Overview. In the second fiscal year of the Section on Behavioral Science and Genetics (November 30, 2004 ? September 30, 2005), the laboratory was outfitted with personnel and equipment. A program of research was initiated to develop mouse models of the early life origins of emotional disorders and addiction, with focus on two major candidate neurotransmitter systems, glutamate and dopamine. Individuals exposed to extreme forms of trauma and neglect in childhood 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 early life stress increase later risk for these neuropsychiatric disorders. Another unresolved question is why some individuals appear especially sensitive to effects of early life stress, while others are resilient. This inter-individual variation suggests that genetics play a significant role in modulating early life 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 of early life 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 the early life origins of emotional abnormalities and addiction. In 2003-2004, research was initiated along parallel lines. Development and validation of the mouse models of early life trauma and neglect. To-date, in contrast to the rat and monkey, there has been relatively little research on the effects of postnatal stress in the mouse. Therefore, a series of studies were conducted with the goal of a developing a mouse model of early life stress that produced reliable effects on emotional- and reward-related behavior. The long-term goal of these studies is to develop a model that can be applied to genetically-modified mice (including NMDA KO, dopamine receptor KO mice described below) to study gene x early life stress interactions underlying emotion and addiction. Study 1 was a comparison of the effects of postnatal maternal separation (MS) 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 MS and at the same time provide insight into genetic factors modulating of MS. Study 2 examined the effects of MS in the C57BL/6J on tests for ethanol-sensitivity/consumption. Study 3 was a comparison of the effects of postnatal maternal separation and postnatal footshock in the gold-standard mouse strain, C57BL/6J, on tests for fear, anxiety and stress and tests for ethanol-sensitivity/consumption.
The aim was to assess whether different forms of postnatal stress produced similar effects. 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 of in postnatal 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 postnatal 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 examinedthe 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 investigated the differential role of NR1, NR2A and NR2B subtypes in modulating stress and emotional behavior in mice. A combination of pharmacological (NR2-R antagonists) and gene mutant (NR2A KO mice, NR1 hippocampal CA3-specific KO mice) was used to assess the effects of NMDA receptor blockade on various anxiety- and stress-related behaviors. Study 3 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. The role of prefrontal cortical dopamine D1-like receptors in mediating cognition and emotion. A wealth of literature implicates the dopamine system in the mediation of reward and stress. Preliminary findings in rats and monkeys suggest that the dopamine system may be altered by early life stress. In parallel, there is also growing evidence that behavioral functions mediated by a dopamine-rich brain region, the prefrontal cortex (PFC), such as decision making and impulse control, may be impaired by early life stress. An initial set of studies examined the role of a major subfamily of PFC dopamine receptors, D1-like (i.e., D1-R and D5-R), in mediating PFC functions. This will provide a foundation for future studies aimed at elucidating whether postnatal stress modifies PFC control of reward and stress via effect on D1-like-R. Study 1 examined the role of D1-like-R in Pavlovian fear learning and extinction, an emotional behavior known to be PFC-mediated, in mice. A combination of pharmacological (D1-like antagonists) and gene mutant (D1-R KO mice, D5-R KO mice) approaches were employed. Study 2 examined the role of D1-like-R in a working memory task (T-maze alternation) in mice, again using both pharmacological (D1-like antagonists) and gene mutant (D1-R KO mice, D5-R KO mice) techniques. Study 3 involves the development of a novel touchscreen-based apparatus for assessing complex operant discriminations in mice. This apparatus will be used in future studies to further test the role of D1-like-R and other systems in mediating PFC functions such as behavioral inhibition (?go-nogo?) and behavioral flexibility (reversal of 2-way visual discriminations).
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