Cholinergic Mesopontine Signals Govern Locomotion and Reward through Dissociable Midbrain Pathways
The mesopontine tegmentum, including the pedunculopontine and laterodorsal tegmental nuclei (PPN and LDT), provides major cholinergic inputs to midbrain and regulates locomotion and reward. To delineate the underlying projection-specific circuit mechanisms, we employed optogenetics to control mesopontine cholinergic neurons at somata and at divergent projections within distinct midbrain areas. Bidirectional manipulation of PPN cholinergic cell bodies exerted opposing effects on locomotor behavior and reinforcement learning. These motor and reward effects were separable via limiting photostimulation to PPN cholinergic terminals in the ventral substantia nigra pars compacta (vSNc) or to the ventral tegmental area (VTA), respectively. LDT cholinergic neurons also form connections with vSNc and VTA neurons; however, although photo-excitation of LDT cholinergic terminals in the VTA caused positive reinforcement, LDT-to-vSNc modulation did not alter locomotion or reward. Therefore, the selective targeting of projection-specific mesopontine cholinergic pathways may offer increased benefit in treating movement and addiction disorders.
© 2016 Elsevier. Received 19 October 2015, Revised 10 February 2016, Accepted 18 March 2016, Available online 20 April 2016. Published: April 20, 2016. We thank the entire V.G. lab for helpful discussions and Drs. David J. Anderson and Henry A. Lester for helpful comments on the manuscript. This work was supported by grants to V.G.: NIH Director's New Innovator IDP20D017782-01 and PECASE; NIH/NIA 1R01AG047664-01 (C.X. is a co-investigator); NIH BRAIN 1U01NS090577; Heritage Medical Research Institute; Pew Charitable Trust; Michael J. Fox Foundation; Sloan Foundation; as well as by funding support from the Beckman Institute for the Resource Center on CLARITY, Optogenetics, and Vector Engineering for technology development and broad dissemination (http://www.beckmaninstitute.caltech.edu/clover.shtml). Work in the V.G. Laboratory at Caltech is also funded by the following awards (to V.G.): NIH/NIMH 1R21MH103824-01; Kimmel Foundation; Human Frontiers in Science Program; Mallinckrodt Foundation; Gordon and Betty Moore Foundation through Grant GBMF2809 to the Caltech Programmable Molecular Technology Initiative; Caltech-GIST; Caltech-CBEA; Caltech-CEMI; Caltech-City of Hope Biomedical Initiative. C.X. is partly supported by Michael J. Fox Foundation. J.B.T. acknowledges the Colvin Postdoctoral Fellowship. K.C. is supported by the NIH Predoctoral Training in Biology and Chemistry (2T32GM007616-36).
Supplemental Material - mmc1.pdf
Accepted Version - nihms774500.pdf