Take a moment to think about all of the actions you perform on a typical day. How does your brain allow you to learn, select, and execute these actions? The basal ganglia is a group of subcortical nuclei involved in motor functions, and its dysfunction is associated with neurological and psychiatric diseases including Parkinson’s and Huntington’s diseases. Dr. Xin Jin studies movement, focusing on the basal ganglia, with the goal of answering questions like these about action learning and selection.

Imagine you’re calling someone for the first time. Except it’s 15 years ago and you’re using a landline. Maybe you even had to look up the number in a book. You press each number, one at a time, careful not to make a mistake. The next time you call you’re a bit faster. Eventually what was once a meaningless string of numbers becomes an effortless sequence. You’ve likely created three chunks: the area code, the next three numbers, and the last four numbers. Whether you’re dialing a phone number, filling in credit card information online, or entering your pin at an ATM, you think about the sequence rather than the individual numbers. Chunking organizes memories and actions into a single unit, making them easier to recall or perform. There is evidence to suggest the basal ganglia plays a role in chunking, but how is this represented at the neural level? In a recent paper Jin et al. investigated action sequences in mice, finding neural activity relating to the entire sequence, rather than its elements, in the basal ganglia.

Instead of learning a new phone number, mice leaned sequences of lever presses, motivated by a sugar reward. As you might expect, the mice performed the sequences faster and with less variability with training. While mice learned these sequences, neural activity was recoded through electrode arrays implanted in the dorsal striatum, substantia nigra pars reticulata (SNr) and external globus pallidus (GPe). Some of the medium spiny neurons (MSNs) in the dorsal striatum displayed activity that related to the beginning or end of the sequence, or start/stop activity, as had been observed in previous studies. However, many MSNs displayed an increase or decrease in activity throughout the sequence. Further, this sustained increase in activity correlated with the lever press frequency, consistent with the concatenation process of motor chunking. Importantly, these results show that action sequences are represented as a single action unit at the neural level in the dorsal striatum.

(a) MSN displaying activity related to the beginning and (b) end of the action sequence. (c) MSN showing inhibited and (d) sustained activity throughout the sequence.

(a) MSN displaying activity related to the beginning and (b) end of the action sequence. (c) MSN showing inhibited and (d) sustained activity throughout the sequence.

The striatum projects to the SNr and GPe, forming the direct and indirect pathways. The classical view of the direct and indirect pathways is that of the gas and the break, to facilitate and inhibit movement, respectively. Recordings from these target regions revealed different sequence-related activity, suggesting a distinction in their roles in sequence learning and performance.

More SNr neurons exhibited start/stop and inhibited activity compared to GPe, and more GPe neurons displayed sustained activity with training.

More SNr neurons exhibited start/stop (d) and inhibited (e) activity compared to GPe, and more GPe neurons displayed sustained (f) activity with training.

Striatonigral and striatopallidal MSNs preferentially express D1 and D2 dopamine receptors, respectively. The authors wondered if the difference in sequence-related activity in the SNr and GPe could be seen in the D1- and D2-MSN subtypes using photostimulation-assisted cell identification. By injecting AAV viruses expressing channelrhodopsin-2 (ChR2) in a cre-dependent manner into the striatum of mice expressing cre recombinase in either D1- or D2-MSNs, ChR2 was expressed specifically in these neurons.

(a) A D1 Cre mouse with viral driven expression of ChR2-YFP; note axons targeting SNr (b) A D2 Cre mouse with viral driven expression of ChR2-YFP; note axons targeting GPe.

(a) A D1 Cre mouse with viral driven expression of ChR2-YFP; note axons targeting SNr (b) A D2 Cre mouse with viral driven expression of ChR2-YFP; note axons targeting GPe.

These mice learned the task and neural activity was again recoded. Neurons could be identified as direct or indirect pathway MSNs by their activation in response to light stimulation. More D2-MSNs exhibited inhibited activity compared to D1-MSNs, and more D1-MSNs displayed sustained activity. This mirrors the separation of inhibited and sustained activity observed in the SNr and GPe, and is consistent with their inhibitory inputs from D1- and D2-MSNs.

(k) More D2-MSNs exhibited inhibited activity compared to D1-MSNs, and more D1-MSNs displayed sustained activity. (l) More SNr neurons exhibited start/stop and inhibited activity compared to GPe, and more GPe neurons displayed sustained activity.

(k) More D2-MSNs exhibited inhibited activity compared to D1-MSNs, and more D1-MSNs displayed sustained activity. (l) More SNr neurons exhibited start/stop and inhibited activity compared to GPe, and more GPe neurons displayed sustained activity.

These results confirm the difference in activity during the execution of motor sequences in the direct and indirect pathways and suggest a need for activation of both for action selection. Further, these results underscore the importance of understanding the functional organization of the basal ganglia during action learning and execution.

Interested in learning more? Dr. Xin Jin will be giving a talk titled “Dissecting the corticostriatal subcircuits for action” as part of the Neurosciences Graduate Program Dart NeuroScience Seminar Series on June 2 at 4:00 pm in the CNCB Marilyn Farquhar Seminar Room

Barbara Spencer is a first-year Neurosciences student currently rotating with Dr. Jim Brewer.

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