Cerebellar-recipient motor thalamus drives behavioral context-specific movement initiation

Abstract

Tel. +44 131 650 3113 53 Email: Ian.Duguid@ed.ac.uk 54 65 Stimulating the MThDN/IPN thalamocortical pathway in the absence of the cue recapitulated cue-66 evoked M1 membrane potential dynamics and forelimb behavior in the learned behavioral 67 context, but generated semi-random movements in an altered behavioral context. Thus, 68 cerebellar-recipient motor thalamocortical input to M1 is indispensable for the generation of 69 motor commands that initiate goal-directed movement, refining our understanding of how the 70 cerebellar-thalamocortical pathway contributes to movement timing. 71 72 129 ( Figure 1c and Video S1). Mice rapidly learned to execute the task (mean = 7.5 days, 95% CI 130 [6.3, 8.6], N = 16 mice, all data, unless otherwise stated, are presented as mean, 131 [bootstrapped 95% confidence interval]; last session task success, mean = 0.64 rewards per 132 cue presentation, 95% CI [0.56, 0.72]), displaying relatively fast reaction times (last session, 133 median = 0.32s [0.30, 0.34]) and reproducible forelimb kinematic trajectories (Figures 1d-1f, 134 Video S1).135 136

Generation of Rapid Sequences by Motor Cortex

“…Preparatory activity is proposed to seed execution-related activity and thus specify the identity of the executed reach. The transition from preparatory to execution-related activity coincides with a large condition-invariant change in the neural state, proposed to result from a movement-triggering input 27,39–41 . Traditionally it has been challenging to discriminate preparation-related activity from execution-related activity when they occur close in time 31 .…”

“…This ‘condition invariant signal’ (CIS) begins ~150 ms before movement onset 27,28,39,40 and is proposed to reflect a large input that triggers movement execution. Consistent with this, the dominant response component in mouse motor cortex during reaching depends upon thalamic inputs, and silencing those inputs interrupts execution 39,41 . Furthermore, the CIS is highly predictive of the exact moment of reach initiation 27 .…”

“…This step ensures that dimensionality reduction focuses on dimensions where activity is selective across conditions. Dimensions capturing condition-invariant activity 27,28,39,40 were identified separately (see below). We employed a recently developed dimensionality reduction approach 21,36,38 , which leverages the fact that motor cortex population activity occupies nearly orthogonal subspaces during preparation and execution 36 .…”

Spatiotemporal organization of movement-invariant and movement-specific signaling in the output layer of motor cortex

“…Mice rapidly learned the task (mean = 12.8 days,95% CI [11.3 14.2], all data, unless otherwise stated, are presented as mean, [bootstrapped 95% confidence interval] and average data is given per mouse, N = 12 mice), performing sequences of abduction / adduction movements with reproducible across-session success but differences in kinematic trajectories, reflecting two independent actions (abduction -41.3 trials / 30 min [37.5.0 45.2], median action duration = 713.5 ms, 95% CI [706.5,733.5];, median action duration = 566 ms 95% CI [537.3,573.0], N = 12 mice) ( Figure 1D -F and Supplementary Video 1). To confirm motor cortical output was required for both actions, we focally injected the GABAA receptor agonist muscimol centred on the caudal forelimb area (Dacre et al, 2019;Schiemann et al, 2015). By applying muscimol during behavioural engagement we could assess the immediate effects of CFA inactivation 5-15 mins after drug injection ( Figure 1G).…”

“…Recent advances in viral tools and optical imaging have enabled access to laminar-specific spatiotemporal dynamics of interconnected neuronal populations in rodent motor cortex (Park et al, 2019;Peters et al, 2014;Peters et al, 2017;Wang et al, 2017). During the execution of single forelimb actions, principal neurons in both superficial and deep layers display dense activity patterns that causally relate to the initiation and/or ongoing evolution of movements (Dacre et al, 2019;Estebanez et al, 2017;Hira et al, 2013;Isomura et al, 2009;Levy et al, 2020;Park et al, 2019;Sauerbrei et al, 2019;Wang et al, 2017). These reproducible, laminar-specific activity patterns emerge across motor learning and correlate with enhanced limb coordination (Laubach et al, 2000;Masamizu et al, 2014;Peters et al, 2014;Peters et al, 2017).…”