Abstract
Neostriatal cholinergic interneurons are believed to be important for reinforcement-mediated learning and response selection by signaling the occurrence and motivational value of behaviorally relevant stimuli through precisely timed multiphasic population responses. An important problem is to understand how these signals regulate the functioning of the neostriatum. Here we describe the synaptic organization of a previously unknown circuit that involves direct nicotinic excitation of several classes of GABAergic interneurons, including neuroptide Y–expressing neurogilaform neurons, and enables cholinergic interneurons to exert rapid inhibitory control of the activity of projection neurons. We also found that, in vivo, the dominant effect of an optogenetically reproduced pause-excitation population response of cholinergic interneurons was powerful and rapid inhibition of the firing of projection neurons that is coincident with synchronous cholinergic activation. These results reveal a previously unknown circuit mechanism that transmits reinforcement-related information of ChAT interneurons in the mouse neostriatal network.
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Acknowledgements
We thank J. Berlin for confocal microscopy, L. Zaborszky for providing ChAT-EGFP mice, R. Yanez-Munoz for providing integration deficient pCMV-dR8.74-D64V plasmid DNA and for advice regarding virus production, N. Altan-Bonnet, W. Friedman and Haesun Kim for generously providing access to an ultracentrifuge facility and other equipment in their laboratories, C.T. Unal and A. Kreitzer for valuable discussion, A. Berenyi, S. Fujisawa and M. Vandecasteele for advice regarding in vivo recording methods, H. Xenias for help with confocal imaging, F. Shah for help with immunocytochemical procedures and other technical assistance, and I. Tadros for virus injections. The research was supported by US National Institutes of Health grant NS072950 and a Busch Biomedical Research Grant of Rutgers University to T.K., US National Institutes of Health grant NS034865 to J.M.T. and Rutgers University funds.
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D.F.E. carried out all of the in vivo recording experiments and data analysis, performed the majority of the in vitro experiments, and contributed to virus production, virus injections and confocal imaging (with the exception of Fig. 1a, which was produced by J. Berlin). O.I.-S. and F.T. performed the initial in vitro analysis of NPY-NGF neurons and O.I.-S. identified nicotinic synapses in these interneurons. E.S. contributed to the design of in vivo recording, optical stimulation methods and data analysis, molecular biology, and virus production. G.B. contributed to optrode design and the design and analysis of in vivo recording experiments. K.D. designed and provided constructs for optogenetic expression vectors, designed and produced the AAV5-DIO-eNpHR3.0-YFP and the AAV5-DIO-ChR2-mCherry virus vectors, and contributed to optogenetic methods. J.M.T. contributed to the development of in vitro and in vivo recording methods. T.K. performed in vitro recordings, recombinant DNA procedures and lentivirus production. The study was designed by T.K., J.M.T. and D.F.E. and the manuscript was written by T.K. with substantial contributions from D.F.E. and J.M.T. and input from all of the authors.
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English, D., Ibanez-Sandoval, O., Stark, E. et al. GABAergic circuits mediate the reinforcement-related signals of striatal cholinergic interneurons. Nat Neurosci 15, 123–130 (2012). https://doi.org/10.1038/nn.2984
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DOI: https://doi.org/10.1038/nn.2984
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