Cell-based reporters reveal in vivo dynamics of dopamine and norepinephrine release in murine cortex
Open accessAbstract
The neuronal coding of stimulus-to-action sequences is believed to involve the release of dopamine (DA) and norepinephrine (NE). The electrochemical similarity of these monoamines, however, confounds real-time measurements of their release. Here we report cell-based neurotransmitter fluorescent engineered reporters (CNiFERs) that use the specificity of G protein-coupled receptors (GPCRs) to discriminate nanomolar concentrations of DA and NE. CNiFERs were implanted into the frontal cortex of mice to measure the timing of neurotransmitter release during classical conditioning with the use of two-photon microscopy. The onset of DA release correlated with that of licking and shifted from the time of the reward toward that of the cue upon conditioning. In contrast, concurrent release of NE did not correlate with licking or the cue. This generation of CNiFERs provides unique tools to assess the release of monoamines. The molecular design of these CNiFERs may be generalized to realize CNiFERs for any molecule that activates a GPCR.
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Catecholamine secretion can be monitored in a real-time manner using specific probes.
“Catecholamine secretion can be monitored in a real-time manner using specific probes (Muller et al., 2014; Wang et al., 2018).”
From Intestinal microbiota modulates adrenomedullary response through Nod1 sensing in chromaffin cells (2021) · cites this paper as Muller et al., 2014
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A neural substrate of prediction and reward
Schultz, W., Dayan, P., & Montague, P. R. (1997) · Science · doi:10.1126/science.275.5306.1593 · Cited by 9,388 · see citing works
A framework for mesencephalic dopamine systems based on predictive Hebbian learning
Montague, P., Dayan, P., & Sejnowski, T. (1996) · The Journal of Neuroscience · doi:10.1523/jneurosci.16-05-01936.1996 · Cited by 2,066 · see citing works
Optical Deconstruction of Parkinsonian Neural Circuitry
Gradinaru, V., Mogri, M., Thompson, K. R., Henderson, J. M., & Deisseroth, K. A. (2009) · Science · doi:10.1126/science.1167093 · Cited by 1,536 · see citing works
Schultz, W., Apicella, P., & Ljungberg, T. (1993) · The Journal of Neuroscience · doi:10.1523/jneurosci.13-03-00900.1993 · Cited by 1,291 · see citing works
Phasic Firing in Dopaminergic Neurons Is Sufficient for Behavioral Conditioning
Tsai, H.-C., Zhang, F., Adamantidis, A., Stuber, G. D., Bonci, A., de Lecea, L., & Deisseroth, K. (2009) · Science · doi:10.1126/science.1168878 · Cited by 1,266 · see citing works
An optimized fluorescent probe for visualizing glutamate neurotransmission
Marvin, J. S., Borghuis, B. G., Tian, L., Cichon, J., Harnett, M. T., Akerboom, J., Gordus, A. G., Renninger, S. L., Chen, T., Bargmann, C. I., et al. (2013) · Nature Methods · doi:10.1038/nmeth.2333 · Cited by 1,006 · see citing works
In vivo dendritic calcium dynamics in neocortical pyramidal neurons
Svoboda, K., Denk, W. T., Kleinfeld, D., & Tank, D. W. (1997) · Nature · doi:10.1038/385161a0 · Cited by 820 · see citing works
Self-citationNetwork reset: a simplified overarching theory of locus coeruleus noradrenaline function
Bouret, S., & Sara, S. J. (2005) · Trends in Neurosciences · doi:10.1016/j.tins.2005.09.002 · Cited by 806 · see citing works
Substitution of three amino acids switches receptor specificity of Gqα to that of Giα
Conklin, B. R., Farfel, Z., Lustig, K. D., Julius, D. J., & Bourne, H. R. (1993) · Nature · doi:10.1038/363274a0 · Cited by 723 · see citing works
Associative learning mediates dynamic shifts in dopamine signaling in the nucleus accumbens
Day, J. J., Roitman, M. F., Wightman, R. M., & Carelli, R. M. (2007) · Nature Neuroscience · doi:10.1038/nn1923 · Cited by 710 · see citing works
Updating dopamine reward signals
Schultz, W. (2013) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2012.11.012 · Cited by 651 · see citing works
Adaptive gain and the role of the locus coeruleus–norepinephrine system in optimal performance
