A major obstacle to understanding the neural mechanisms underlying behavior is our inability to distinguish between neuronal classes in recordings from behaving animals. Mouse transgenic lines, including CRE lines, have made it possible to use optogenetic techniques to selectively activate different classes to determine their role in behavior. However, it remains a challenge to determine the neuronal identity based on optogenetic stimulation, as the latency of response to direct stimulation can overlap with strong but indirect disynaptic excitation. The proposed research will introduce novel methods for distinguishing direct from indirect stimulation in order to label neuronal identity. It will furthe develop these methods for extracellular recordings made with linear array electrodes and using current source density (CSD) analysis to identify laminar location. These methods will be validated in CRE mice, and then applied to the marmoset (Callithrix jacchus). The marmoset is a particularly interesting primate model because it offers opportunities for dissecting neural circuitry that are comparable to the mouse. It matures quickly and breeds well in captivity, so it is amenable to the kinds of genetic manipulation used in mice and has produced the first primate transgenic lines. It also has a lissencephalic (flat) cortex which aids in laminar recordings. Preliminary data show marmosets can perform visual tasks under head-restraint, making them suitable to awake neurophysiology. Establishing these methods will create opportunities to study cortical circuits at a mechanistic level, enabling the field to understand how aberrations in the cortical circuitry give rise to devastating disorders such as schizophrenia and autism.

Public Health Relevance

Understanding the functional role of different neuronal classes in the cortical circuit is crucial for understanding the origins 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 use in the awake and behaving primate that will distinguish neuronal classes and the laminar location of neurons from extracellular recordings. The results from these studies will also establish the methods for a new model system, the behaving marmoset, a small bodied New World monkey that offers many opportunities to investigate the neural mechanisms of behavior using the kinds of genetic manipulation that have been successful in mice.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Exploratory/Developmental Grants (R21)
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Freund, Michelle
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Salk Institute for Biological Studies
La Jolla
United States
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Miller, Cory T; Freiwald, Winrich A; Leopold, David A et al. (2016) Marmosets: A Neuroscientific Model of Human Social Behavior. Neuron 90:219-33
MacDougall, Matthew; Nummela, Samuel U; Coop, Shanna et al. (2016) Optogenetic manipulation of neural circuits in awake marmosets. J Neurophysiol 116:1286-94
Mitchell, Jude F; Priebe, Nicholas J; Miller, Cory T (2015) Motion dependence of smooth pursuit eye movements in the marmoset. J Neurophysiol 113:3954-60
Mitchell, Jude F; Leopold, David A (2015) The marmoset monkey as a model for visual neuroscience. Neurosci Res 93:20-46
Izpisua Belmonte, Juan Carlos; Callaway, Edward M; Caddick, Sarah J et al. (2015) Brains, genes, and primates. Neuron 86:617-31
Chow, Cecilia P; Mitchell, Jude F; Miller, Cory T (2015) Vocal turn-taking in a non-human primate is learned during ontogeny. Proc Biol Sci 282:20150069