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.
Highlights
Repetitive and restricted behaviors, known as stereotypies, occur in numerous disorders and are notably difficult to disrupt, suggesting a failure in attention to environmental cues that might normally direct a change in behavior
Control mice spent between 30 and 50% of the time sniffing the female bedding (Figure 1B). We compared this level to the times that they interacted with bedding that had been taken from their own home cage and found that they spent significantly more time interacting with the female cage bedding (Figure 1B), supporting the interpretation that female cage bedding is a salient cue
Mice that were treated with repeated amphetamine spent most of their time engaging in stereotypic behaviors, sometimes interrupted by running bouts, and did not interact with the female cage bedding at all (Figure 1B)
Summary
Repetitive and restricted behaviors, known as stereotypies, occur in numerous disorders and are notably difficult to disrupt, suggesting a failure in attention to environmental cues that might normally direct a change in behavior. Animals with drug-induced stereotypic behavior exhibit high c-Fos immediate-early gene induction in striatal projection neurons (SPNs) within the striosome compartment of the striatum, relative to low activation in SPNs located in the surrounding matrix compartment (Canales and Graybiel, 2000; Tan et al, 2000; Saka et al, 2004; Crittenden and Graybiel, 2011, 2016; Horner et al, 2012; Jedynak et al, 2012) Such differential c-Fos induction in striosomes, relative to c-Fos induction in the matrix, is blocked by intrastriatal ablation of cholinergic interneurons (referred to as ChIs), along with somatostatin-expressing interneurons (Saka et al, 2002), and manipulations of ChI signaling have a direct impact on the severity of cocaine- and amphetamine-induced stereotypies (Schoffelmeer et al, 2002; Collins and Izenwasser, 2004; Thomsen et al, 2010; Aliane et al, 2011; Crittenden et al, 2014). These findings suggest that a balance in activity between striosome-based and matrix-based cortico-basal ganglia loops could be critical for behavioral flexibility
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