A region of the brain called the primary motor cortex (M1) is a critical site for learning motor skills (such as riding a bicycle). Moreover, reward is known to accelerate and enhance motor learning, however, it is not understood how reward exerts these effects. While reward has previously been shown to activate neurons in M1 of primates, the cell-types exhibiting this activity were unknown. Candice Lee, a PhD student at the University of Ottawa led a study using live brain imaging techniques in mice while they were learning a task and demonstrated that different cell-types do indeed have distinct responses to reward and reward-predicting cues and these responses evolve differentially with learning.
Candice Lee, who was at the time of this work a PhD student at the University of Ottawa, won a CAN-CIHR-INMHA Brain Star award for these discoveries.
In this experiment, a specific sound cue was linked to a reward, and researcher knew the mice had learned the association when they observed anticipatory licking for the reward when the sound was heard. This allowed the researchers to use a live imaging technique, called in vivo two-photon calcium imaging, to investigate which specific neuron types were activated during this classical conditioning task. They demonstrated that excitatory neurons and the inhibitory GABAergic interneuron subtypes, PV-, SST- and VIP-expressing interneurons all have distinct responses to both reward and reward-related cues. Moreover, different neuronal cell-types underwent differential changes as the animal progressed through reward-based associative learning. While excitatory neurons were initially responsive to reward, reward responses were reduced after associative learning occurred. Remarkably, PV-interneurons were preferentially responsive to reward-related cues rather than the reward itself, and became more responsive with associative learning, suggesting that PV-interneurons could have a specialized role in preparatory activity during reward-expectation. In contrast, VIP-interneurons, which specialize in inhibiting other inhibitory interneurons and are thereby disinhibitory, were preferentially responsive to reward itself and became more responsive to reward with learning. Changes in PV- and VIP-interneuron activity were not seen in the absence of reward or if reward was given randomly, denoting specificity to associative learning. Together, these findings demonstrate that reward is faithfully represented within M1, despite being outside of canonical reward-processing regions. This suggests that during reward-based associative learning, VIP-interneurons act as a gate, whereby reward activates VIP-interneurons to disinhibit pyramidal neurons and enable plastic changes.
This publication connects and expands on multiple findings within the fields of reward processing and motor learning. Since the activation of different cell-types exert opposing and precise effects on local circuitry, elucidating cell-type specific activity is a critical step in understanding how reward affects motor cortex activity. There is hope that mechanisms discovered in this study can be leveraged to enhance motor learning following the loss of motor skills such as after stroke or traumatic brain injury, potentially through VIP-interneuron targeted therapies.
About Candice Lee
Dr. Candice Lee joined Dr. Simon Chen’s lab as a doctoral student and was the first member of the newly minted lab. During this time, she established two-photon calcium imaging, and imaged the activity of hundreds of cells in the brains of behaving animals, as described in this study. Candice and Dr. Chen conceived the project. Candice performed the experiments and data analysis, with the exception of figure 3, which was contributed by collaborators from Dr. Richard Naud’s lab. She also took the lead on writing the manuscript with Dr. Chen. Candice completed her PhD in 2022 and is now a postdoctoral fellow at the University of Oxford in the UK.
Sources of funding
This work was supported by grants for Dr. Simon Chen from Canada Research Chair (CRC) (grant no. 950-231274) and Natural Sciences and Engineering Research Council of Canada (NSERC) (grant no. 05308), and a grant for Dr. Richard Naud from NSERC (grant no. 06972). Emerson Harkin was supported by a NSERC graduate scholarship. Candice Lee was supported by Ontario Graduate Scholarship and Queen Elizabeth II Graduate Scholarship.
Original research article
Candice Lee, Emerson F Harkin, Xuming Yin, Richard Naud, Simon Chen, (2022). Cell-type-specific responses to associative learning in the primary motor cortex. eLife 11:e72549.
