I am interested in how cellular and synaptic properties of neurons affect emergent patterns of activity such as network oscillations, and how these patterns in turn affect the function of neural circuits. Although myriad properties of cells and synapses are known to be altered in neuropsychiatric diseases such as schizophrenia, it has been difficult to understand exactly how these alterations cause the circuit dysfunction thought to produce clinical symptoms. My goal is to be the principal investigator of a laboratory which (1) identifies cellular and synaptic lesions in animal models of psychiatric disease using in vitro electrophysiology, (2) uses in vitro and in silico experiments to measure circuit functions that are deficient as a result of these lesions, and (3) tests whether restoring these circuit functions can rescue pathological behaviors in vivo. To complement my knowledge of electrophysiology and computational neuroscience, I propose learning to use optogenetic stimulation in vitro and in vivo, and to study rodent behavioral phenotypes relevant to neuropsychiatric disease. I will be mentored by Karl Deisseroth, whose laboratory has pioneered optogenetic technology. Using optogenetic tools to precisely control patterns of stimulation in prefrontal microcircuits, and information theory to quantitatively measure information processing, we have already elucidated mechanisms by which brain rhythms enhance information processing in prefrontal microcircuits. Now, I propose to study the effects of dopamine and manipulations that model aspects of schizophrenia to answer the following questions: (1) Do Dl and D2 receptor stimulation have opposing effects on the signal-to-noise ratio in prefrontal microcircuits? (2) Does blocking NMDA receptors and/or disrupting DISCI suppress gamma-frequency synchronization or alter information processing in prefrontal microcircuits? (3) Can rhythmic optogenetic stimulation of prefrontal neurons ameliorate effects of PCP and DISCI disruption on working memory? We believe that these experiments will not only shed light on the workings of prefrontal microcircuits and possible modes of dysfunction in schizophrenia, but also establish powerful new ways to study circuit dysfunction in neuropsychiatric disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Transition Award (R00)
Project #
5R00MH085946-04
Application #
8306310
Study Section
Special Emphasis Panel (NSS)
Program Officer
Glanzman, Dennis L
Project Start
2009-07-06
Project End
2013-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
4
Fiscal Year
2012
Total Cost
$238,889
Indirect Cost
$62,609
Name
University of California San Francisco
Department
Psychiatry
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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Cho, Kathleen K A; Hoch, Renee; Lee, Anthony T et al. (2015) Gamma rhythms link prefrontal interneuron dysfunction with cognitive inflexibility in Dlx5/6(+/-) mice. Neuron 85:1332-43
Lee, Anthony T; Gee, Steven M; Vogt, Daniel et al. (2014) Pyramidal neurons in prefrontal cortex receive subtype-specific forms of excitation and inhibition. Neuron 81:61-8
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Gee, Steven; Ellwood, Ian; Patel, Tosha et al. (2012) Synaptic activity unmasks dopamine D2 receptor modulation of a specific class of layer V pyramidal neurons in prefrontal cortex. J Neurosci 32:4959-71
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Seybold, Bryan A; Stanco, Amelia; Cho, Kathleen K A et al. (2012) Chronic reduction in inhibition reduces receptive field size in mouse auditory cortex. Proc Natl Acad Sci U S A 109:13829-34