The broad goal of this project is study affective disorders, specifically anxiety, spanning multiple levels of analysis (genomic, molecular, cellular, circuits, behavior) in rodents. Anxiety-like behavior, defined as decreased exploratory activity and increased fear of aversive environments, can result from disrupted serotonergic signaling in the forebrain during the early postnatal period in rodents. Although it is clear mat altered serotonergic signaling can affect hippocampal circuitry and result in anxiety-like behavior, the molecular mechanisms by which this occurs are still unknown. A widely used mouse model of anxiety is the serotonin 1A receptor knock-out mouse (5HT1AR-/-). This mouse shows increased hippocampal dendritic branching coincident with anxiety-like behavior. Genes involved or acting to compensate in this anxiety-like behavior have been identified by a microarray screen of this anxious 5HT1AR-/- mouse. One gene that is overexpressed in this mouse model of anxiety is a transcription factor called Kruppel-like factor 9 (KLF9). KLF9 is implicated in hippocampal circuit maturation and anxiety-like behavior. KLF9 may act during the early postnatal period to influence dendritic branching and anxiety-like behavior in adulthood. Mouse molecular genetic techniques will allow the construction of a mouse that conditionally lacks KLF9 during the early postnatal period. Neuroanatomical and behavioral analyses of this conditional KLF9 knock out will be used to study the role of KLF9 in hippocampal circuitry and anxiety-like behavior. We hypothesize that KLF9 is required during the early postnatal period for normal hippocampal circuit maturation and adult anxiety-like behavior. KLF9 may therefore represent a novel target for therapeutic intervention in the treatment of anxiety disorders. Identification of genes and processes downstream of serotonin signaling that influence anxiety-like behavior hi mice will advance our knowledge of anxiety disorders in humans. By learning more about which parts of the brain and what molecular mechanisms are involved in the development of anxiety disorders, we may be able to devise better treatments for anxiety disorders. For example, if specific molecular and neuroanatomical changes are known to occur in a particular region of the brain resulting in anxiety, drugs may be developed that will block them and decrease fear responses. ? ? ?