Aston‐Jones, G., & Cohen, J. D. (2005) · The Journal of Comparative Neurology · doi:10.1002/cne.20723 · Cited by 630 · see citing works
Detecting Subsecond Dopamine Release with Fast-Scan Cyclic Voltammetry in Vivo
Robinson, D. L., Venton, B. J., Heien, M. L., & Wightman, R. M. (2003) · Clinical Chemistry · doi:10.1373/49.10.1763 · Cited by 602 · see citing works
Turning of nerve growth cones induced by neurotransmitters
Zheng, J. Q., Felder, M., Connor, J. A., & Poo, M.-M. (1994) · Nature · doi:10.1038/368140a0 · Cited by 580 · see citing works
Cortical remodelling induced by activity of ventral tegmental dopamine neurons
Bao, S., Chan, V. T., & Merzenich, M. M. (2001) · Nature · doi:10.1038/35083586 · Cited by 569 · see citing works
A FlAsH-based FRET approach to determine G protein–coupled receptor activation in living cells
Hoffmann, C., Gaietta, G. M., Bünemann, M., Adams, S., Oberdorf‐Maass, S. U., Behr, B., Vilardaga, J., Tsien, R. Y., Ellisman, M. H., & Lohse, M. J. (2005) · Nature Methods · doi:10.1038/nmeth742 · Cited by 481 · see citing works
A genetically encoded calcium indicator for chronic in vivo two-photon imaging
Mank, M., Santos, A. F., Direnberger, S., Mrsic-Flogel, T. D., Hofer, S. B., Stein, V., Hendel, T., Reiff, D. F., Levelt, C., Borst, A., et al. (2008) · Nature Methods · doi:10.1038/nmeth.1243 · Cited by 475 · see citing works
Hoover, J. E., & Strick, P. L. (1999) · Journal of Neuroscience · doi:10.1523/jneurosci.19-04-01446.1999 · Cited by 469 · see citing works
In Vivo Multiphoton Microscopy of Deep Brain Tissue
Levene, M. J., Dombeck, D. A., Kasischke, K. A., Molloy, R. P., & Webb, W. W. (2004) · Journal of Neurophysiology · doi:10.1152/jn.01007.2003 · Cited by 457 · see citing works
Basal-ganglia 'Projections' to the Prefrontal Cortex of the Primate
Middleton, F. A. (2002) · Cerebral Cortex · doi:10.1093/cercor/12.9.926 · Cited by 451 · see citing works
Pan, W.-X., Schmidt, R., Wickens, J. R., & Hyland, B. I. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.1478-05.2005 · Cited by 429 · see citing works
Chronic optical access through a polished and reinforced thinned skull
Drew, P. J., Shih, A. Y., Driscoll, J. D., Knutsen, P. M., Blinder, P., Davalos, D., Akassoglou, K., Tsai, P. S., & Kleinfeld, D. (2010) · Nature Methods · doi:10.1038/nmeth.1530 · Cited by 406 · see citing works
Self-citationIn Vivo Mammalian Brain Imaging Using One- and Two-Photon Fluorescence Microendoscopy
Jung, J. C., Mehta, A. D., Aksay, E. R. F., Stepnoski, R. A., & Schnitzer, M. J. (2004) · Journal of Neurophysiology · doi:10.1152/jn.00234.2004 · Cited by 382 · see citing works
Chronic microsensors for longitudinal, subsecond dopamine detection in behaving animals
Clark, J. J., Sandberg, S. G., Wanat, M. J., Gan, J. O., Horne, E. A., Hart, A. S., Akers, C. A., Parker, J. G., Willuhn, I., Martinez, V., et al. (2010) · Nature Methods · doi:10.1038/nmeth.1412 · Cited by 378 · see citing works
Loughlin, S. E., Foote, S. L., & Bloom, F. E. (1986) · Neuroscience · doi:10.1016/0306-4522(86)90155-7 · Cited by 364 · see citing works
Adamantidis, A. R., Tsai, H.-C., Boutrel, B., Zhang, F., Stuber, G. D., Budygin, E. A., Tourino, C., Bonci, A., Deisseroth, K., & de Lecea, L. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.2246-11.2011 · Cited by 357 · see citing works
Dopaminergic Projections from Midbrain to Primary Motor Cortex Mediate Motor Skill Learning
Hosp, J. A., Pekanovic, A., Rioult-Pedotti, M. S., & Luft, A. R. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.5411-10.2011 · Cited by 354 · see citing works
Romo, R., & Schultz, W. (1990) · Journal of Neurophysiology · doi:10.1152/jn.1990.63.3.592 · Cited by 353 · see citing works
Floresco, S. B. (2013) · Frontiers in Neuroscience · doi:10.3389/fnins.2013.00062 · Cited by 336 · see citing works
Making Waves: Initiation and Propagation of Corticothalamic Ca2+ Waves In Vivo
Stroh, A., Adelsberger, H., Groh, A., Rühlmann, C., Fischer, S., Schierloh, A., Deisseroth, K. A., & Konnerth, A. (2013) · Neuron · doi:10.1016/j.neuron.2013.01.031 · Cited by 249 · see citing works
