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| Animal Models of Human Behavioral Disorders |
| Tuesday, June 1, 2004 |
| 9:00 AM–10:20 AM |
| Independence East |
| Area: TPC/DDA; Domain: Applied Research |
| Chair: Gene S. Fisch (NS; LIJ Research Institute) |
| Discussant: Patrick M. Ghezzi (University of Nevada, Reno) |
| Abstract: . |
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| The Nature and Utility of Animal Models |
| DIANA M. DELGADO (University of Nevada), Linda J. Parrott Hayes (University of Nevada) |
| Abstract: When a subject of inquiry is too complex to be studied directly, or when such is prohibited on ethical grounds, a simpler model of this phenomenon may be constructed for purposes of its investigation. It is assumed in such cases that an understanding of the more complex phenomenon will emerge as facts pertaining to the simpler one are accumulated. Murine models of human psychiatric disorders exemplify this circumstance. In this paper we argue that animal performances do not share sufficient similarities to human psychopathologies in either form or function to constitute meaningful representations of latter. We further argue that an adequate understanding of complex events cannot be achieved by an additive procedure with respect to facts gleaned from the study of simpler phenomena. Finally, while we agree that a modeling strategy may prove valuable in this context, we believe that this value will be realized in disciplines other than psychology. |
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| Mouse Models of Mood and Anxiety Disorders |
| ANDREW HOLMES (Section on Behavioral Science and Genetics, NIAAA) |
| Abstract: Genetically-modified mice provide novel insights into the neural basis of behavior. Mouse models are used to assess the roles of specific molecules in cases where other research tools are unavailable. Studies that engineer mouse mutations in candidate genes for psychiatric diseases, e.g., anxiety disorders, are unusual, partly because it is difficult to identify strong gene candidates. A portion of the regulatory region of the serotonin transporter (5-HTT) gene is believed to regulate brain 5-HT function and is associated with individual differences in trait anxiety and depression. To study how genetically-driven variation in 5-HTT function affects anxiety, mice were generated with a deletion in part of the 5-HTT (htt) gene. Loss of serotonin reuptake in these mutant mice causes increased extracellular serotonin, and alterations in serotonin neuronal firing and receptor function. These mutant mice show abnormal behaviors related to the symptomatology of mood and anxiety disorders. These mutant mice show exaggerated neuroendocrine and adrenomedullary responses to stress, increased paradoxical sleep, reduced aggression, increased anxiety-like behavior and reduced exploratory locomotion. These behavioral abnormalities are consistent with the hypothesis that genetically-driven 5-HTT hypofunction is a risk factor for mood and anxiety disorders. Engineering mice with mutations in candidate genes cannot model the full complexity of human disease. However, this approach is of potential utility for understanding gene-gene, gene-environment and gene-drug interactions of mood and anxiety disorders. |
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| The Fragile X Knockout Mouse: A Model of Mental Retardation? |
| GENE S. FISCH (NS; LIJ Research Institute) |
| Abstract: A mutation in the fragile X (fmr1) gene is the most common single cause of mental retardation (MR). The fragile X syndrome (FXS) produced by the mutation is characterized by MR, craniofacial abnormalities, attention deficits and hyperactivity. A consortium of researchers produced a potential knockout mouse model (fmr1 ko) for FXS, however their behavioral studies using the Morris maze were inconclusive. We examined the behavior of the fmr1 ko compared to controls, using several operant procedures involving visual and auditory discrimination, complex negative discrimination, and delayed-matching-to-sample tasks. In the set of discrimination tasks, fmr1 ko mice performed better than normal controls. In the delayed matching to sample procedure, knockouts performed only slightly better than normal littermates. Post-mortem genetic and protein analyses showed that some mice that were identified as knockouts were actually producing protein. These findings suggest caution regarding the use of genetically produced animal models for behavioral disorders. |
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