This application addresses broad Challenge Area (15) Translational Science, Gene x environment x development (GxExD) studies of brain function and mental disorders. Gene x environment epidemiology and psychiatry research studies have only recently been used and 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 and development, but usually includes the examination of gene x environment, gene x development, or development x environment, often producing inconsistent findings. In many cases the genetic disposition is understood and development in terms of how it influences brain structure, but how the environment alters brain function to interact with the genetic and development factors is unknown. The challenge, then is to determine how the genetic predisposition, development of the relevant neural circuitry of the nervous system and the environment interact to alter brain function to produce the psychiatric disorder. In this application, using an animal model, we propose to examine all three factors using genetic, behavioral, electrophysiological and morphological/anatomical techniques. The disorder under investigation is anxiety. Anxiety can be defined as a state of cognitive and 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 and arousal that enables an organism to navigate an unfamiliar environment of unknown danger, and 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 and are associated with high levels of morbidity and 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 $44 billion dollars in the United States alone. The mean age of onset for an anxiety disorder is 11. This early onset is consistent with the finding that individual levels of trait anxiety are established at an early age and are fairly constant over a lifetime. Thus, both trait anxiety and 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 and 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 and epidemiological. Neither approach alone is capable of providing a full explanation of the environmental and genetic contributions to behavior. This is because genes do not generate behaviors directly. Rather, they act in developmental pathways that first generate neurons and then circuits and finally systems that mediate behavioral responses. The genetic program therefore unfolds in a predictable manner that samples the surrounding environment and 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 and the potential impact of environmental stress to amplify the genetic effect.
Recently attention has been focused on how genetic variation interacts with the environment and development. The goal of the proposed research is to determine how lack of the 5-HT1A receptor interacts with the development of a crucial neural circuit of the raphe and an environmental stressor. This research is relevant to public health because knowledge of the early neurodevelopmental modifications that lead to the future occurrence of anxiety/depression will define therapeutic targets for early intervention which may prevent the development of mental illness in adulthood.
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