The NIMH transgenic core facility has several major functions: 1) to produce transgenics for neuroscience research, 2) support research with associated techniques in genetic research in neuroscience, 3) develop new transgenic techniques and model system and 4) engage in collaborative projects that promote genetic approaches to neuroscience research. 1) Production Meterics of production over the past year included: a) 15 transgenic mouse projects produced by oocyte injection, with multiple lines produced for each project. b) 7 transgenic rat projects produced by oocyte injection, with multiple lines produced for each project. c) 6 mouse projects have first altering the genes of ES cell and then using those to produce mice. 2) Technical Support a) 127 transgenic rodent lines have been archived by cryopreserving germ cells or embryos. b) 61 lines have been rederived, by transferring lines from pathogen bearing animals into those with defined health status. c) transgenic project design and assistance have continued to be significant to NIH neuroscience labs without experience in producing transgenic animals. 3) Development a) transgenic marmosets: Over the last year the effort to make transgenic marmosets has increased with addition of personnel and the establishing of a collaborative agreement with Erika Sasaki at the Central Institute for Experimental Animals in Kawasaki, Japan. Because of this collaboration the methods to harvest ooctyes and blastocysts, which had been successful were further improved. Methods for in vitro methods have been completely changed to reflec them methods that are used in Dr Sasaki's laboratory. The media, the culture conditions and the analysis of ooctyes and embryos is now modelled on the successful methods that their laboratory demonstrated. The collaboration with NINDS continues, with a new postdoctoral fellow in that institute and a postBAC fellow in the core facility. b) rat ES lines: Rat ES (embryonic stem) lines, some of which ubiquitously express the orange fluorescent protein have been created in the lab. These lines from Long Evans rats have been cultured for several passages, still express OFP and maintain a morphology that is representative of ES cells. Especially with rat ES lines this is not enough to insure that these lines will contribute to a chimeric animal. At this point the karyotype of the lines will be checked before any are injected or fused to embryos in order to determine the potential to produce chimeras and transmit the OFP gene to offspring through the germline. c) Transgenic rat production: in collaboration with NIDA, the core produces transgenic rat lines that are designed in conjunction with acutely delivered transgenes to express genes in discrete populations of central nervous system neurons. These lines are produced in the core facility and then screened for useful expression patterns in NIDA laboratories. d) support techniques: several techniques are under development to increase the capacity of the core's support functions. Freezing mouse sperm and improving IVF by using newer methods is a major effort. Freezing rat sperm and completing IVF at an acceptable level is a challenging task in all laboratories, but having consulted with investigators in Japan, these methods will be improved. e) enhanced recombination methods: While the core has used TALENS in ES cells, we have had no success using this method in embryos. We are now collaboration with NIDA and NIDCR laboratories to develop new methods of enhanced recombination using the CRISPR/cas system. 4) Collaborative projects: below is a list of projects that have been initiated in 2011, or have continued from last year. Stress and neurogenesis: Mice produced in the transgenic core were described in a paper that showed the necessity of neurogenesis for the normal response to stress. Since it has been shown that stress reduces neurogenesis this newer result indicates that a cycle of increasing stress. Learning and memory: The effect of specific and tightly controlled protein synthesis on learning and memory was studied. In addition, transgenic mouse models have been used to show the rrole of specific peptide-expressing cells to influence the link between fear and behavior and learning. Manipulating circuitry: Mice have been produced for two separate laboratories which have specific neurons that could be rendered transiently inactive by light activated ion channels. Those laboratories are investigating different neural circuits that are active in learning and addiction. Addictive and reward behavior: Lines of transgenic rats that express GFP in response to afferent input activation of the fos gene were generated in the core facility. These rats are being used by Bruce Hopes laboratory in NIDA to study patterns of neural activity in response to addictive drugs and most recently in the role of stress in reducing the re-establishment of rewarded behavior. mRNA trafficking in neurons: An RNA stem loop structure is necessary for the translocation of message to specific cell compartments of the neuron. Mice that over express mRNA with this structure have been produced in an effort to disrupt this translocation machinery. By expressing this transgenic mRNA in different neuronal subtypes, the role for this mechanism for normal function is being studied. In addition this mechanism could be useful to target specific messages specifically to the synapse.

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National Institute of Mental Health (NIMH)
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Carr, G V; Chen, J; Yang, F et al. (2016) KCNH2-3.1 expression impairs cognition and alters neuronal function in a model of molecular pathology associated with schizophrenia. Mol Psychiatry 21:1517-1526
Snyder, Jason S; Grigereit, Laura; Russo, Alexandra et al. (2016) A Transgenic Rat for Specifically Inhibiting Adult Neurogenesis. eNeuro 3:
Nieto-Estévez, Vanesa; Oueslati-Morales, Carlos O; Li, Lingling et al. (2016) Brain Insulin-Like Growth Factor-I Directs the Transition from Stem Cells to Mature Neurons During Postnatal/Adult Hippocampal Neurogenesis. Stem Cells 34:2194-209
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Kavarthapu, Raghuveer; Tsai-Morris, Chon-Hwa; Fukushima, Masato et al. (2013) A 5'-flanking region of gonadotropin-regulated testicular RNA helicase (GRTH/DDX25) gene directs its cell-specific androgen-regulated gene expression in testicular germ cells. Endocrinology 154:2200-7
Samie, Mohammad; Wang, Xiang; Zhang, Xiaoli et al. (2013) A TRP channel in the lysosome regulates large particle phagocytosis via focal exocytosis. Dev Cell 26:511-24
Debbache, Julien; Zaidi, M Raza; Davis, Sean et al. (2012) In vivo role of alternative splicing and serine phosphorylation of the microphthalmia-associated transcription factor. Genetics 191:133-44
Liu, Jie; Zhou, Liang; Xiong, Keming et al. (2012) Hepatic cannabinoid receptor-1 mediates diet-induced insulin resistance via inhibition of insulin signaling and clearance in mice. Gastroenterology 142:1218-1228.e1

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