Disrupting cortico-cerebellar communication impairs dexterity

Guo, Jian-Zhong; Sauerbrei, Britton; Cohen, Jack B.; Mischiati, Matteo; Graves, Austin R; Pisanello, Ferruccio; Branson, Kristin; Hantman, Adam W.

doi:10.7554/elife.65906

Cited by 56 publications

(71 citation statements)

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“…For example, it has often been proposed that dexterity demands could be intimately tied to the function of corticopontine PT pathways ( 4 ), and yet, inactivation of dSTR also profoundly impairs movement amplitude during reach-to-grasp tasks ( 21 ) as it does for joystick movements ( 22 ), perhaps consistent with a role for corticostriatal IT neurons. Moreover, inactivation of the basal pons produces little effect on movement speed and amplitude ( 17 ).…”

Section: Resultsmentioning

confidence: 99%

Motor cortical output for skilled forelimb movement is selectively distributed across projection neuron classes

et al. 2022

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The interaction of descending neocortical outputs and subcortical premotor circuits is critical for shaping skilled movements. Two broad classes of motor cortical output projection neurons provide input to many subcortical motor areas: pyramidal tract (PT) neurons, which project throughout the neuraxis, and intratelencephalic (IT) neurons, which project within the cortex and subcortical striatum. It is unclear whether these classes are functionally in series or whether each class carries distinct components of descending motor control signals. Here, we combine large-scale neural recordings across all layers of motor cortex with cell type–specific perturbations to study cortically dependent mouse motor behaviors: kinematically variable manipulation of a joystick and a kinematically precise reach-to-grasp. We find that striatum-projecting IT neuron activity preferentially represents amplitude, whereas pons-projecting PT neurons preferentially represent the variable direction of forelimb movements. Thus, separable components of descending motor cortical commands are distributed across motor cortical projection cell classes.

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Section: Resultsmentioning

confidence: 99%

Motor cortical output for skilled forelimb movement is selectively distributed across projection neuron classes

et al. 2022

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“…For example, it has often been proposed that dexterity demands could be intimately tied to the function of corticopontine PT pathways ( 4 ) and yet inactivation of dorsal striatum also profoundly impairs movement amplitude during reach-to-grasp tasks ( 21 ) as it does for joystick movements ( 22 ) perhaps consistent with a role for corticostriatal IT neurons. Moreover, inactivation of the basal pons produces little effect on movement speed and amplitude ( 56 ).…”

Section: Resultsmentioning

confidence: 99%

Motor cortical output for skilled forelimb movement is selectively distributed across projection neuron classes

Park

Phillips

Martin

et al. 2019

Preprint

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Motor cortex is part of a network of central brain circuits that together enable robust, flexible, and efficient movement in mammals. Recent work has revealed rich dynamics in mammalian motor cortex 1-7 thought to underlie robust and flexible movements. These dynamics are a consequence of recurrent connectivity between individual cortical neuron subtypes 8 , but it remains unclear how such complex dynamics relate to individual cell types and how they covary with continuous behavioral features. We investigated this in mice, combining a selfpaced, kinematically-variable, cortex-dependent, bimanual motor task 9,10 with large-scale neural recordings that included cell-type information. This revealed highly distributed correlates of movement execution across all layers of forelimb motor cortex and subcortical areas. However, we observed a surprising relative lack of modulation in the putative source of motor commands brain-stem projecting (pyramidal tract, PT) neurons 11 . By contrast, striatal/cortical projecting (intratelencephalic, IT) neurons showed much stronger correlations with movement kinematics. Cell-type specific inactivation of PT neurons during movement execution had little effect on behavior whereas inactivation of IT neurons produced dramatic decreases in the speed and amplitude of forelimb movements. PT inactivation elicited rapid, compensatory changes in activity distributed across multiple cortical layers and subcortical regions helping to explain minimal effects of inactivation on behavior. This work illustrates how cortical-striatal population dynamics play a critical role in the control of movement while maintaining substantial flexibility in the extent to which PT projection neurons are a requisite contributor to descending motor commands. † equal contribution FIGURE 1 Distributed task related neural dynamics in a self-initiated variable amplitude operant taskA) Mice were trained to perform an self-initiated (uncued) vigor-control task, in which movements were made for delayed reward (left). To perform this, mice were head-fixed, and moved a joystick bimanually (middle). Recordings were made in forelimb motor cortex and striatum with a neuropixels 3A probe, which densely sampled neural activity in the depth axis (right, see inset for recording site spacing). B) Mice adjusted their reach amplitude across the three blocks. Left plot shows data from a single session, right plot shows the data across sessions. See main text for statistics. C) Population neural activity showed two peaks, one around reach and one around reward. Mean population activity relative to joystick velocity (thresholded to only show outward) and lick rate. Mean activity of units was taken for units above 1600um depth (cortical units) and those below 1800um depth (striatal units), then binned into 50ms bins, and each resulting array was normalized to the range 0-1. D) Many units were tuned to movement kinematics. Two example units (left and middle) show tuning of neural activity to each tertile of reach amplitudes. Right figure ...