Simultaneous BOLD fMRI and fiber-optic calcium recording in rat neocortex
Schulz, K., Sydekum, E., Krueppel, R., Engelbrecht, C. J., Schlegel, F., Schroeter, A., Rudin, M., & Helmchen, F. (2012) · Nature Methods · doi:10.1038/nmeth.2013 · Cited by 233 · see citing works
Mesencephalic dopaminergic unit activity in the behaviorally conditioned rat
Miller, J. D., Sanghera, M. K., & German, D. C. (1981) · Life Sciences · doi:10.1016/0024-3205(81)90231-9 · Cited by 170 · see citing works
Substantia nigra and ventral tegmental area projections to cortex: Topography and collateralization
Loughlin, S. E., & Fallon, J. H. (1984) · Neuroscience · doi:10.1016/0306-4522(84)90034-4 · Cited by 163 · see citing works
Imaging extrasynaptic glutamate dynamics in the brain
Okubo, Y., Sekiya, H., Namiki, S., Sakamoto, H., Iinuma, S., Yamasaki, M., Watanabe, M., Hirose, K., & Iino, M. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0913154107 · Cited by 153 · see citing works
Park, J., Takmakov, P. A., & Wightman, R. M. (2011) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2011.07494.x · Cited by 151 · see citing works
Ihalainen, J. A., Riekkinen Jr, P., & Feenstra, M. G. P. (1999) · Neuroscience Letters · doi:10.1016/s0304-3940(99)00840-x · Cited by 148 · see citing works
An in vivo biosensor for neurotransmitter release and in situ receptor activity
Nguyen, Q.-T., Schroeder, L. F., Mank, M., Muller, A., Taylor, P., Griesbeck, O., & Kleinfeld, D. (2009) · Nature Neuroscience · doi:10.1038/nn.2469 · Cited by 124 · see citing works
Self-citationFeenstra, M. G. P. (2000) · Progress in brain research · doi:10.1016/s0079-6123(00)26012-3 · Cited by 103 · see citing works
Kinetics of M1 muscarinic receptor and G protein signaling to phospholipase C in living cells
Falkenburger, B. H., Jensen, J. B., & Hille, B. (2010) · The Journal of General Physiology · doi:10.1085/jgp.200910344 · Cited by 101 · see citing works
Behavioral associations of neuronal activity in the ventral tegmental area of the rat
Kosobud, A., Harris, G. C. M., & Chapin, J. K. (1994) · Journal of Neuroscience · doi:10.1523/jneurosci.14-11-07117.1994 · Cited by 98 · see citing works
Edeline, J., Manunta, Y., & Hennevin, E. (2010) · Hearing Research · doi:10.1016/j.heares.2010.08.005 · Cited by 96 · see citing works
Ji, C., Li, W., Ren, X.-D., et al. (2008) · Analytical Chemistry · doi:10.1021/ac801339z · Cited by 91 · see citing works
Relation of Locus Coeruleus Neurons in Monkeys to Pavlovian and Operant Behaviors
Bouret, S., & Richmond, B. J. (2008) · Journal of Neurophysiology · doi:10.1152/jn.91048.2008 · Cited by 78 · see citing works
The projection of the locus coeruleus upon the neocortex in the macaque monkey
Gatter, K. C., & Powell, T. P. S. (1977) · Neuroscience · doi:10.1016/0306-4522(77)90009-4 · Cited by 78 · see citing works
Mingote, S., de Bruin, J. P. C., & Feenstra, M. G. P. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.4547-03.2004 · Cited by 76 · see citing works
Microdialysate analysis of monoamine neurotransmitters—A versatile and sensitive LC–MS/MS method
Greco, S., Danysz, W., Živković, A., et al. (2013) · Analytica Chimica Acta · doi:10.1016/j.aca.2013.02.004 · Cited by 74 · see citing works
Engleman, E. A., Ingraham, C. M., McBride, W. J., Lumeng, L., & Murphy, J. M. (2006) · Alcohol · doi:10.1016/j.alcohol.2006.03.001 · Cited by 50 · see citing works
Application of in Vivo Microdialysis to the Study of Cholinergic Systems
Day, J. C., Kornecook, T. J., & Quirion, R. (2001) · Methods · doi:10.1006/meth.2000.1103 · Cited by 47 · see citing works
Rapid Dopamine Release in Freely Moving Rats
Robinson, D. L., & Wightman, R. M. (2006) · Frontiers in neuroengineering series/Frontiers in neuroengineering · doi:10.1201/9781420005868.ch2 · Cited by 44 · see citing works
Characterizing Ligand-Gated Ion Channel Receptors with Genetically Encoded Ca++ Sensors
Yamauchi, J. G., Nemecz, Á., Nguyen, Q. T., Muller, A., Schroeder, L. F., Talley, T. T., Lindstrom, J. M., Kleinfeld, D., & Taylor, P. (2011) · PLoS ONE · doi:10.1371/journal.pone.0016519 · Cited by 37 · see citing works
