Pauses in Cholinergic Interneuron Activity Are Driven by Excitatory Input and Delayed Rectification, with Dopamine...

Area of Science:

• Neuroscience
• Computational Neuroscience
• Cellular Electrophysiology

Background:

• Cholinergic interneurons (ChIs) in the striatum exhibit firing pauses in response to salient and conditioned stimuli.
• Previous studies proposed various mechanisms for pause generation, lacking a unifying explanation.

Purpose of the Study:

• To elucidate the underlying biophysical mechanisms driving ChI pauses in the striatum.
• To establish a unifying basis for understanding ChI pause generation and its role in learning.

Main Methods:

• In vivo and ex vivo electrophysiological recordings in rat and mouse brain.
• Development and application of a computational model to simulate ChI activity.
• Pharmacological manipulation using K_v7.2/7.3 blocker XE-991.

Main Results:

• ChI pauses are primarily driven by the withdrawal of excitatory inputs to the striatum.
• A delayed rectifier potassium current (I_Kr), sensitive to XE-991, is crucial for pause generation.
• ChIs report input changes, pause upon excitatory input recession, and scale pauses with input strength, consistent with learning-induced changes.
• Dopamine's augmentation of pauses is mainly mediated by strengthening excitatory inputs, not direct hyperpolarization.

Conclusions:

• The study provides a unifying biophysical mechanism for ChI pause generation, centered on I_Kr and excitatory input dynamics.
• Findings offer insights into how ChIs signal changes in neural input and contribute to associative learning.
• The results highlight the interplay between intrinsic neuronal properties and network activity in shaping neuronal function.