title: Striatal Cholinergic Interneurons Modulate Spike-Timing in Striosomes and Matrix by an Amphetamine-Sensitive Mechanism.
abstract: The striatum is key for action-selection and the motivation to move. Dopamine and acetylcholine release sites are enriched in the striatum and are cross-regulated, possibly to achieve optimal behavior. Drugs of abuse, which promote abnormally high dopamine release, disrupt normal action-selection and drive restricted, repetitive behaviors (stereotypies). Stereotypies occur in a variety of disorders including obsessive-compulsive disorder, autism, schizophrenia and Huntington's disease, as well as in addictive states. The severity of drug-induced stereotypy is correlated with induction of c-Fos expression in striosomes, a striatal compartment that is related to the limbic system and that directly projects to dopamine-producing neurons of the substantia nigra. These characteristics of striosomes contrast with the properties of the extra-striosomal matrix, which has strong sensorimotor and associative circuit inputs and outputs. Disruption of acetylcholine signaling in the striatum blocks the striosome-predominant c-Fos expression pattern induced by drugs of abuse and alters drug-induced stereotypy. The activity of striatal cholinergic interneurons is associated with behaviors related to sensory cues, and cortical inputs to striosomes can bias action-selection in the face of conflicting cues. The neurons and neuropil of striosomes and matrix neurons have observably separate distributions, both at the input level in the striatum and at the output level in the substantia nigra. Notably, cholinergic axons readily cross compartment borders, providing a potential route for local cross-compartment communication to maintain a balance between striosomal and matrix activity. We show here, by slice electrophysiology in transgenic mice, that repetitive evoked firing patterns in striosomal and matrix striatal projection neurons (SPNs) are interrupted by optogenetic activation of cholinergic interneurons either by the addition or the deletion of spikes. We demonstrate that this cholinergic modulation of projection neurons is blocked in brain slices taken from mice exposed to amphetamine and engaged in amphetamine-induced stereotypy, and lacking responsiveness to salient cues. Our findings support a model whereby activity in striosomes is normally under strong regulation by cholinergic interneurons, favoring behavioral flexibility, but that in animals with drug-induced stereotypy, this cholinergic signaling breaks down, resulting in differential modulation of striosomal activity and an inability to bias action-selection according to relevant sensory cues.
authors.affiliation: Department of Brain and Cognitive Sciences, McGovern Institute for Brain Research, Massachusetts Institute of Technology Cambridge, MA, USA.
authors.forename: Jill R
authors.initials: JR
authors.lastname: Crittenden
authors.affiliation: Department of Brain and Cognitive Sciences, McGovern Institute for Brain Research, Massachusetts Institute of Technology Cambridge, MA, USA.
authors.forename: Carolyn J
authors.initials: CJ
authors.lastname: Lacey
authors.affiliation: Department of Brain and Cognitive Sciences, McGovern Institute for Brain Research, Massachusetts Institute of Technology Cambridge, MA, USA.
authors.forename: Feng-Ju
authors.initials: FJ
authors.lastname: Weng
authors.affiliation: Department of Brain and Cognitive Sciences, McGovern Institute for Brain Research, Massachusetts Institute of Technology Cambridge, MA, USA.
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Garrison
authors.affiliation: Department of Brain and Cognitive Sciences, McGovern Institute for Brain Research, Massachusetts Institute of Technology Cambridge, MA, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Gibson
authors.affiliation: Department of Brain and Cognitive Sciences, McGovern Institute for Brain Research, Massachusetts Institute of Technology Cambridge, MA, USA.
authors.forename: Yingxi
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Department of Brain and Cognitive Sciences, McGovern Institute for Brain Research, Massachusetts Institute of Technology Cambridge, MA, USA.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Graybiel
keywords: amphetamine; cholinergic interneuron; stereotypy; striatum; striosome