A neural circuit state change underlying skilled movements

Wagner, Mark J.; Savall, Joan; Hernandez, Oscar; Mel, Gabriel C.; Inan, Hakan; Rumyantsev, Oleg; Lecoq, Jérôme; Kim, Tony Hyun; Li, Jin Zhong; Ramakrishnan, Charu; Deisseroth, Karl; Luo, Liqun; Ganguli, Surya; Schnitzer, Mark J.

doi:10.1016/j.cell.2021.06.001

Cited by 57 publications

(75 citation statements)

References 89 publications

(119 reference statements)

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“…Therefore, our results strongly suggest that re-adapted locomotion is underpinned by strong synaptic plasticity in the cerebellar cortex re-organizing GC-PC synaptic maps at least for a month after an injury or learning of new motor skills. We acknowledge that other areas of the cerebellar cortex are certainly involved in these adaptations as recently suggested using mesoscale CF imaging 64 , 65 , but our recordings demonstrated that the vermal lobules III-IV encode at least partly this adaptive behavior. The patchy and context-specific reorganization of the GC-PC functional connectivity is also in agreement with the fractured somatotopy identified during in vivo micro mappings in the GC layer 47 .…”

Section: Discussionsupporting

confidence: 68%

Cerebellar connectivity maps embody individual adaptive behavior in mice

et al. 2022

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The cerebellar cortex encodes sensorimotor adaptation during skilled locomotor behaviors, however the precise relationship between synaptic connectivity and behavior is unclear. We studied synaptic connectivity between granule cells (GCs) and Purkinje cells (PCs) in murine acute cerebellar slices using photostimulation of caged glutamate combined with patch-clamp in developing or after mice adapted to different locomotor contexts. By translating individual maps into graph network entities, we found that synaptic maps in juvenile animals undergo critical period characterized by dissolution of their structure followed by the re-establishment of a patchy functional organization in adults. Although, in adapted mice, subdivisions in anatomical microzones do not fully account for the observed spatial map organization in relation to behavior, we can discriminate locomotor contexts with high accuracy. We also demonstrate that the variability observed in connectivity maps directly accounts for motor behavior traits at the individual level. Our findings suggest that, beyond general motor contexts, GC-PC networks also encode internal models underlying individual-specific motor adaptation.

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Section: Discussionsupporting

confidence: 68%

Cerebellar connectivity maps embody individual adaptive behavior in mice

et al. 2022

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“…In 14 of 46 recorded cells, Cspks could be sorted across the experiment (see Methods). Within these cells, Cspk probability increased dramatically shortly before movement onset, consistent with reports of synchronized Cspk activity occurring at movement initiation 48–50 , then remained elevated during and after reach (Fig. 2a).…”

Section: Resultssupporting

confidence: 88%

Cerebellar associative learning underlies skilled reach adaptation

Calame

Becker

Person

2021

Preprint

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Cerebellar output has been shown to enhance movement precision by scaling the decelerative phase of reaching movements in mice. We hypothesized that during reach, initial kinematics cue late-phase adjustments through cerebellar associative learning. We identify a population-level response in mouse PCs that scales inversely with reach velocity, suggesting a candidate mechanism for anticipatory control to target limb endpoint. We next interrogate how such a response is generated by combining high-density neural recordings with closed-loop optogenetic stimulation of cerebellar mossy fiber afferents originating in the pontine nuclei during reach, using perturbation schedules reminiscent of classic adaptation paradigms. We found that reach kinematics and PC electrophysiology adapt to position-locked mossy fiber perturbations and exhibit aftereffects when stimulation is removed. Surprisingly, we observed partial adaptation to position-randomized stimulation schedules but no opposing aftereffect. A model that recapitulated these findings provided novel insight into how the cerebellum deciphers cause-and-effect relationships to adapt.

