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dc.contributor.advisorDuguid, Ian
dc.contributor.advisorRochefort, Nathalie
dc.contributor.authorSánchez Rivera, Michelle
dc.date.accessioned2022-11-15T16:51:40Z
dc.date.available2022-11-15T16:51:40Z
dc.date.issued2022-11-15
dc.identifier.urihttps://hdl.handle.net/1842/39481
dc.identifier.urihttp://dx.doi.org/10.7488/era/2731
dc.description.abstractThe ability to generate appropriate movements depending on environmental context is crucial for survival. When navigating their environment animals execute appropriate actions according to their goals, and through the process known as response inhibition, they also avoid executing habitual actions in situations where they would be inappropriate. In mammals, the primary motor cortex (M1) plays a pivotal role in the generation of coordinated movement. Pyramidal tract (PT) neurons located in layer 5B (L5B) generate descending output that innervates subcortical, brainstem and spinal cord circuits necessary to execute voluntary movements. A subset of PT neurons, termed corticospinal neurons (CSNs), give rise to the descending pathway that carries information from the cortex to the circuits in the spinal cord that control muscle activation. Studies in primates and rodents have demonstrated strong correlations between the activity of CSNs and a variety of cue-evoked motor responses. However, the spatiotemporal patterns of CSN activity during the execution of appropriate and avoidance of inappropriate actions, remains unresolved. To address this, we used the mouse as a model system given its genetic tractability, ease of imaging large scale populations of CSNs deep within cortex, and their ability to learn and perform complex forelimb motor tasks. Initially, we developed an intersectional viral strategy to target CSNs with projections terminating in the C6 segment of the spinal cord, which primarily controls proximal forelimb muscles. This strategy was used to selectively express the genetically encoded calcium indicator GCaMP6 to image behaviour-related activity in head-fixed mice. To investigate the role of C6-projecting CSNs during movement execution and response inhibition. we developed a Go/NoGo lever push task that required mice to discriminate between two auditory cues and either push (Go trials) or avoid pushing (NoGo trials) a horizontal lever. During Go trials, mice reliably executed lever pushes with highly stereotyped and reproducible movement trajectories. To avoid pushing the lever during NoGo trials, mice adopted a strategy whereby they executed a lever release-and-regrasp action, ensuring a high level of task success. We imaged a population of 1019 CSNs from 8 mice performing the Go/NoGo task and found that approximately half exhibited activity changes immediately after cue presentation. The vast majority (91%) of these neurons displayed trial-type specific activity changes, with 69% responding exclusively during Go trials, 23% responding exclusively during NoGo trials and 8% exhibiting trial-type specific bidirectional changes (increase vs decrease) in activity. NoGo trials were characterised by increased activity in neurons located in superficial L5B, while the dominant change during Go trials was decreased activity in neurons located deeper within L5B. These results suggest that the vast majority of CSNs convey specific information about movement depending on their intralaminar location. Experiments in ex vivo slices have shown that apical dendritic tufts of PT neurons receive spatially segregated synaptic inputs that drive local, branch specific computations. In vivo studies, however, have shown widespread and highly correlated somatodendritic activity contrary to the view of sparse, branch-specific dendritic integration. To investigate whether CSNs exhibit compartment-specific activity changes during the selective execution of different actions, we performed near-simultaneous imaging of the apical trunk and dendritic arbour of 9 identified CSNs while mice performed the Go/NoGo task. Congruent with population activity profiles, 3 neurons exhibited reduced activity during lever pushes, 1 displayed increased activity during release-and-regrasps and 5 displayed no task-related activity. During behaviour, activity across different neuronal compartments within the same cell was highly correlated, and ~90% of dendritic events were detected across multiple branches. This suggests that coupled somato-dendritic, rather than compartmentalised branch-specific activity underlies CSN population responses during the execution of appropriate and avoidance of inappropriate actions.en
dc.language.isoenen
dc.publisherThe University of Edinburghen
dc.subjectcentral nervous systemen
dc.subjectprimary motor cortexen
dc.subjectpyramidal tracten
dc.subjectPT neuronsen
dc.subjectcorticospinal neuronsen
dc.subjectfluorescent calcium indicator proteinen
dc.subjectGCaMP6en
dc.titleCorticospinal neurons in the execution of goal-appropriate actionsen
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen
dc.rights.embargodate2023-11-15en
dcterms.accessRightsRestricted Accessen


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