Overview. In this year (October, 2007 to September, 2008) the Section on Behavioral Science and Genetics continued a program of research designed to develop mouse models of emotional disorders and addiction, with focus on the glutamate system.? ? Individuals exposed to extreme forms of trauma and neglect are more prone to suffer from emotional disorders, such as anxiety and depression, and more likely to develop addiction to alcohol and illicit drugs of abuse. However, it is far from clear exactly how stress increase later risk for these neuropsychiatric disorders. Another unresolved question is why some individuals appear especially sensitive to effects of stress, while others are resilient. This inter-individual variation suggests that genetics play a significant role in modulating stress, a notion supported by recent research in humans. Unfortunately, there are inherent limitations to the study of genetic and environmental influences on behavior under tightly controlled conditions in humans. Animal models provide a valuable alternative. The laboratory mouse potentially provides an excellent model system to study genetic factors modulating behavior due to the availability of genetically-distinct mouse strains and the capacity for engineering genetic mutants. The Section on Behavioral Science and Genetics seeks to develop mouse models of emotional abnormalities and addiction.? ? A series of studies were conducted with the goal of a developing a mouse model of stress that produced reliable effects on emotional behaviors and executive fucntions. The long-term goal of these studies is to develop a model that can be applied to genetically-modified mice (including NMDA KO mice described below) to study gene x stress interactions underlying emotion and addiction. Study 1 was a comparison of the effects of restraint on a battery of tests for fear, anxiety and stress, across 8 genetically-distinct mouse strains.
The aim was to gather information on which strains are suitable for studies of stress and at the same time provide insight into genetic factors modulating of stress. Study 2 assessed knockout mice lacking the NR2A or NR2B receptor subunits on tests for cognition such as the Morris water maze and the pairwise visual discrmination. These experiments will provide baseline phenotypic data guiding later studies on the effects of stress on these behaviors in these mice.? ? The role of glutamate NMDA receptors in mediating emotional behaviors and the behavioral effects of ethanol. Glutamate neurotransmission via NMDA receptors plays a major role in brain development, in mediating the behavioral effects of ethanol and, it is increasingly thought, modulating emotional behaviors. Therefore, the NMDA receptor represents a potential mechanism underlying the effects of stress on subsequent changes in emotion- and reward-related behaviors. The goal of initial studies was to identify which NMDA receptor subtypes are critical mediators of NMDA receptor effects on ethanol sensitivity and emotional behavior in mice and, therefore, which subtypes should be the focus of future studies of the effects of postnatal stress on possible NMDA receptor-mediated changes in these behaviors. Study 1 examined the differential contribution of the NR2A-R and NR2B-R subtypes to the ability of NMDA receptor-blockade to potentiate ethanol sensitivity (as measured by sedation/hypnosis). A combination of pharmacological (NR2-R antagonists) and gene mutant (NR2A KO mice) was employed. Study 2 assessed whether exposure to stress altered behavioral response to ethanol and, whether NMDA receptors, mediated these alterations, again using both pharmacological (NR2-R antagonists) and gene mutant (NR2A KO mice, NR1 hippocampal CA3-specific KO mice) approaches.
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