Animal Models Of Neuropsychiatric Disorders

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Our Section collaborates with several molecular geneticists laboratories on behavioral phenotyping of transgenic and knockout mice with mutations in genes expressed in the brain, relevant to our research interests in animal models of neuropsychiatric diseases. Over the past years, we have developed and refined a multitiered strategy for behavioral phenotyping. Rigorous methods for quantitate observations of general health, home cage behaviors, tests for sensory abilities, and motor functions, to ensure that the mutant line has no gross physical defects that would produce false positives on more complex behavioral tasks. Further, we have developed new behavioral tasks for mice, and adapted rat behavioral tasks for mice. The strategy for hypothesis testing reduces false negatives in the first characterization of a new mutant line. A constellation of ccomplementary tests is conducted for each behavioral domain, e.g. memory, feeding, anxiety, social behaviors, motor coordination. During the past year, these methods have been applied to the characterization of several mutant lines relevant to neuropsychiatric disorders. A dopamine D5 receptor knockout mouse generated by Dave Sibley, NINDS, was tested for behavioral phenotype by our postdoctoral fellow Andrew Holmes. Results indicate normal baseline behaviors but altered responses to a serotonergic agonist drug treatment on exploratory locomotion and on prepulse inhibition of acoustic startle. Knockout mice deficient in neurogranin, a substrate of calmodulin which regulates neuronal calcium flux, generated by Dr. Huang, NICHD, were tested by Tsuyoshi Miyakawa. Results indicate poor performance on spatial learning, associated with an anxiety-like phenotype. M3 and M5 muscarinic receptor knockout mice, generated by Jurgen Wess, NIDDK, were tested by Dr. Miyakawa. Severe deficits in feeding and body weight were detected in M3 null mutants, which appear to be related to a disturbance in insulin secretion. Serotonin transporter knockout mice, generated by Dennis Murphy, NIMH, were tested by postdoctoral fellow Andrew Holmes. A striking anxiety-like phenotype was confirmed in three different anxiety tasks, the elevated plus maze, the light/dark transitions task, and the emergence test in an open field. Galanin overexpressing transgenic mice, generated by Robert Steiner, University of Washington in Seattle, were tested by postdoctoral fellow Andrew Holmes. Anxiety-related and depression-related phenotypes were investigated, based on the coexistence of galanin with norepinephrine in the locus coeruleus and with serotonin in the dorsal raphe. Drug challenge experiments are in progress.