1. Reviewer #3 (Public Review):

    This study provides a concept of circuit organization of a pathway from the brainstem to the primary somatosensory (S1) and motor (M1) cortices through the thalamus to control the hand/forelimb movements. Previous studies reveal detailed circuit organization of ascending somatosensory pathways in the whisker system. In contrast, much less is known about circuit organization of another ascending pathway controlling the hand/forelimb movements, although it is known that there are some similarities and differences between two different somatosensory systems.

    This paper revealed detailed circuit organization of the ascending pathways including the lemnisco-cortical and corticocortical pathways to control the hand/forelimb movements. The strength of this study is to use a variety of sophisticated techniques, such as optogenetics, trans-synaptic viruses, both anterograde and retrograde viruses, mouse genetics, and electrophysiology, to map the neural circuits in details. The circuit was revealed by electrophysiology together with optogenetics, which is very convincing. In addition, the detailed circuit organization revealed by this study will provide an important information for future behavioral studies. The weakness is the limitation of trans-synaptic viruses. For example, pseudorabies viruses move between multiple neurons, so to interpret the results may be complicated. Although behavioral analyses have not been performed in this study, it is beyond the scope of this study and future study will follow up the behavioral analyses.

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  2. Reviewer #2 (Public Review):

    This study traces the detailed excitatory connections of mouse forepaw sensorimotor circuits from the spinal cord, through brainstem, thalamus, sensory and motor cortical areas, and their motor outputs. This is a welcome and important contribution, considering the technical advantages of mice for circuit cracking and the increasing number of labs studying the functions of their limbs. Although the structure and function of forelimb sensorimotor circuits have been extensively studied in primates, they have been relatively neglected in the rodent, especially compared to the enormous scope of research that has been done on the rodent vibrissae system over the past 50 years. This study uses a variety of contemporary methods to reveal important similarities and differences between the forelimb and vibrissae sensorimotor circuits.

    Overall, the results do not hold major surprises, although this is itself a noteworthy result. The authors did identify a few qualitative and quantitative differences between the forelimb circuit and the parallel vibrissae-related circuit; the functional significance of these differences is as yet unclear.

    The weaknesses of the manuscript are few and minor. The study would have been stronger if it had performed comparable, parallel experiments on the hand and vibrissae circuits, however the scope of the study is already ambitious and strong enough as it stands. I do have a question about the identity of the cortical L4 neurons that were recorded, and this issue should be discussed.

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  3. Reviewer #1 (Public Review):

    Sensorimotor integration is required for the accurate execution of volitional movements, but the neural circuits underlying sensorimotor integration are still not fully understood. The whisker system of the rodent has emerged as one model of sensorimotor integration with many recent studies focused on the synaptic organization of the underlying circuitry. Here, Yamawaki et al report results regarding the synaptic organization of the ascending sensory pathways related to mouse forelimb somatosensory and motor cortex. Using anatomical and functional approaches, they elucidate the circuitry from the cuneate nucleus through thalamus to forelimb S1 and M1. This work complements recent studies in the mouse of other aspects of the forelimb sensorimotor pathways and leads to informative comparisons to the circuit organization of the whisker system. The studies are well executed and well explained. The use of multiple approaches compensates for the limitations of each individual technique, although some limitations such as any effects of viral tropism are difficult to overcome. Overall, this work contributes to a better understanding of the wiring diagram of sensorimotor circuits in the mouse.

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  4. Evaluation Summary:

    This paper will be of interest to those studying the sensorimotor functions of the hand and forelimb. It traces the anatomy and strength of excitatory pathways from the spinal cord, through the brainstem, thalamus, somatosensory and motor cortex, and descending outputs. The methods are contemporary, and include multiple viral tracing, genetic targeting, and transsynaptic strategies, optogenetic and electrophysiological methods; the data are compelling; and the paper is clear and concise.

    (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 #2 and Reviewer #3 agreed to share their names with the authors.)

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