title: A major external source of cholinergic innervation of the striatum and nucleus accumbens originates in the brainstem.
abstract: 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. Here we show that cholinergic neurons in the brainstem also provide a direct innervation of the striatal complex. By the expression of fluorescent proteins in choline acetyltransferase (ChAT)::Cre(+) transgenic rats, we selectively labeled cholinergic neurons in the rostral PPN, caudal PPN, and LDT. We show that cholinergic neurons topographically innervate wide areas of the striatal complex: rostral PPN preferentially innervates the dorsolateral striatum, and LDT preferentially innervates the medial striatum and nucleus accumbens core in which they principally form asymmetric synapses. Retrograde labeling combined with immunohistochemistry in wild-type rats confirmed the topography and cholinergic nature of the projection. Furthermore, transynaptic gene activation and conventional double retrograde labeling suggest that LDT neurons that innervate the nucleus accumbens also send collaterals to the thalamus and the dopaminergic midbrain, thus providing both direct and indirect projections, to the striatal complex. The differential activity of cholinergic interneurons and cholinergic neurons of the brainstem during reward-related paradigms suggest that the two systems play different but complementary roles in the processing of information in the striatum.
authors.affiliation: Medical Research Council Anatomical Neuropharmacology Unit, Department of Pharmacology, University of Oxford, Oxford OX1 3TH, United Kingdom, School of Psychology, University of Leicester, Leicester LE1 9HN, United Kingdom, Princeton Neuroscience Institute, Princeton New Jersey 08540, and Department of Psychiatry, Stanford University, Stanford, California 94305.
authors.forename: Daniel
authors.initials: D
authors.lastname: Dautan
authors.forename: Icnelia
authors.initials: I
authors.lastname: Huerta-Ocampo
authors.forename: Ilana B
authors.initials: IB
authors.lastname: Witten
authors.forename: Karl
authors.initials: K
authors.lastname: Deisseroth
authors.forename: J Paul
authors.initials: JP
authors.lastname: Bolam
authors.forename: Todor
authors.initials: T
authors.lastname: Gerdjikov
authors.forename: Juan
authors.initials: J
authors.lastname: Mena-Segovia
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000344:Afferent Pathways / Q000502:physiology*; D000818:Animals; D001933:Brain Stem / Q000502:physiology*; D000075402:Channelrhodopsins; D002772:Cholera Toxin / Q000378:metabolism; D002795:Choline O-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D003342:Corpus Striatum / Q000166:cytology / Q000378:metabolism* / Q000648:ultrastructure; D005260:Female; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000378:metabolism* / Q000648:ultrastructure; D009714:Nucleus Accumbens / Q000166:cytology / Q000378:metabolism* / Q000648:ultrastructure; D051381:Rats; D020318:Rats, Long-Evans; D055647:Rats, Transgenic; D013569:Synapses / Q000378:metabolism / Q000648:ultrastructure; D050494:Vesicular Acetylcholine Transport Proteins / Q000378:metabolism; D014909:Wheat Germ Agglutinins / Q000378:metabolism
chemical_list: D000075402:Channelrhodopsins; D008164:Luminescent Proteins; C493461:Slc18a3 protein, rat; D050494:Vesicular Acetylcholine Transport Proteins; D014909:Wheat Germ Agglutinins; D002772:Cholera Toxin; D002795:Choline O-Acetyltransferase; D000109:Acetylcholine
keywords: cholinergic; innervation; laterodorsal tegmental nucleus; pedunculopontine nucleus; striatum; topography