Role of Striatal Cholinergic Interneurons in Set-Shifting in the Rat

Abstract

The ability to change strategies in different contexts is a form of behavioral flexibility that is crucial for adaptive behavior. The striatum has been shown to contribute to certain forms of behavioral flexibility such as reversal learning. Here we report on the contribution of striatal cholinergic interneurons-a key element in the striatal neuronal circuit-to strategy set-shifting in which an attentional shift from one stimulus dimension to another is required. We made lesions of rat cholinergic interneurons in dorsomedial or ventral striatum using a specific immunotoxin and investigated the effects on set-shifting paradigms and on reversal learning. In shifting to a set that required attention to a previously irrelevant cue, lesions of dorsomedial striatum significantly increased the number of perseverative errors. In this condition, the number of never-reinforced errors was significantly decreased in both types of lesions. When shifting to a set that required attention to a novel cue, rats with ventral striatum lesions made more perseverative errors. Neither lesion impaired learning of the initial response strategy nor a subsequent switch to a new strategy when response choice was indicated by a previously relevant cue. Reversal learning was not affected. These results suggest that in set-shifting the striatal cholinergic interneurons play a fundamental role, which is dissociable between dorsomedial and ventral striatum depending on behavioral context. We propose a common mechanism in which cholinergic interneurons inhibit neurons representing the old strategy and enhance plasticity underlying exploration of a new rule.

Cholinergic Interneurons Use Orbitofrontal Input to Track Beliefs about Current State

“…Individual DMS CINs represented state from the start to the end of the trials within each block. The finding that CINs code state is consistent with evidence that interference with cholinergic function in the striatum often causes problems with flexible behavior (Tzavos et al, 2004;Ragozzino et al, 2009;Okada et al, 2014;Aoki et al, 2015) and with very specific evidence that this reflects a role for DMS CINs in integrating new learning with old without interference (Bradfield et al, 2013). Bradfield et al…”

“…Consistent with this proposal, interference with cholinergic function in the striatum often causes problems with flexible behavior (Tzavos et al, 2004;Ragozzino et al, 2009;Okada et al, 2014;Aoki et al, 2015). In one such study, Bradfield et al, 2013 used a series of well controlled behavioral tasks to demonstrate that interfering with CIN activity in the posterior dorsomedial striatum (DMS) specifically results in confusion between old learning and new after response-outcome contingencies have been changed.…”

Rule Encoding in Orbitofrontal Cortex and Striatum Guides Selection

“…For example, VS inactivation impairs behavioral performance during rule switching (Floresco et al, 2006), whereas VS cholinergic interneurons have been shown to play an important role in rule switching (Aoki et al, 2015). A recent comprehensive review of VS function also proposes that VS serves to refine action selection dynamically by incorporating multiple sources of information including, but not limited to, reward (Floresco, 2015).…”

Neurophysiology of rule switching in the corticostriatal circuit

“…Without a functioning mDS, rats demonstrated impairment in the formation of sets and the maintenance of new sets when shifts in responses were required(Lindgren et al, 2013, Bissonette and Roesch, 2015c). Recent work has even uncovered a critical role for cholinergic interneurons of the medial and ventral striatum in shifting between rule based responses in the rat(Aoki et al, 2015) and ventral striatal neurons showing outcome representations while animals learn new tasks(Atallah et al, 2014). However, our understanding of how dorsal striatum presumably uses and interprets signals from PFC about how and when to shift between rule based response strategies is very limited.…”