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 #
5P30NS069375-03
Application #
8427317
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
3
Fiscal Year
2013
Total Cost
$168,705
Indirect Cost
$61,839
Name
Stanford University
Department
Type
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Cheng, Yunfeng; Xie, Jinghang; Lee, Kyung-Hyun et al. (2018) Rapid and specific labeling of single live Mycobacterium tuberculosis with a dual-targeting fluorogenic probe. Sci Transl Med 10:
Joshi, Amit U; Saw, Nay L; Vogel, Hannes et al. (2018) Inhibition of Drp1/Fis1 interaction slows progression of amyotrophic lateral sclerosis. EMBO Mol Med 10:
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Joshi, Amit U; Saw, Nay L; Shamloo, Mehrdad et al. (2018) Drp1/Fis1 interaction mediates mitochondrial dysfunction, bioenergetic failure and cognitive decline in Alzheimer's disease. Oncotarget 9:6128-6143
Stamatakis, Alice M; Schachter, Mike J; Gulati, Srishti et al. (2018) Simultaneous Optogenetics and Cellular Resolution Calcium Imaging During Active Behavior Using a Miniaturized Microscope. Front Neurosci 12:496
Kramer, Nicholas J; Haney, Michael S; Morgens, David W et al. (2018) CRISPR-Cas9 screens in human cells and primary neurons identify modifiers of C9ORF72 dipeptide-repeat-protein toxicity. Nat Genet 50:603-612
Li, Shi-Bin; Nevárez, Natalie; Giardino, William J et al. (2018) Optical probing of orexin/hypocretin receptor antagonists. Sleep 41:
Liu, Qing; Van Bortle, Kevin; Zhang, Yue et al. (2018) Disruption of mesoderm formation during cardiac differentiation due to developmental exposure to 13-cis-retinoic acid. Sci Rep 8:12960
Razavi, Mehdi; Thakor, Avnesh S (2018) An oxygen plasma treated poly(dimethylsiloxane) bioscaffold coated with polydopamine for stem cell therapy. J Mater Sci Mater Med 29:54

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