Impairment of reward-related learning by cholinergic cell ablation in the striatum

Yasuji Kitabatake, Takatoshi Hikida, Dai Watanabe, Ira Pastan, and Shigetada Nakanishi

PNAS (2003)

Doi: 10.107310.1073/pnas.1032899100

Brief summary: kitabatake and colleagues found that selectively eliminated the cholinergic interneurons (ChIs) in the striatum impaired cue-guided discrimination learning and working memory performance of a delayed-alternation task in a T-maze. Importantly, the elimination of ChIs did not affect the motor control under habitual condition and the learning of the water-maze task.

Before the study, there were many recording results showing that the ChIs in the striatum specifically responded to the motivationally significant stimuli (both rewarding and aversive). And it had known that the blockade of the muscarinic receptors in the striatum impaired the response reversal learning but leaving the initial learning intact (Involvement of the dorsomedial striatum in behavioral flexibility: role of muscarinic cholinergic receptors, 2002, shared in 2021-07-20). In this study, the authors extended the behavior repertoire used to test the elimination effects of ChIs. To test the effects on procedural learning, they trained mice to perform a tone-cued T-maze memory task. In this task, there are two tones indicate that the baited reward is at the left or right arm of the T-maze, respectively. The tone is delivered up to 20s until animal makes the choice. The performance was dramatically decreased by the elimination of ChIs. The effects may be attributed to the deficits in the discrimination of tones, because later studies shown that the dorsolateral part of the striatum is critical for processing auditory information. The lesions performed in the study covered both the anterior and posterior, medial and lateral parts of the striatum with 11 injection sites! Furthermore, to test its role in working memory, they utilized the delayed alternation task based on the T-maze. In the first trial of the task, mouse can get reward by going to any arm. After that, mouse is required to go to the alternative arm, comparing to the previous choice, to get reward. By modulating the duration of the inter-trial-interval (ITI), they found that the elimination of ChIs specifically impaired the performance with long ITIs (30s/60s), but had no effects if the ITI was zero. This is the characteristic measurement for working memory. The results are persuasive. At last they also shown some control experiments showing the the eliminations of ChIs did not directly affect the habitual motor control functions by using the rota-rod test or the long-term memory by using the water-maze test.

The observation of the impaired procedural learning by elimination of ChIs was inconsistent with later studies (e.g. Enhanced flexibility of place discrimination learning by targeting striatal cholinergic interneurons, Nature communications, 2014, shared in 2021-07-07). It’s always difficult to reconcile the conflicting findings from different labs by using different behavioral tests. One possible reason might be the different sensory modalities they used (visual/spatial versus auditory).