Examining neural circuits crucially relies on the ability to activate or silence individual circuit components to subsequently assess their impact on other parts of the circuit and their influence on behavior. Recent refinements of viral tools for gene delivery have allowed optogenetic methods to target cells based on specific cell types, localization, and connectivity. The physiological dissection of targeted circuits has been extremely successful in the mouse brain, but remains of limited use in non-human primate brain. We plan to develop and test a new generation of viral tools that will allow us to both activate and suppress different cell types in non-human primate models. To accomplish our aims we have assembled an expert team with complementary expertise composed of a biochemist and photobiologist (John Spudich), a molecular neuroscientist (Roger Janz), and a systems and computational neuroscientist (Valentin Dragoi). Our approach builds upon recently discovered anion-conducting channelrhodopsins (ACRs), which perform with perfect anion selectivity, photosensitivity orders of magnitude greater than current optogenetic rhodopsins, and enable highly efficient neuron hyperpolarization. We believe that our ACR constructs will open a new chapter in targeted neuro-suppression. In addition, we will use new neuron-activating (depolarizing) cation-conducting channelrhodopsins (CCRs) that have ~3-fold greater unitary conductance, faster recovery from excitation, and higher sodium selectivity than the commonly used channelrhodopsin-2. We will construct viral vectors encoding ACR-CCR pairs and, using spectrally different ACRs, ACR-ACR pairs, enabling efficient wavelength-selected neuron activation or suppression in large populations. The effectiveness of these viral vectors will be tested in cultured and in situ mouse neurons and in the primary visual cortex (V1) of behaving monkeys. Developing these powerful tools will be invaluable for probing neural circuits in non-human primate models, finally allowing the interrogation of microcircuits underlying primate cognitive function.

Public Health Relevance

Understanding the mechanisms by which brain networks process and store information to influence behavior is of great interest for basic neuroscience as well as for the understanding of neurological and psychiatric diseases. This research project will develop new molecular tools that will allow scientists to examine the role of specific neuronal subpopulations for information processing in the brain of higher mammals.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01MH109146-03
Application #
9321918
Study Section
Special Emphasis Panel (ZMH1)
Program Officer
Freund, Michelle
Project Start
2015-09-21
Project End
2019-06-30
Budget Start
2017-07-01
Budget End
2019-06-30
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Neurosciences
Type
Schools of Medicine
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77030
Govorunova, Elena G; Sineshchekov, Oleg A; Rodarte, Elsa M et al. (2017) The Expanding Family of Natural Anion Channelrhodopsins Reveals Large Variations in Kinetics, Conductance, and Spectral Sensitivity. Sci Rep 7:43358
Govorunova, Elena G; Sineshchekov, Oleg A; Spudich, John L (2016) Structurally Distinct Cation Channelrhodopsins from Cryptophyte Algae. Biophys J 110:2302-2304
Govorunova, Elena G; Sineshchekov, Oleg A; Spudich, John L (2016) Proteomonas sulcata ACR1: A Fast Anion Channelrhodopsin. Photochem Photobiol 92:257-263