Distinct Descending Motor Cortex Pathways

 

Nature volume 563, pages 79–84 (2018)

Distinct descending motor cortex pathways and their roles in movement

Michael N. Economo, et.al.

Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA, USA

Allen Institute for Brain Science, Seattle, WA, USA

National Institute of Mental Health, Bethesda, MD, USA

[paraphrase]

Activity in the motor cortex predicts movements, seconds before they are initiated. This preparatory activity has been observed across cortical layers, including in descending pyramidal tract neurons in layer 5. A key question is how preparatory activity is maintained without causing movement, and is ultimately converted to a motor command to trigger appropriate movements. Here, using single-cell transcriptional profiling and axonal reconstructions, we identify two types of pyramidal tract neuron. Both types project to several targets in the basal ganglia and brainstem. One type projects to thalamic regions that connect back to motor cortex; populations of these neurons produced early preparatory activity that persisted until the movement was initiated. The second type projects to motor centres in the medulla and mainly produced late preparatory activity and motor commands. These results indicate that two types of motor cortex output neurons have specialized roles in motor control.

Motor cortex activity anticipates specific future movements, often seconds before the onset of movement. This dynamic process, referred to as preparatory activity, moves motor cortex population activity to an initial condition that is appropriate for eliciting rapid, accurate movements. In addition, motor cortex activity is modulated milliseconds before and during the onset of movement, consistent with commands that control the timing and direction of movements.

 Reconciling these dual roles of the motor cortex requires an understanding of motor cortex cell types, and how these cell types integrate into multi-regional circuits. The motor cortex comprises cell types that differ in their location, gene expression, electrophysiology and connectivity. Intratelencephalic neurons in layers (L) 2–6 receive input from other cortical areas and excite pyramidal tract (PT) neurons.    PT neurons, the somata of which define neocortical L5b, link the motor cortex with premotor centres in the brainstem and spinal cord and directly influence behaviour. PT neurons also project to the thalamus. Preparatory activity requires reverberations in a thalamocortical loop. Consistent with roles in both the planning and initiation of movement,    PT neurons are structurally heterogeneous and show diverse activity patterns, including preparatory activity and movement commands.

 Here we show that PT neurons in the mouse motor cortex comprise two cell types with distinct gene expression and axonal projections. We refer to these cell types as PTupper and PTlower neurons, reflecting their distributions in different sublaminae in L5b.    PTupper neurons project to the thalamus, which forms a feedback loop with the motor cortex. PTlower cells project to premotor centres in the medulla. Cell-type-specific extracellular recordings in the anterior lateral motor cortex (ALM) during a delayed-response task suggest that PTupper neurons are preferentially involved in motor planning, whereas PTlower neurons have roles in movement execution.

Two types of PT neuron in layer 5

Single-cell RNA sequencing (scRNA-seq) was used to produce a taxonomy of cell types in the ALM and visual cortex. From 9,573 single-cell transcriptomes, glutamatergic neurons in the ALM were grouped into 27 clusters, which were distinct from glutamatergic clusters identified in the visual cortex.    PT neurons form the sole cortical projection to motor areas in the midbrain and hindbrain, and are therefore likely to have important roles in motor planning and execution. ALM PT neurons mapped to three transcriptomic clusters: the Slco2a1 cluster and two other closely related clusters.

We mapped the structural diversity of PT neurons by reconstructing individual cells (n= 12;  median axonal length: 121,037 µm, range: 80,873–188,105 µm; median branch points: 243, range: 144–540).    Patterns of axonal collaterals revealed two neuron types: one group innervated the thalamus (n= 8) the other group bypassed the thalamus and branched in the medulla, including the reticular nuclei containing premotor neurons for orofacial movements (n= 4). All cells innervated the superior colliculus and subsets of both groups branched in other areas.

We used the adeno-associated virus rAAV2-retro to label neurons retrogradely from the thalamus and medulla.    Thalamus-projecting PT neurons were in upper L5b, and medulla-projecting PT neurons were in lower L5b. This pattern was similar across the primary and secondary motor cortex.

 Discussion

PT neurons exhibit diverse activity patterns that are related to movement planning and execution. We have shown that motor cortex PT neurons comprise two cell types.    PTupper neurons connect with the thalamus and avoid motor centres in the medulla. These neurons tend to show early and persistent preparatory activity.    PTlower neurons avoid the thalamus and project to motor nuclei in the medulla. These neurons show late preparatory activity and seem to control movement initiation and termination. The segregation of PT neurons into two distinct types persists across the motor cortex and may generalize to other cortical areas and other mammals

Previous studies have suggested that collaterals of PT neurons to the thalamus might provide an efference copy of motor commands. Instead, we show that neurons that project to motor centres do not project to the thalamus. Corticothalamic PTupper neurons encode more cognitive signals related to motor planning. The thalamus also receives a projection from L6 corticothalamic neurons, but these neurons are sparsely active, uncoupled from PT neurons, and have weak synapses on thalamic neurons.

Preparatory activity appeared early and remained persistent in PTupper neurons, whereas movement commands were observed in PTlower neurons. At the same time, several signals were multiplexed within both populations of PT neurons. For example, preparatory activity emerged in PTlower neurons during the delay epoch (along CDlate) and persisted through the go cue and up to the termination of licking bouts. In the same cell type, and sometimes in the same individual cells, activity was modulated after the go cue along a different direction (CDgo), consistent with a movement command. In addition, cell type explained relatively little of the overall variance in neural activity. This highlights that even defined cell types express rich population coding.

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