Monoamine neurotransmitters (dopamine, norepinephrine, and serotonin) play important roles in modulating the strength of both excitatory and inhibitory neurotransmission via activation of the corresponding receptors. Monoamine neurons project their axons throughout the brain and regulate diverse brain functions including arousal, stress, emotion, reward, learning, and cognition. On a cellular level, monoamines modulate responsiveness of the target cells and synapses. Aberrations in monoamine neurotransmission have been implicated in numerous neurological and neuropsychiatric disorders including Parkinson's disease, schizophrenia, ADHD, drug addiction, depression, and anxiety. However, due to methodological limitations, monoamine neurotransmission have only been studied on the bulk level of large ensembles of monoaminergic synapses. There have been no experimental tools to examine the monoamine release characteristics of individual presynaptic boutons, a fundamental physiological parameter. Drs. Dalibor Sames (PI-1) and David Sulzer (PI-2) established an interdisciplinary research program focused on addressing this challenge. Specifically, optical probes termed Fluorescent False Neurotransmitters (FFNs) were designed as tracers of dopamine. This new application aims to expand the scope of the FFN concept to the entire monoamine system, many different brain areas, and living rodents. We propose to develop FFN probes selective for norepinephrine and serotonin synapses, and in vivo microscopic imaging methods applicable in living rodents. The proposed new imaging methods will enable, for the first time, visualization of synaptic content release at individual presynaptic terminals of specific neurochemical types in vivo in several brain areas (striatum, somatosensory cortex, hippocampus). These new probes and associated imaging methods will unlock the possibility of addressing many long-standing questions about release properties of single synapses and their physiological regulation and deregulation in rodent disease models. The FFN probes are compatible with the existing calcium and voltage sensors and thus jointly these tools will provide a more complete readout of synaptic function and plasticity in intact circuitry.

Public Health Relevance

Monoamine neurotransmission plays key roles in many brain functions in both health (arousal, attention, stress, reward, emotion, learning, and cognition) and disease (depression, anxiety, drug addiction, Parkinson's disease). The new imaging agents proposed in this application will provide the first means to monitor function and malfunction of the three major monoamine systems (dopamine, norepinephrine, and serotonin) on the level of individual synapses in living mammalian brain. These novel tools will enable not only fundamental neuroscience but also the study of CNS drug effects on synaptic circuitry.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH108186-03
Application #
9233754
Study Section
Special Emphasis Panel (ZRG1-EBIT-J (09)F)
Program Officer
Nadler, Laurie S
Project Start
2015-05-18
Project End
2020-02-29
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
3
Fiscal Year
2017
Total Cost
$450,153
Indirect Cost
$165,375
Name
Columbia University (N.Y.)
Department
Chemistry
Type
Other Domestic Higher Education
DUNS #
049179401
City
New York
State
NY
Country
United States
Zip Code
10027
Lieberman, Ori J; McGuirt, Avery F; Tang, Guomei et al. (2018) Roles for neuronal and glial autophagy in synaptic pruning during development. Neurobiol Dis :
Henke, Adam; Kovalyova, Yekaterina; Dunn, Matthew et al. (2018) Toward Serotonin Fluorescent False Neurotransmitters: Development of Fluorescent Dual Serotonin and Vesicular Monoamine Transporter Substrates for Visualizing Serotonin Neurons. ACS Chem Neurosci 9:925-934
Clark, Samuel D; Mikofsky, Rachel; Lawson, Jacqueline et al. (2018) Piezo High Accuracy Surgical Osteal Removal (PHASOR): A Technique for Improved Cranial Window Surgery in Mice. J Vis Exp :
Dunn, Matthew; Henke, Adam; Clark, Samuel et al. (2018) Designing a norepinephrine optical tracer for imaging individual noradrenergic synapses and their activity in vivo. Nat Commun 9:2838
Bamford, Nigel S; Wightman, R Mark; Sulzer, David (2018) Dopamine's Effects on Corticostriatal Synapses during Reward-Based Behaviors. Neuron 97:494-510
Aguilar, Jenny I; Dunn, Matthew; Mingote, Susana et al. (2017) Neuronal Depolarization Drives Increased Dopamine Synaptic Vesicle Loading via VGLUT. Neuron 95:1074-1088.e7
Covey, Dan P; Mateo, Yolanda; Sulzer, David et al. (2017) Endocannabinoid modulation of dopamine neurotransmission. Neuropharmacology 124:52-61
Kempadoo, Kimberly A; Mosharov, Eugene V; Choi, Se Joon et al. (2016) Dopamine release from the locus coeruleus to the dorsal hippocampus promotes spatial learning and memory. Proc Natl Acad Sci U S A 113:14835-14840
Pereira, Daniela B; Schmitz, Yvonne; Mészáros, József et al. (2016) Fluorescent false neurotransmitter reveals functionally silent dopamine vesicle clusters in the striatum. Nat Neurosci 19:578-86
Freyberg, Zachary; Sonders, Mark S; Aguilar, Jenny I et al. (2016) Mechanisms of amphetamine action illuminated through optical monitoring of dopamine synaptic vesicles in Drosophila brain. Nat Commun 7:10652

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