Ventral tegmental area GABA projections pause accumbal cholinergic interneurons to enhance associative learning

Matthew T. C. Brown, Kelly R. Tan, Eoin C. O’Connor, Irina Nikonenko, Dominique Muller & Christian Luscher

Nature (2012)

Doi: 10.1038/nature11657

Brief summary: it was widely reported that cholinergic interneurons (ChIs) in striatum shown a bursting-pause-rebound activity pattern. How the pause activity of ChIs is modulated? And what’s the behavioral significance? In this study, Brown et al, found that the projections from the GABAergic interneurons in ventral tegmental area (VTA) to nucleus accumbens (NAc) could inhibit the ChIs’ activity (pause pattern), and the suppression of ChIs could improve the learning of context-dependent fear conditioning.

About 30 years ago before the publication of the current study, researcher first reported the bursting-pause-rebound activity pattern of tonically active neurons (TANs) in the striatum of primates (Tonically discharging putamen neurons exhibit set-dependent responses, PNAS, 1984). Benefiting from the powerful genetic tools in rodents, people confirmed that the so called TANs were choline acetyltransferase (ChAT) positive neurons. In striatum, ChIs comprise about 1~2% of the total neurons. Despite its small proportion, ChIs have extensive arborizations onto the medial spiny neurons (~95% neurons in striatum), which are believed to exert important modulations on striatum-dependent functions. However, how the pause activity of ChIs to motivational saliency was modulated was still unclear at the time. And its behavioral significance was also needed  to be pinned down. By using electron microscopy, Brown et al found that GABAergic interneurons in VTA specifically synapse onto ChIs, but not the MSNs in NAc. Optogenetically activating the axonal terminals of GABAergic interneurons in NAc could mimic the pause activity of ChIs in physiological condition. To further verify its functional significance, the authors trained mice to pair a conditioned stimulus (CS+) with a foot shock, and a CS- with no specific outcome under context 1. After 2 days’ training in context 1, mice shown significant fear response to both CS+ and CS- in context 2 in the following test session, showing a generalization effect. However, if the ChIs were transiently suppressed by activating the GABAergic projections in NAc, the fear response to CS- was significantly decreased in context 2, indicating an enhanced discrimination between CS+ and CS-. Thus, the authors demonstrated that the pause of ChIs was critical for mice to learn the motivational significance of environmental stimuli.

This study is very inspiring. To suppress ChIs in striatum, besides the activation of the inhibitory inputs, it is also feasible to inactivate the excitatory inputs from cortices (also from thalamus), such as the lateral orbitofrontal cortex (lOFC). Thus the improved learning of reward-dependent discrimination by suppressing the lOFC-dmStriatum pathway might works through the inhibition of ChIs in striatum. It is worth to be verified experimentally.