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

  1. Junchol Park
  2. James W. Phillips
  3. Jian-Zhong Guo
  4. Kathleen A. Martin
  5. Adam W. Hantman
  6. Joshua T. Dudman

  • Curated by eLife

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    Evaluation Summary:

    Park and colleagues examined the activity and function of different projection neuron types, pyramidal tract (PT) and intratelencephalic (IT) neurons, in the primary motor cortex using a joystick manipulation task in mice. During forelimb movements, the activity of IT neurons was more correlated with movement kinematics than that of PT neurons was, and inactivation of IT neurons caused larger effects on movement kinematics (amplitude and velocity). The results highlight different activity patterns and functions between PT and IT neurons. Discussion among reviewers focused on two main issues. One centered on the interpretation of the PT neural activity; the second on the evidence underlying the claim of a dissociation between the PT and IT neurons.

    “(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)”

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Abstract

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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  1. eLife

    Evaluation Summary:

    Park and colleagues examined the activity and function of different projection neuron types, pyramidal tract (PT) and intratelencephalic (IT) neurons, in the primary motor cortex using a joystick manipulation task in mice. During forelimb movements, the activity of IT neurons was more correlated with movement kinematics than that of PT neurons was, and inactivation of IT neurons caused larger effects on movement kinematics (amplitude and velocity). The results highlight different activity patterns and functions between PT and IT neurons. Discussion among reviewers focused on two main issues. One centered on the interpretation of the PT neural activity; the second on the evidence underlying the claim of a dissociation between the PT and IT neurons.

    “(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)”

  2. eLife

    Reviewer #1 (Public Review):

    Park and colleagues examined the activity and functional role of different projection neuron types in the primary motor cortex in mice performing a joystick-based forelimb movement task. The authors characterized the activity of pyramidal tract (PT) neurons and intratelencephalic (IT) neurons using electrophysiological recordings with optogenetic tagging as well as cell-type specific single cell calcium imaging. The results showed that the activity of IT neurons was better correlated with movement kinematics (reach amplitude) and contained more information about kinematics compared to PT neurons. Optogenetic inactivation of IT neurons caused a marked reduction in reach amplitude and velocity while inactivation of PT neurons had smaller effects. Inactivation of PT neurons caused a significant transient perturbation in reach direction while the change caused by IT neuron inactivation did not reach significance. Recording from neurons in the striatum, the authors show that IT neuron inactivation caused reduction in the neuronal firing in the striatum while PT neuron inactivation caused an increase.

    This study addresses a long-standing, important question in the motor cortex: the role of different projection neuron types, PT and IT neurons, in motor control. The authors performed a series of very interesting experiments and obtained an important data set. The results are presented clearly in general (but see some questions below). The authors' conclusion that IT neurons have predominant role in determining movement amplitudes while PT neurons regulate movement trajectories (presumably by determining "muscle identity") is potentially very interesting. However, there are some interpretational difficulties in the inactivation experiments. It would be helpful if the authors discuss some of the caveats of these experiments.

    Major issues:

    1. Interpretation of cell-type specific inactivation experiments does not appear to be straightforward. As shown in Figure 3a and b, optogenetic inactivation of PT neurons or IT neurons caused a significant increase in unidentified neurons. Therefore, it is unclear whether the results of inactivation experiments are due to intended inactivation of opsin-expressing neurons, or due to off-target effect due to activation of the rest of the neurons. For instance, activation of striatal neurons during PT neuron inactivation may be due to indirect activation of IT neurons (Figure 7d). Furthermore, the effect of PT inactivation on movement trajectory may be due to IT activation rather than PT inactivation (e.g. activation of some neurons might have caused an abrupt movement). Besides these specific cases, all of the inactivation experiments are likely confounded by off-target activations. These caveats are inevitable in these experiments generally, and the results need to be interpreted carefully.

    2. One of the main points of this study is that PT inactivation caused a lateral deviation in movement trajectories but IT inactivation did not. However, this result is poorly analyzed. If movement trajectory can deviate in both directions in x-axis, comparing the average trajectories between experimental and control animals might not be very informative because deviations in opposite directions can cancel out. The number of animals is also relatively low. The results should be analyzed more thoroughly to convincingly make the authors' conclusion.

    3. The authors claim that mice adjusted movement amplitudes based on thresholds set by the experimenter but the result is not very convincing. The presented result is, for instance, consistent with a time-dependent gradual increase followed by asymptotic performance, followed by some fatigue. To demonstrate that the animals actually followed the thresholds, randomizing the order of blocks would be helpful or required.

    4. A previous work from the Komiyama lab (e.g. Peters et al., 2017; PMID: 28671694) has reported that a large fraction of corticospinal neurons decrease their activity at or after the onset of forelimb movements. It would be good to cite this work.

  3. eLife

    Reviewer #2 (Public Review):

    This paper uses cell type-specific recording and inhibition to investigate differences in activity and behavioral relevance of PT and IT cells within the motor cortex. IT cells are shown to be largely positively correlated with the amplitude of joystick presses, while PT cells are heterogeneous with a majority being negatively modulated during joystick presses. Related behavioral differences are found during inhibition of each cell type, with IT cells reducing press amplitude and speed and PT cells altering press trajectory. Likewise, inhibition of each cell type has a different impact on striatal activity, with a press amplitude-related projection of activity decreased by IT inhibition and unchanged by PT inhibition. Overall, these results suggest an interesting functional dissociation between PT and IT cells, though it is not entirely clear how specific these roles are or how they are enacted.

