Gene Vector and Virus Core (GWC) Over the last decade, the use of viral vectors has emerged as a powerful approach to express proteins for manipulating and dissecting neuronal function. For example it is possible, using a single virus particle, to reduce expression of specific proteins by expressing short hairpin RNAs (shRNAs) and to replace them with shRNA-resistant versions or other proteins in specific cells. It is also possible to use viruses to express proteins that enable precise, light-activated control over the electrical activity of individual nerve cells (e.g., channel rhodopsins). These virally-mediated molecular manipulators allow unprecedented experimental control over synapses, cells, and circuits in model systems, as well as in vivo in the mammalian brain. These two powerful complementary approaches are applicable to virtually all topics encompassed by modern neuroscience research ranging from the study of the detailed molecular mechanisms underlying brain development to the neural circuit mechanisms that underlie sensory perception and complex behaviors. They can also be applied to studies aimed at elucidating the pathophysiological processes underlying all brain disorders including neurodevelopmental disorders such as autism, neurodegenerative disorders such as Alzheimer's or Parkinson's disease, and psychiatric disorders such as depression and schizophrenia. To cite just a few examples, viral vectors have been used to examine the molecular mechanisms underlying addiction and depression (2-4);to study the role of specific proteins in synaptic plasticity and learning and memory(5-7);to explore the molecular regulation of growth cone dynamics (8);and to examine the mechanisms of experiencedependent plasticity of primary sensory cortex (9). The most exciting recent advance that takes advantage of viral vectors is the development of "optogenetics" by Karl Deisseroth, a member of SINTN (10). This new technology involves the expression via viral vectors of proteins that, when activated by light, can increase or decrease individual neuronal activity in a temporally and spatially precise manner. Viral vectors expressing light-activated proteins have been used by Stanford researchers to probe the role of hypocretin-expressing neurons in the hypothalamus in sleep-awake transitions (11) to delineate the neural circuit mechanisms that underlie the therapeutic efficacy of deep brain stimulation in Parkinson's disease (12), and to map the spatial distribution of synaptic inputs to cells in defined layers of primary sensory cortex (13) . Most recently, it has allowed expression of light-activated G-protein coupled receptors in the nucleus accumbens to explore how temporally precise control of intracellular signaling influences spike firing and behavior (14). These powerful optogenetic tools depend on the use of viral vectors and are applicable to a wide range of invertebrate and mammalian species.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Center Core Grants (P30)
Project #
5P30NS069375-04
Application #
8586488
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
4
Fiscal Year
2014
Total Cost
$157,844
Indirect Cost
$57,943
Name
Stanford University
Department
Type
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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Ebert, Antje D; Kodo, Kazuki; Liang, Ping et al. (2014) Characterization of the molecular mechanisms underlying increased ischemic damage in the aldehyde dehydrogenase 2 genetic polymorphism using a human induced pluripotent stem cell model system. Sci Transl Med 6:255ra130
He, Yingbo; Zhang, Hui; Yung, Andrea et al. (2014) ALK5-dependent TGF-? signaling is a major determinant of late-stage adult neurogenesis. Nat Neurosci 17:943-52
Fenno, Lief E; Mattis, Joanna; Ramakrishnan, Charu et al. (2014) Targeting cells with single vectors using multiple-feature Boolean logic. Nat Methods 11:763-72

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