This new Facility will enable a more accurate evaluation of the role of identified genes in regulating the biochemical pathways relevant to physiology, behavior, and response to drug treatment. The transgenic and knock out methodologies are necessary to complement the other molecular methodologies used in this Program Grant. This Core will provide support for breeding and selection, genotyping, and behavioral assays of the mice for the studies proposed in Projects 1-3. Coordination of this work under the Transgenic Core will also make these studies far more cost- effective. Initially, behavioral and physiologic evaluation will be conducted on four available gene knock out strains: 1) GAP-43, a protein important in synapse formation; these mice will be used to examine the role of GAP-43 and behavioral and cellular responses to antidepressant treatments (Project 2); 2) b2 subunit of the nicotinic acetylcholine receptor, which is important in modulating the reward characteristics of nicotine in the brain; these mice will be used to examine the role of the nicotinic receptor in models of anxiety (Project 3); 3) cAMP response element binding protein (CREB) and FosB, important transcription factors involved in many aspects of neuronal function; these mice will be used to study the role of these proteins in antipsychotic (Project 1) and antidepressant (Project 2) drug actions, as well as in models of anxiety (Project 3); 4) BDNF, a neurotrophic factor important for the survival and function of many neurons in brain. We have found that expression of BDNF, as well as its receptor, TrkB, is increased by chronic antidepressant treatments; these mice will be used to determine the functional consequences of the up-regulated BDNF response (Project 2). Another specific aim of this Core (5) is to generate new conditional CREB and delta FosB transgenic mice to further evaluate the role of these transcription factors in the actions of antipsychotic and antidepressant treatments (Projects 1 and 2), as well as in fear potentiated startle (Project 3). The conditional transgenics will provide a method for time-dependent and tissue-specific expression of CREB and delta FosB so that the direct effects, not secondary adaptations, of the transgenes can be determined. Finally, this facility will generate additional knock out and conditional transgenic mice of specific interest to investigators in the Program.
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