Recombinase-driver rat lines: tools, techniques, and optogenetic application to dopamine-mediated reinforcement
Open accessAbstract
Currently there is no general approach for achieving specific optogenetic control of genetically defined cell types in rats, which provide a powerful experimental system for numerous established neurophysiological and behavioral paradigms. To overcome this challenge we have generated genetically restricted recombinase-driver rat lines suitable for driving gene expression in specific cell types, expressing Cre recombinase under the control of large genomic regulatory regions (200-300 kb). Multiple tyrosine hydroxylase (Th)::Cre and choline acetyltransferase (Chat)::Cre lines were produced that exhibited specific opsin expression in targeted cell types. We additionally developed methods for utilizing optogenetic tools in freely moving rats and leveraged these technologies to clarify the causal relationship between dopamine (DA) neuron firing and positive reinforcement, observing that optical stimulation of DA neurons in the ventral tegmental area (VTA) of Th::Cre rats is sufficient to support vigorous intracranial self-stimulation (ICSS). These studies complement existing targeting approaches by extending the generalizability of optogenetics to traditionally non-genetically-tractable but vital animal models.
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VTA DA neurons are thought to play a causal role in social reward.
“However, since optogenetic activation of VTA DA neurons increases social interaction (Gunaydin et al., 2014) and supports positive reinforcement (Tsai et al., 2009, Witten et al., 2011), they are thought to play a causal role in social reward.”
From Dorsal raphe dopamine neurons represent the experience of social isolation (2016) · cites this paper as Witten et al., 2011
DRN and VTA DA neurons may be functionally distinct.
“Amid the sparse existing knowledge of the functional role of DRN DA neurons, optical stimulation of these neurons does not support intra-cranial self-stimulation (ICSS) (McDevitt et al., 2014), in contrast to the VTA (Witten et al., 2011), suggesting that DRN and VTA DA neurons may be functionally distinct.”
From Dorsal raphe dopamine neurons represent the experience of social isolation (2016) · cites this paper as Witten et al., 2011
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- Authors
- Witten, I. B., Steinberg, E. E., Lee, S. Y., Davidson, T. J., Zalocusky, K. A., Brodsky, M., Yizhar, O., Cho, S. L., Gong, S., Ramakrishnan, C., Stuber, G. D., Tye, K. M., Janak, P. H., & Deisseroth, K.
- Affiliations
- Princeton University (US)
- University of California, San Francisco (US)
- Stanford University (US)
- University of Washington (US)
- Weizmann Institute of Science (IL)
- Rockefeller University (US)
- University of North Carolina at Chapel Hill (US)
- Massachusetts Institute of Technology (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Witten, Ilana B.
- Janak, Patricia H.
- Deisseroth, Karl
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2011-12
- Volume
- 72
- Issue
- 5
- Pages
- 721-733
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC3282061
- OpenAlex
- W2069441590
- Cited by
- 680
- References
- 63
- Citations by year
- 2026: 20 · 2025: 32 · 2024: 27 · 2023: 34 · 2022: 34 · 2021: 40 · 2020: 55 · 2019: 72 · 2018: 53 · 2017: 61 · 2016: 55 · 2015: 53 · 2014: 59 · 2013: 51 · 2012: 32
- FWCI
- 18.95
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 594 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- National Science Foundation
- Howard Hughes Medical Institute
- McKnight Foundation
- National Institutes of Health (DP1OD000616)
- Defense Advanced Research Projects Agency
- University of California, San Francisco
- National Institute on Alcohol Abuse and Alcoholism (P50AA017072)
- National Institute of Mental Health (F32 MH880102, R01MH075957)
- National Institute on Drug Abuse (R01DA020794, DP2DA035149, R01DA015096)
- National Institute of Diabetes and Digestive and Kidney Diseases (DP2DK102256)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Photoreceptor and optogenetics research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- Cre recombinase, tyrosine hydroxylase, choline acetyltransferase, optogenetics, dopaminergic neurons, ventral tegmental area, intracranial self-stimulation, positive reinforcement, freely moving rats
- MeSH terms
- Action Potentials, Animals, Choline O-Acetyltransferase, Conditioning, Operant, Dopamine, Gene Expression Regulation, Male, Neurons, Reinforcement, Psychology, Reinforcement Schedule, Self Stimulation, Transduction, Genetic, Tyrosine 3-Monooxygenase, Ventral Tegmental Area, Integrases, Rats, Optics and Photonics, Opsins, Rats, Transgenic, In Vitro Techniques
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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