Whole-brain mapping of monosynaptic inputs to midbrain cholinergic neurons.

The cholinergic midbrain is involved in a wide range of motor and cognitive processes. Cholinergic neurons of the pedunculopontine (PPN) and laterodorsal tegmental nucleus (LDT) send long-ranging axonal projections that target sensorimotor and limbic areas in the thalamus, the dopaminergic midbrain and the striatal complex following a topographical gradient, where they influence a range of functions including attention, reinforcement learning and action-selection. Nevertheless, a comprehensive examination of the afferents to PPN and LDT cholinergic neurons is still lacking, partly due to the neurochemical heterogeneity of this region.

Cholinergic midbrain afferents modulate striatal circuits and shape encoding of action strategies.

Assimilation of novel strategies into a consolidated action repertoire is a crucial function for behavioral adaptation and cognitive flexibility. Acetylcholine in the striatum plays a pivotal role in such adaptation, and its release has been causally associated with the activity of cholinergic interneurons. Here we show that the midbrain, a previously unknown source of acetylcholine in the striatum, is a major contributor to cholinergic transmission in the striatal complex.

Distribution of Midbrain Cholinergic Axons in the Thalamus.

Cholinergic transmission is essential for adaptive behavior and has been suggested to play a central role in the modulation of brain states by means of the modulation of thalamic neurons. Midbrain cholinergic neurons from the pedunculopontine nucleus (PPN) and the laterodorsal tegmental nucleus (LDT) provide dense innervation of the thalamus, but a detailed connectivity mapping is missing. Using conditional tracing of midbrain cholinergic axons in the rat, together with a detailed segmentation of thalamic structures, we show that projections arising in PPN and LDT are topographically organized along the entire extent of the thalamus.

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

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.

A major external source of cholinergic innervation of the striatum and nucleus accumbens originates in the brainstem.

Cholinergic transmission in the striatal complex is critical for the modulation of the activity of local microcircuits and dopamine release. Release of acetylcholine has been considered to originate exclusively from a subtype of striatal interneuron that provides widespread innervation of the striatum. Cholinergic neurons of the pedunculopontine (PPN) and laterodorsal tegmental (LDT) nuclei indirectly influence the activity of the dorsal striatum and nucleus accumbens through their innervation of dopamine and thalamic neurons, which in turn converge at the same striatal levels.