The NIMH transgenic core facility has several major functions: 1) to produce transgenics for neuroscience research at NIH 2) develop new transgenic techniques and model systems 3) support research with associated techniques in genetic research in neuroscience and 4) engage in collaborative projects that promote genetic approaches to neuroscience research. 1) Production Meterics of production over the past year included: a) 48 transgenic mouse lines produced by oocyte injection. b) 14 rat lines have been produced by oocyte injection. c) 13 mouse projects have first altering the genes of embryonic stem cell and then using those to produce mice. 2) Development Over the last year projects to allow more productive methods have been developed. Two notable projects are a) development of a panel of rats that produce CRE recombinase under the control of transcriptional promoters that are specific for subpopulations of neurons. b) developing methods to produce transgenic marmosets. Over the past year rapid progress in developing techniques to produce transgenic marmosets have been made in the core facility. The methods to produce an excess of embryos, to optimize surgical procedures to harvest those embryos most efficiently, to culture those embryos, develop transgenic lentivirus, infect embryos, transfer those embryos into recipient females using ultrasound visualization and develop tissue culture methods for primary marmoset cells have been developed. This extensive effort has set the stage for several projects for NIH researchers to use these transgenic animals in basic research in the intramural program. 3) Technical Support a) 98 transgenic rodent lines have been archived by cryopreserving germ cells or embryos. b) 68 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. 4) Collaborative projects: below is a list of projects that have been initiated in 2011, or have continued from last year. Stress: The role of a specific gene (catachol-O-methyltransferase) in the susceptibility to stress was demonstrated in mice that were engineered to have reduced levels of this gene. Neurogenesis: Transgenic mice and, more recently, transgenic rats have been generated to study the role of neurogenesis in adults. From mid-gestation and continuing into old age, new neurons are produced in the brain. The role of new cells appearing in adults is especially interesting, and suggests a function in learning and memory and potential treatments for neurodegenerative disease. Schizophrenia: Mice with behavioral characteristics that resemble schizophrenia were produced by mating effecter mice from the core facility with responder mice. The latter carried a conditional ablation of the NMDA receptor. The offspring of these matings were engineered to lack NMDA receptors in a subset of corticolimbic interneurons. They displayed behavioral deficits in normal mating, nest-building and anxiety-like behavior. Memory dysfunction was also revealed in these animals. Stress and neurogenesis: A recent paper using mice developed in the transgenic core has shown that neurogenesis is critical for maintaining a normal response to stress. This finding is significant because it conlusively identifies this role for neurogenesis in adult animals. Following other work that shows that stress reduces neurogenesis, this new finding implies a cycle in which stress can increase. 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 role 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. Drug addiction: 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. . Mucolipidosis IV: The mouse model of this disease resulted from a long-standing collaboration with the Slaugenhaupt laboratory and has continued to yield results, including a description of the neuropathy that may be associated with this disease. The core facility continues to distribute these animals. Familial dysautonomia: Another collaboration with the Slaugenhaupt lab resulted in a model for this disease. Lines carrying either a human normal or disease gene are being created in the core. These lines are crossed into a null line to replace the endogenous IKBKAP gene with its human disease equivalent. Glial activity reporters: The core produced a mouse line with a transgene that indicated the concentration of calcium in glial cells. By changes in its fluorescent properties, the calcium concentration and associated activity has been demonstrated in these cell. Reporter and effector mice and rats:

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Scientific Cores Intramural Research (ZIC)
Project #
1ZICMH002901-05
Application #
8342304
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2011
Total Cost
$1,990,267
Indirect Cost
Name
U.S. National Institute of Mental Health
Department
Type
DUNS #
City
State
Country
Zip Code
Sharpe, Melissa J; Marchant, Nathan J; Whitaker, Leslie R et al. (2017) Lateral Hypothalamic GABAergic Neurons Encode Reward Predictions that Are Relayed to the Ventral Tegmental Area to Regulate Learning. Curr Biol 27:2089-2100.e5
Richie, Christopher T; Whitaker, Leslie R; Whitaker, Keith W et al. (2017) Near-infrared fluorescent protein iRFP713 as a reporter protein for optogenetic vectors, a transgenic Cre-reporter rat, and other neuronal studies. J Neurosci Methods 284:1-14
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
Carr, Gregory V; Chen, Jingshan; Yang, Feng 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
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Kar, Amar N; Sun, Ching-Yu; Reichard, Kathryn et al. (2014) Dysregulation of the axonal trafficking of nuclear-encoded mitochondrial mRNA alters neuronal mitochondrial activity and mouse behavior. Dev Neurobiol 74:333-50
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

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