Our understanding of the neural mechanisms underlying action, perception and cognition has been limited by the lack of tools to modulate the activity of specific neural circuits in the awake, behaving animal. This technical hurdle has, in turn, limited our understanding of devastating disorders of the nervous system that result from dysfunction of neural circuits. The proposed research addresses this challenge by developing a new set of optogenetic techniques that will make it possible to selectively manipulate the activity of projection neurons with precise temporal control in the brain of the behaving non-human primate. We plan to inject viral vectors, specifically designed to be taken up by axon terminals, into the brain in order to get projection neurons to express the light-sensitive channels channelrhodopsin-2 and archaerhodopsin-3. We will then be able to selectively activate or inactivate projection neurons using light introduced into the brain with specially designed optitrodes. Our proposal focuses on projections from primary visual cortex (V1) to the superficial layers of the superior colliculus and V1 neurons projecting to the secondary visual area (V2), taking advantage of the well- defined retinotopic maps in these regions, and using physiological, behavioral, and histological methods to measure our ability to selectively manipulate the activity of projection neurons. The results of these studies are likely to have a large impact, because the tools and techniques developed in this research program will have wide applicability for those studying the relationships between functional neural networks in the CNS and primate behavior. They will also provide important tests of the feasibility of optical and virus-based methods as possible therapeutic approaches in CNS disorders.

Public Health Relevance

Understanding the functional role of particular neural connections is crucial for unraveling the etiology of neuropsychological disorders such as neglect, Balint's syndrome, visual agnosia, schizophrenia, ADHD and autism. The goal of this project is to establish new techniques for selectively manipulating the activity of projection neurons in the behaving non-human primate under precise temporal control using combinations of physiological, molecular, and genetic methods. The results from our studies will demonstrate powerful new tools for studying the functional relationships between neural networks and primate behavior, and provide important tests of the feasibility of optical and virus-based methods as possible therapeutic approaches in CNS disorders.

National Institute of Health (NIH)
National Eye Institute (NEI)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1-IFCN-E (04))
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Steinmetz, Michael A
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Salk Institute for Biological Studies
La Jolla
United States
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Nassi, Jonathan J; Avery, Michael C; Cetin, Ali H et al. (2015) Optogenetic Activation of Normalization in Alert Macaque Visual Cortex. Neuron 86:1504-17
Cetin, Ali; Callaway, Edward M (2014) Optical control of retrogradely infected neurons using drug-regulated ""TLoop"" lentiviral vectors. J Neurophysiol 111:2150-9
Ruiz, Octavio; Lustig, Brian R; Nassi, Jonathan J et al. (2013) Optogenetics through windows on the brain in the nonhuman primate. J Neurophysiol 110:1455-67
Nielsen, Kristina J; Callaway, Edward M; Krauzlis, Richard J (2012) Viral vector-based reversible neuronal inactivation and behavioral manipulation in the macaque monkey. Front Syst Neurosci 6:48