Striatal Cholinergic Interneurons Are Required for Contending Strategy Selection While Solving Spatial Navigation Problems

J Neurosci. 2022 Feb 16;42(7):1303-1315. doi: 10.1523/JNEUROSCI.1130-21.2021. Epub 2021 Dec 21.


How do animals adopt a given behavioral strategy to solve a recurrent problem when several effective strategies are available to reach the goal? Here we provide evidence that striatal cholinergic interneurons (SCINs) modulate their activity when mice must select between different strategies with similar goal-reaching effectiveness. Using a cell type-specific transgenic murine system, we show that adult SCIN ablation impairs strategy selection in navigational tasks where a goal can be independently achieved by adopting an allocentric or egocentric strategy. SCIN-depleted mice learn to achieve the goal in these tasks, regardless of their appetitive or aversive nature, in a similar way as controls. However, they cannot shift away from their initially adopted strategies, as control mice do, as training progresses. Our results indicate that SCINs are required for shaping the probability function used for strategy selection as experience accumulates throughout training. Thus, SCINs may be critical for the resolution of cognitive conflicts emerging when several strategies compete for behavioral control while adapting to environmental demands. Our findings may increase our understanding about the emergence of perseverative/compulsive traits in neuropsychiatric disorders with a reported SCIN reduction, such as Tourette and Williams syndromes.SIGNIFICANCE STATEMENT Selecting the best suited strategy to solve a problem is vital. Accordingly, available strategies must be compared across multiple dimensions, such as goal attainment effectiveness, cost-benefit trade-off, and cognitive load. The striatum is involved in strategy selection when strategies clearly diverge in their goal attainment capacity; however, its role whenever several strategies can be used for goal reaching-therefore making selection dependent on additional strategy dimensions-remains poorly understood. Here, we show that striatal cholinergic interneurons can signal strategy competition. Furthermore, they are required to adopt a given strategy whenever strategies with similar goal attainment capacity compete for behavioral control. Our study suggests that striatal cholinergic dysfunction may result in anomalous resolution of problems whenever complex cognitive valuations are required.

Keywords: Barnes maze; allocentric–egocentric navigation; cell type-specific ablation; cognitive flexibility; problem-solving strategies; striatal cholinergic interneurons.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cholinergic Neurons / physiology*
  • Corpus Striatum / physiology*
  • Interneurons / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Problem Solving / physiology*
  • Spatial Navigation / physiology*