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

Daniel Dautan,James M Tepper,Icnelia Huerta-Ocampo,Miguel Valencia,Karl Deisseroth,J Paul Bolam,Ilana B Witten,Juan Mena-Segovia,Todor V Gerdjikov,Maxime Assous,Albert S Souza

doi:10.1038/nn.4335

Abstract

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.

Highlights

Dopamine neurons (DA) of the ventral tegmental area (VTA) are implicated in goal-directed behaviors and reinforcement learning[1]
The combined results from the anatomical characterization reveal that cholinergic axons originating in the pedunculopontine nucleus (PPN) and laterodorsal tegmental nucleus (LDT) are intermingled within the VTA and contact both DA and non-DA neurons
While the number of VTA-projecting cholinergic neurons is similar between PPN and LDT, there is an indication from the axonal mapping that the latter has a higher level of collateralization that gives rise to a larger number of synaptic contacts with non-DA neurons

Summary

Introduction

Dopamine neurons (DA) of the ventral tegmental area (VTA) are implicated in goal-directed behaviors and reinforcement learning[1]. Their discharge mode changes from tonic to phasic in response to sensory events that predict a reward outcome[2]. The VTA receives excitatory inputs from several regions including the prefrontal cortex, amygdala, lateral hypothalamus, subthalamic nucleus and mesopontine tegmentum in the brainstem[6] While all of these afferent systems provide a glutamatergic input, the mesopontine tegmentum, composed of the pedunculopontine nucleus (PPN) and the laterodorsal tegmental nucleus (LDT), provides the main source of cholinergic innervation of DA neurons[7]. It is likely that cholinergic afferents, derived from the mesopontine tegmentum, play a role in tuning the activity of DA neurons in the VTA

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Results

Conclusion