Recombinase-driver rat lines: tools, techniques, and optogenetic application to dopamine-mediated reinforcement

By Ilana Witten, Elizabeth E Steinberg, Soo Yeun Lee, T. J. Davidson, K. Zalocusky, M. Brodsky, Ofer Yizhar, Saemi L. Cho, Shiaoching Gong, Charu Ramakrishnan and 4 more. Neuron, 2011

663 citations recorded by the source corpus.

Summary 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 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 generalizability of optogenetics to traditionally non-genetically-tractable but vital animal models.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/56939f051c380e7478dcae46faf17083370bf0ae

Citations in the corpus

• Model-Based and Model-Free Pavlovian Reward Learning: Revaluation, Revision and Revelation (2014, neutral): “Animals readily learn to emit actions in order to activate dopamine neurons in the VTA and SNc (Nieh, Kim, Namburi, & Tye, 2013; Rossi, Sukharnikova, Hayrapetyan, Yang, & Yin, 2013; Witten et al., 2011).”
• Reward and aversion in a heterogeneous midbrain dopamine system (2013, neutral): “…VTA DA neurons do not respond to DA application (Bannon and Roth, 1983; Lammel et al., 2008) and (3) VTA DA neurons have been identified that have very small or no Ih (Ford et al., 2006; Hnasko et al., 2012; Jones and Kauer 1999; Lammel et al., 2008, 2011; Witten et al., 2011; Zhang et al., 2010).”
• Mesolimbic Dopamine Signals the Value of Work (2015, neutral): “Male rats (300-500g, either wild-type Long-Evans or TH-Cre + with a Long-Evans background 51 were maintained on a reverse 12:12 light:dark cycle and tested during the dark phase.”
• Synaptic and Behavioral Profile of Multiple Glutamatergic Inputs to the Nucleus Accumbens (2012, neutral): “Ventral tegmental area dopamine neurons innervate the NAc, and similar behaviors have been observed when these neurons are selectively stimulated (Witten et al., 2011).”
• Optical Control of Mammalian Endogenous Transcription and Epigenetic States (2013, neutral): “However, for transfection, equal ratios of AAV1 and AAV2 serotype plasmids were used instead of AAV1 alone.”
• Flexible near field wireless optoelectronics as subdermal implants for broad applications in optogenetics (2017, neutral): “To test for the reliable application of these devices in vivo, we targeted the mesolimbic dopaminergic (DA) pathway, a circuit known to facilitate reward and positive reinforcement (Tsai et al., 2009; Witten et al., 2011), by injecting AAV5-DIO-ChR2-eYFP or AAV5-hSynFLEX-ChrimsonR-tdTomato into the ”
• Neuronal Reward and Decision Signals: From Theories to Data. (2015, neutral): “The longer-than-natural activations induce more dopamine release in vitro (641) but may be compromised by the limited capacity of dopamine neurons for prolonged discharges due to pronounced tendency for depolarization block (54, 463).”