    The paper reinforces previous findings about activity heterogeneity across cell types in the motor cortex, specifically that IT cells increase activity during movement while PT cells more often decrease activity during movement. This is achieved by both inhibition-based optotagging during electrophysiology and cell-type specific calcium imaging, although it is not discussed why a major difference between the two modalities appears to be a balanced or net-negative modulation of PT cells during the joystick press (Fig. 3j vs. Fig. 4d).

    The most exciting novel result is that inhibiting these cell types produces complementary effects on behavior (Fig. 6). It appears that PT inactivation produces a consistent deviation of the forelimb horizontally away from the mouse (Fig. 6f), though the vertical direction is not analyzed and it is not shown if the degree of horizontal deflection is related to vertical amplitude. Related, it is not clear whether this effect requires an ongoing movement or is an induced movement on top of the normal press, as PT inactivation is only triggered by movement initiation and not tested at rest. Furthermore, IT inactivation is shown to reduce press amplitude and speed more than PT inactivation (Fig. 6c), although it is unclear whether this may be related to number of cells affected in each condition. IT cells are also known to provide input to PT cells, and it is not clear whether inhibiting IT cells in this case also inhibits PT cells to account for the larger overall effect. Towards this point, inhibition of IT cells at rest is shown to not induce inhibition in non-IT cells (Fig. 3b), although this analysis may be confounded by the fact that IT cells in this case are defined by their inhibitory response to light.

    Support for the conclusion that IT cells modulate press amplitude by driving specific striatal activity is indirectly suggested by the average effect of inactivating IT and PT cells on striatal activity. It is noteworthy and surprising that, whereas IT inactivation decreases movement-related striatal activity, PT inactivation increases it (Fig. 7d). However, it is not made clear how specific these effects are to the amplitude-related "KN dimension" as opposed to total striatal activity (Fig. 7f), and it is not exactly clear what the KN dimension represents in terms of specific cells or specific responses across many cells. It is also not noted whether the increase in striatal activity during PT inactivation is related to the trajectory deviation, for example to demonstrate that striatal activity contains information only about press amplitude and not trajectory.

  4. eLife

    Reviewer #3 (Public Review):

    The major goal of this study is to distinguish the contributions of two classes of motor cortex neurons to the control of the forelimb during a learned task that requires variable-amplitude movement. The first class are pyramidal tract (PT) neurons that travel down the spinal cord and synapse near the motor neuron pools. The second are intratelencephalic (IT) neurons that project within the brain but do not exit it.

    These are, slightly unusually, described by the authors as two different output pathways. PT neurons are obviously an output so that makes sense. IT neurons aren't normally thought of as an output (given that their projections, by definition, stay in the brain) but they project to the striatum. Although the basal ganglia have no spinal projection (a major influence is thought to be back to cortex via the thalamus) they connect to brainstem areas that do. Thus, the authors are comparing the contribution of a direct pathway (traditionally thought to directly drive movement) with that of a more indirect pathway (which could exert its influence both via recurrence onto the first pathway, and via other pathways).

    Two major findings are:

    1. the impact of PT inactivation is different from than that of IT inactivation. That difference argues that PT neurons are likely not the primary drivers of movement but perform some trajectory shaping function. More broadly it is argued that PT and IT pathways have dissociable impacts on behavior (e.g., one determining direction and the other determining amplitude).
    1. PT neurons have responses inconsistent with the view that they are primary drivers of movement.

    The first finding leads to the claim that PT and IT neurons have dissociable functions. E.g., controlling movement direction and amplitude. The evidence for a dissociation is present in their data but not necessarily compelling. Both PT inactivation and IT inactivation decrease movement amplitude and both alter the trajectory. The difference is that, with amplitude, the impact of PT inactivation is about 40% as large as that of IT inactivation. With trajectory, the impact of PT inactivation appears cleaner and tighter in time but isn't obviously larger (the claim that there is a differential effect rests on the 'one effect is significant and the other isn't fallacy). The results can certainly support the claim that effects are not the same. They are also surprising in the sense that the PT impact is smaller than expected. But the idea that they are cleanly differentiable (e.g., adjusting orthogonal aspects of movement) goes beyond what the data can support.

    The claim that PT neurons aren't primary drivers of movement rests upon the second finding: PT neurons become less active around the time of the forelimb movement, and are instead more likely to be active around the time of the subsequent lick. This is clear in the data and is described by the authors as follows: "IT+ neurons, showed greater peri-movement activation than PT neurons, while PT neurons had greater activation timed to reward collection". Why not then conclude that these PT neurons ARE involved in movement, but that the movement in question involves facial movements during reward projection. After all, the authors back-label the PT neurons from the brainstem (where the motoneurons for the face reside) rather than the cord (where the motoneurons for the forelimb reside).

    In summary, I found the dissociation between the effects of IT an PT inactivation to be not overly compelling. There are interesting differences, but they seem like ones of degree and not of kind. The argument that PT neurons are not primary drivers of movement is intriguing, and could be right (which would likely indicate a species difference between rodent and primate). But given that the neurons in question seem destined for the brainstem I found this hard to interpret. It seems like the neurons one would want to investigate are PT neurons that project to the cord, or neurons that project to the brainstem (and thence to the cord).

  5. Version published to 10.1126/sciadv.abj5167
  6. Version published to 10.1101/772517 on bioRxiv