Self-citationActivation of Nucleus Basalis Facilitates Cortical Control of a Brain Stem Motor Program
Berg, R. W., Friedman, B., Schroeder, L. F., & Kleinfeld, D. (2005) · Journal of Neurophysiology · doi:10.1152/jn.01125.2004 · Cited by 36 · see citing works
Self-citationMicrodialysis probes alter presynaptic regulation of dopamine terminals in rat striatum
Wang, Y., & Michael, A. (2012) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2012.04.009 · Cited by 25 · see citing works
Nguyen, Q.-T., Dolnick, E., Driscoll, J. D., & Kleinfeld, D. (2009) · Frontiers in neuroscience · doi:10.1201/9781420076851.ch4 · Cited by 13 · see citing works
Self-citation
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- [52]Nguyen Q-T Dolnick EM Driscoll J Kleinfeld D Frostig RD Methods for In Vivo Optical Imaging 2 117 142 CRC Press 2009
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Reimer, J., McGinley, M. J., Liu, Y., Rodenkirch, C., Wang, Q., McCormick, D. A., & Tolias, A. S. (2016) · Nature Communications · doi:10.1038/ncomms13289 · Cited by 926 · see citing works
A genetically encoded fluorescent sensor for rapid and specific in vivo detection of norepinephrine
Feng, J., Zhang, C., Lischinsky, J. E., Jing, M., Zhou, J., Wang, H., Zhang, Y., Dong, A., Wu, Z., Wu, H., et al. (2019) · Neuron · doi:10.1016/j.neuron.2019.02.037 · Cited by 545 · see citing works
Striatal dopamine neurotransmission: Regulation of release and uptake
Sulzer, D., Cragg, S. J., & Rice, M. E. (2016) · Basal Ganglia · doi:10.1016/j.baga.2016.02.001 · Cited by 382 · see citing works
Imaging neurotransmitter and neuromodulator dynamics in vivo with genetically encoded indicators
Sabatini, B. L., & Tian, L. (2020) · Neuron · doi:10.1016/j.neuron.2020.09.036 · Cited by 203 · see citing works
Wang, H., Jing, M., & Li, Y. (2018) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2018.03.010 · Cited by 109 · see citing works
Imaging neuromodulators with high spatiotemporal resolution using genetically encoded indicators
Patriarchi, T., Cho, J. R., Merten, K., Marley, A., Broussard, G. J., Liang, R., Williams, J., Nimmerjahn, A., von Zastrow, M., Gradinaru, V., et al. (2019) · Nature Protocols · doi:10.1038/s41596-019-0239-2 · Cited by 66 · see citing works
Intestinal microbiota modulates adrenomedullary response through Nod1 sensing in chromaffin cells
Xiang, C., Chen, P., Zhang, Q., Li, Y., Pan, Y., Xie, W., Sun, J., & Liu, Z. (2021) · iScience · doi:10.1016/j.isci.2021.102849 · Cited by 15 · see citing works
- Authors
- Muller, A., Joseph, V., Slesinger, P. A., & Kleinfeld, D.
- Affiliations
- University of California San Diego (US)
- Corresponding author
- Slesinger, Paul A
- Kleinfeld, David
- Venue
- Nature Methods
- Published
- 2014-10-26
- Volume
- 11
- Issue
- 12
- Pages
- 1245-1252
- ISSN
- 1548-7091 (ISSN-L)
- 1548-7105
- PMC
- PMC4245316
- OpenAlex
- W2123300469
- Cited by
- 139
- References
- 53
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 12 · 2023: 14 · 2022: 13 · 2021: 17 · 2020: 17 · 2019: 12 · 2018: 18 · 2017: 6 · 2016: 11 · 2015: 4 · 2014: 1
- FWCI
- 4.36
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Methods (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (DP1OD006831)
- University of California, San Diego
- National Institute on Drug Abuse (DA007315, R01DA029706, DA029706)
- National Institute of Neurological Disorders and Stroke (DP1NS082097)
- National Institute of Biomedical Imaging and Bioengineering (R01EB003832, EB/003832)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biophysics › Advanced Fluorescence Microscopy Techniques
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- dopamine release, noradrenaline release, G protein-coupled receptors, frontal cortex, classical conditioning, monoamine release, two-photon microscopy, in vivo imaging
- MeSH terms
- Animals, Behavior, Animal, Cerebral Cortex, Dopamine, Fluorescent Dyes, Learning, Synaptic Transmission, Norepinephrine, Fluorescence Resonance Energy Transfer, Receptors, G-Protein-Coupled, Mice
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