Striatal Cholinergic Interneurons: How to Elucidate Their Function in Health and Disease

Striatal cholinergic interneurons (CINs) are the main source of acetylcholine in the striatum and are believed to play an important role in basal ganglia physiology and pathophysiology. The role of CINs in striatal function is known mostly from extracellular recordings of tonically active striatal neurons in monkeys, which are believed to correspond to CINs. Because these neurons transiently respond to motivationally cues with brief pauses, flanked by bursts of increased activity, they are classically viewed as key players in reward-related learning. However, CIN modulatory function within the striatal network has been mainly inferred from the action of acetylcholine agonists/antagonists or through CIN activation. These manipulations are far from recapitulating CIN activity in response to behaviorally-relevant stimuli. New technical tools such as optogenetics allow researchers to specifically manipulate this sparse neuronal population and to mimic their typical pause response. For example, it is now possible to investigate how short inhibition of CIN activity shapes striatal properties. Here, we review the most recent literature and show how these new techniques have brought considerable insights into the functional role of CINs in normal and pathological states, raising several interesting and novel questions. To continue moving forward, it is crucial to determine in detail CIN activity changes during behavior, particularly in rodents. We will also discuss how computational approaches combined with optogenetics will contribute to further our understanding of the CIN role in striatal circuits.