Abstract
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. Neurons of the pedunculopontine and laterodorsal tegmental nuclei synapse with striatal cholinergic interneurons and give rise to excitatory responses. Furthermore, they produce uniform inhibition of spiny projection neurons. Inhibition of acetylcholine release from midbrain terminals in the striatum impairs the association of contingencies and the formation of habits in an instrumental task, and mimics the effects observed following inhibition of acetylcholine release from striatal cholinergic interneurons. These results suggest the existence of two hierarchically-organized modes of cholinergic transmission in the striatum, where cholinergic interneurons are modulated by cholinergic neurons of the midbrain.
Highlights
Assimilation of novel strategies into a consolidated action repertoire is a crucial function for behavioral adaptation and cognitive flexibility
By calculating the area of transduction (Supplementary Fig. 1C–E) and the number of starter neurons, we found that the proportion of pedunculopontine nucleus (PPN) input neurons innervating cholinergic interneurons (CINs) is significantly larger than the proportion innervating either striatonigral or striatopallidal spiny projection neurons (SPNs) (Fig. 1j; Supplementary Fig. 1B; similar proportions were observed when wheat germ agglutinin (WGA)-Cre replaced Cav2-Cre, Supplementary Fig. 1F)
We show that PPN and laterodorsal tegmental nucleus (LDT) axon terminals inhibit the activity of SPNs while activating CINs, suggesting a circuit mechanism in which PPN/LDT may potentially modulate striatal activity through CINs
Summary
Assimilation of novel strategies into a consolidated action repertoire is a crucial function for behavioral adaptation and cognitive flexibility. Inhibition of acetylcholine release from midbrain terminals in the striatum impairs the association of contingencies and the formation of habits in an instrumental task, and mimics the effects observed following inhibition of acetylcholine release from striatal cholinergic interneurons These results suggest the existence of two hierarchically-organized modes of cholinergic transmission in the striatum, where cholinergic interneurons are modulated by cholinergic neurons of the midbrain. Cholinergic markers and released ACh were considered to be exclusively associated with cholinergic interneurons (CINs), which profusely innervate the entire extent of the striatum While they are more densely concentrated in the matrix of the dorsal striatum[5,6], their distribution is predominantly random and heterogeneous, lacking functional domains[7]. Our results reveal two intricately related but distinct modes of cholinergic transmission in the striatum
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