Neurons of the mammalian brain, including the human brain, receive inputs from many different classes of other neurons. The integrative response to these various inputs determines the time course of action potential firing in the cell, its internal biochemical state, and the induction of plasticity. Thus integration of signals from multiple neurons determines both information transfer between cells and the long-term plasticity of circuits. Nevertheless, how signals arriving at multiple classes of synapses interact to determine neural responses is unclear. We propose to address this question using optical approaches to manipulate synaptic activity while reading out biochemical and electrical signals in the recipient cell. These results will inform the basic mechanisms of information processing in the brain. In addition, since specific classes of synapses are perturbed in human disease or are targeted for treatment of disease, these studies will allow us to understand the integrative mechanism of disease and its therapy.

Public Health Relevance

Brain cells communicate via the release of neurotransmitters such as glutamate, GABA and dopamine that modulate the electrical and biochemical state of each cell. Each neurotransmitter has typically been studied in isolation even though the response of the cell depends on interactions between many signaling molecules. We will use novel tools to understand the process of integration of signals from multiple neurotransmitters and mechanisms by which neural function is controlled.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS046579-10
Application #
8639849
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Stewart, Randall R
Project Start
2003-07-01
Project End
2017-07-31
Budget Start
2013-09-01
Budget End
2014-07-31
Support Year
10
Fiscal Year
2013
Total Cost
$454,304
Indirect Cost
$185,263
Name
Harvard University
Department
Biology
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Khibnik, Lena A; Tritsch, Nicolas X; Sabatini, Bernardo L (2014) A direct projection from mouse primary visual cortex to dorsomedial striatum. PLoS One 9:e104501
Chen, Yao; Saulnier, Jessica L; Yellen, Gary et al. (2014) A PKA activity sensor for quantitative analysis of endogenous GPCR signaling via 2-photon FRET-FLIM imaging. Front Pharmacol 5:56
Tritsch, Nicolas X; Oh, Won-Jong; Gu, Chenghua et al. (2014) Midbrain dopamine neurons sustain inhibitory transmission using plasma membrane uptake of GABA, not synthesis. Elife 3:e01936
Murphy, Jessica A; Stein, Ivar S; Lau, C Geoffrey et al. (2014) Phosphorylation of Ser1166 on GluN2B by PKA is critical to synaptic NMDA receptor function and Ca2+ signaling in spines. J Neurosci 34:869-79
Straub, Christoph; Tritsch, Nicolas X; Hagan, Nellwyn A et al. (2014) Multiphasic modulation of cholinergic interneurons by nigrostriatal afferents. J Neurosci 34:8557-69
Pisanello, Ferruccio; Sileo, Leonardo; Oldenburg, Ian A et al. (2014) Multipoint-emitting optical fibers for spatially addressable in vivo optogenetics. Neuron 82:1245-54
Beier, Kevin T; Saunders, Arpiar B; Oldenburg, Ian A et al. (2013) Vesicular stomatitis virus with the rabies virus glycoprotein directs retrograde transsynaptic transport among neurons in vivo. Front Neural Circuits 7:11
Olson, Jeremy P; Kwon, Hyung-Bae; Takasaki, Kevin T et al. (2013) Optically selective two-photon uncaging of glutamate at 900 nm. J Am Chem Soc 135:5954-7
Ding, Jun B; Oh, Won-Jong; Sabatini, Bernardo L et al. (2012) Semaphorin 3E-Plexin-D1 signaling controls pathway-specific synapse formation in the striatum. Nat Neurosci 15:215-23
Liu, Tiemin; Kong, Dong; Shah, Bhavik P et al. (2012) Fasting activation of AgRP neurons requires NMDA receptors and involves spinogenesis and increased excitatory tone. Neuron 73:511-22

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