11 for onset of anxiety disorder. This early onset is consistent with the finding that individual levels of trait anxiety are established at an early age & are fairly constant over a lifetime. Thus, both trait anxiety & anxiety disorders are likely to be determined by early developmental processes or events that affect the way an individual's brain is 'wired'. Prior to the publication of landmark studies like those by Caspi et al demonstrating how early maltreatment interacts with the monoamine oxidase A genotype to yield antisocial behavior & how the 5-HTT transporter interacts with adverse early adult events to increase risk of depression, our understanding of how early environmental conditions might differentially impact the expression of underlying genetic risk had been limited, as these two fields of inquiry had been the purvey of two separate disciplines, i.e., genetic & epidemiological. Neither approach alone is capable of providing a full explanation of the environmental & genetic contributions to behavior. This is because genes do not generate behaviors directly. Rather, they act in developmental pathways that first generate neurons & then circuits & finally systems that mediate behavioral responses. The genetic program therefore unfolds in a predictable manner that samples the surrounding environment & is in turn shaped by it. In such a model, one would predict that the effect of any given environment will depend on the developmental program that is unfolding at the time. Thus, gene x environment interactions are perhaps more appropriately conceived of as gene x environment x development, with some time periods being more susceptible to environmental manipulation than others. We will test this hypothesis with the use of a genetically manipulated animal model, the 5-HT1A autoreceptor KO mouse, to determine the critical period for its influence on the serotonergic raphe nuclei in producing anxiety & the potential impact of environmental stress to amplify the genetic effect.
Project Description: X Protocol Development X Recruit and hire staff X Project Planning X Collect Data X Initiate experiments X Conduct experiments X Analyze Data X Training
Jobs Summary: N/A (Total jobs reported: 0)
Project Status: Less Than 50% Completed
This award's data was last updated on Sep. 23, 2009. Help expand these official descriptions using the wiki below.
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