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“…The SC is thought to be an area for sensorimotor integration to initiate motor behaviors, including eye and head movements ( Ito and Feldheim, 2018 ), leading to the idea that the DCN-SC pathway directly controls eye and head movements, apart from the function of the cerebellovestibular tract in oculomotor control ( Roldán and Reinoso-Suárez, 1981 ). Alternatively, considering the functions of the SC in visually guided limb movement ( Courjon et al, 2004 ; Steinmetz et al, 2019 ) and the importance of the cerebellum in controlling the precision of limb positions ( Becker and Person, 2019 ; Wagner et al, 2021 ), the DCN-SC pathway may provide predictive information of limb positions to successfully achieve a target, as proposed ( Doykos et al, 2020 ). The precise motor functions of this pathway need to be determined in further studies.…”

Section: Historically Studied Efferent Pathways Of the Cerebellummentioning

confidence: 99%

“…In addition, the nucleo-olivary projections have been proposed to control synchronous activity of IO neurons ( Lefler et al, 2014 ), which are electrically coupled through gap junctions. Indeed, another recent study showed that the inhibition of nucleo-olivary projections triggered synchronous activity of IO neurons, and this was the mechanism of state changes underlying skilled movement ( Wagner et al, 2021 ).…”

Section: Historically Studied Efferent Pathways Of the Cerebellummentioning

confidence: 99%

“…In these experiments, the abovementioned rAAV-retro or CAV2 expressing Cre was injected into target brain regions, and AAVs triggering Cre-dependent expression of chemogenetic or optogenetic molecules were injected into the DCN, which resulted in the specific expression of molecules in the DCN neurons projecting to the target brain regions. The manipulation of these neurons during behavioral tests by chemogenetic drug administration or photostimulation of the DCN clarified the functions of these efferent pathways ( Frontera et al, 2020 ; Sathyamurthy et al, 2020 ; Baek et al, 2021 ; Wagner et al, 2021 ). Furthermore, disynaptically connected cerebellar efferent pathways were also investigated, as follows: AAV serotype 1 expressing Cre, or AAV expressing WGA-Cre was injected into the DCN, and AAV triggering the Cre-dependent expression of chemogenetic or optogenetic molecules was injected into the intermediate regions, which resulted in the expression of these molecules specifically in neurons of the intermediate regions receiving inputs from the DCN.…”

Section: Techniques To Unravel the Complexity Of Cerebellar Efferent Pathwaysmentioning

confidence: 99%

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Recent Advances in the Understanding of Specific Efferent Pathways Emerging From the Cerebellum

et al. 2021

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The cerebellum has a long history in terms of research on its network structures and motor functions, yet our understanding of them has further advanced in recent years owing to technical developments, such as viral tracers, optogenetic and chemogenetic manipulation, and single cell gene expression analyses. Specifically, it is now widely accepted that the cerebellum is also involved in non-motor functions, such as cognitive and psychological functions, mainly from studies that have clarified neuronal pathways from the cerebellum to other brain regions that are relevant to these functions. The techniques to manipulate specific neuronal pathways were effectively utilized to demonstrate the involvement of the cerebellum and its pathways in specific brain functions, without altering motor activity. In particular, the cerebellar efferent pathways that have recently gained attention are not only monosynaptic connections to other brain regions, including the periaqueductal gray and ventral tegmental area, but also polysynaptic connections to other brain regions, including the non-primary motor cortex and hippocampus. Besides these efferent pathways associated with non-motor functions, recent studies using sophisticated experimental techniques further characterized the historically studied efferent pathways that are primarily associated with motor functions. Nevertheless, to our knowledge, there are no articles that comprehensively describe various cerebellar efferent pathways, although there are many interesting review articles focusing on specific functions or pathways. Here, we summarize the recent findings on neuronal networks projecting from the cerebellum to several brain regions. We also introduce various techniques that have enabled us to advance our understanding of the cerebellar efferent pathways, and further discuss possible directions for future research regarding these efferent pathways and their functions.

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A neural circuit state change underlying skilled movements

Cited by 57 publications

References 89 publications

Cerebellar connectivity maps embody individual adaptive behavior in mice

Cerebellar connectivity maps embody individual adaptive behavior in mice

Cerebellar associative learning underlies skilled reach adaptation

Recent Advances in the Understanding of Specific Efferent Pathways Emerging From the Cerebellum

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