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Nat Neurosci. 2016 Aug;19(8):1025-33. doi: 10.1038/nn.4335. Epub 2016 Jun 27.

Segregated cholinergic transmission modulates dopamine neurons integrated in distinct functional circuits.

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MRC Anatomical Neuropharmacology Unit, Department of Pharmacology, University of Oxford, Oxford, UK.
School of Psychology, University of Leicester, Leicester, UK.
Center for Molecular and Behavioral Neuroscience, Rutgers University, Newark, New Jersey, USA.
CIMA, Universidad de Navarra, Pamplona, Spain.
diSNA, Navarra Institute for Health Research, Pamplona, Spain.
Princeton Neuroscience Institute, Princeton, New Jersey, USA.
Department of Psychiatry, Stanford University, Stanford, California, USA.


Dopamine neurons in the ventral tegmental area (VTA) receive cholinergic innervation from brainstem structures that are associated with either movement or reward. Whereas cholinergic neurons of the pedunculopontine nucleus (PPN) carry an associative/motor signal, those of the laterodorsal tegmental nucleus (LDT) convey limbic information. We used optogenetics and in vivo juxtacellular recording and labeling to examine the influence of brainstem cholinergic innervation of distinct neuronal subpopulations in the VTA. We found that LDT cholinergic axons selectively enhanced the bursting activity of mesolimbic dopamine neurons that were excited by aversive stimulation. In contrast, PPN cholinergic axons activated and changed the discharge properties of VTA neurons that were integrated in distinct functional circuits and were inhibited by aversive stimulation. Although both structures conveyed a reinforcing signal, they had opposite roles in locomotion. Our results demonstrate that two modes of cholinergic transmission operate in the VTA and segregate the neurons involved in different reward circuits.

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