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“…The circuit regulating voluntary movements was first described as the cerebro-cerebellar pathway (Brodal, 2010 ). However, several recent studies have shown how other brain regions, such as the pontine nuclei and the ventrolateral nuclei of the thalamus (VL), also retain an active role in the regulation of distinct voluntary movements (Schwarz and Thier, 1999 ; Bosch-Bouju et al, 2013 ; Guo et al, 2021 ). This network connects the cerebral neocortex to the cerebellum via the pontine nuclei and vice versa the cerebellum to the neocortex through the VL nucleus of the thalamus.…”

Section: Nr2f1 -Dependent Development Of the Sensorimotor Systemmentioning

confidence: 99%

“…Further, a recent study assessing the role of pontine nuclei in voluntary movements supports their direct involvement in the timing and accuracy of movements rather than its initiation. Specifically, upon optogenetic disruption of the pontine nuclei activity, the animals retained the ability to initiate the reaching phase of the single-pellet task but showed either reduced precision of the grasping phase or a general delay in the complete execution of the task (Guo et al, 2021 ). Since the defects showed by Nr2f1 cortical cKO mice resemble those presented in this work, with an almost intact reaching phase but inaccurate grasping (Tomassy et al, 2010 ), it is tempting to speculate that gradient cortical Nr2f1 expression could impart topographic information to descending tracts during development by influencing their connectivity to subcortical structures, such as the pontine nuclei and the spinal cord.…”

Section: Nr2f1 -Dependent Development Of the Sensorimotor Systemmentioning

confidence: 99%

Structural and Functional Aspects of the Neurodevelopmental Gene NR2F1: From Animal Models to Human Pathology

Tocco

Bertacchi

Studer

2021

Front. Mol. Neurosci.

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The assembly and maturation of the mammalian brain result from an intricate cascade of highly coordinated developmental events, such as cell proliferation, migration, and differentiation. Any impairment of this delicate multi-factorial process can lead to complex neurodevelopmental diseases, sharing common pathogenic mechanisms and molecular pathways resulting in multiple clinical signs. A recently described monogenic neurodevelopmental syndrome named Bosch-Boonstra-Schaaf Optic Atrophy Syndrome (BBSOAS) is caused by NR2F1 haploinsufficiency. The NR2F1 gene, coding for a transcriptional regulator belonging to the steroid/thyroid hormone receptor superfamily, is known to play key roles in several brain developmental processes, from proliferation and differentiation of neural progenitors to migration and identity acquisition of neocortical neurons. In a clinical context, the disruption of these cellular processes could underlie the pathogenesis of several symptoms affecting BBSOAS patients, such as intellectual disability, visual impairment, epilepsy, and autistic traits. In this review, we will introduce NR2F1 protein structure, molecular functioning, and expression profile in the developing mouse brain. Then, we will focus on Nr2f1 several functions during cortical development, from neocortical area and cell-type specification to maturation of network activity, hippocampal development governing learning behaviors, assembly of the visual system, and finally establishment of cortico-spinal descending tracts regulating motor execution. Whenever possible, we will link experimental findings in animal or cellular models to corresponding features of the human pathology. Finally, we will highlight some of the unresolved questions on the diverse functions played by Nr2f1 during brain development, in order to propose future research directions. All in all, we believe that understanding BBSOAS mechanisms will contribute to further unveiling pathophysiological mechanisms shared by several neurodevelopmental disorders and eventually lead to effective treatments.

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Disrupting cortico-cerebellar communication impairs dexterity

Cited by 56 publications

References 56 publications

Motor cortical output for skilled forelimb movement is selectively distributed across projection neuron classes

Motor cortical output for skilled forelimb movement is selectively distributed across projection neuron classes

Motor cortical output for skilled forelimb movement is selectively distributed across projection neuron classes

Structural and Functional Aspects of the Neurodevelopmental Gene NR2F1: From Animal Models to Human Pathology

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