GABAergic inhibitory neurons are known to play a critical regulatory role in memory formation and learning. During motor learning, pyramidal neurons (PNs) of the primary motor cortex (M1) undergo spine reorganization and firing pattern refinement. Cortical PNs are directly inhibited and regulated by two inhibitory neuronal subtypes: somatostatin-expressing interneurons (SOM-INs) and parvalbumin-expressing interneurons (PV-INs). Interestingly, SOM-mediated inhibition has been shown to regulate the observed dynamics of PNs during motor learning. Despite our expanded understanding, the molecular mechanisms that underlie these processes remain unclear. Here, I identified that the immediate-early gene transcription factor, NPAS4, is selectively expressed in a subset of SOM-INs, but not in PV-INs or PNs, during the head-fixed pellet reaching motor learning task. Furthermore, I characterized its expression pattern within the SOM-INs of M1 and found that there was no change at early phases; but as training progressed, there was a gradual increase and plateau in the number of NPAS4-expressing SOM-INs. In collaboration with other lab members, we showed that Npas4 region- and cell-type specific deletion within SOM-INs of M1, impaired motor skill acquisition and disrupted the motor learning-induced spine reorganization. In addition, I validated and employed the novel NRAM system to examine if NPAS4 is continually expressed within the same subset of SOM-INs and found that an ensemble of SOM-INs repetitively express NPAS4 at various phases of learning. Lastly, chronic in vivo two-photon Ca²⁺ imaging during training showed that the ensemble of NPAS4-expressing SOM-INs had reduced activity during task-related movements compared to other SOM-INs. Together, our results reveal an important instructive role of NPAS4 within the microcircuits of M1, in which it modulates the inhibition of a distinct subset of SOM-INs during motor learning to promote spine stabilization of downstream task-related PNs that are important for motor skill acquisition.
| Identifer | oai:union.ndltd.org:uottawa.ca/oai:ruor.uottawa.ca:10393/43959 |
| Date | 25 August 2022 |
| Creators | Serrano, Pablo Valentin |
| Contributors | Chen, Simon |
| Publisher | Université d'Ottawa / University of Ottawa |
| Source Sets | Université d’Ottawa |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | application/pdf |
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