Transcriptomic encoding of sensorimotor transformation in the midbrain
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Evaluation Summary:
This excellent manuscript combines molecular, anatomical and behavioral methods to characterize neuron types in the mouse superior colliculus. It will likely be a significant resource to those who study how these circuits integrate sensory information to promote motor output. A diverse set of experiments supports the conclusion that the superior colliculus includes separate circuit modules involved in distinct behaviors: prey capture and predator escape.
(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
Sensorimotor transformation, a process that converts sensory stimuli into motor actions, is critical for the brain to initiate behaviors. Although the circuitry involved in sensorimotor transformation has been well delineated, the molecular logic behind this process remains poorly understood. Here, we performed high-throughput and circuit-specific single-cell transcriptomic analyses of neurons in the superior colliculus (SC), a midbrain structure implicated in early sensorimotor transformation. We found that SC neurons in distinct laminae expressed discrete marker genes. Of particular interest, Cbln2 and Pitx2 were key markers that define glutamatergic projection neurons in the optic nerve (Op) and intermediate gray (InG) layers, respectively. The Cbln2+ neurons responded to visual stimuli mimicking cruising predators, while the Pitx2+ neurons encoded prey-derived vibrissal tactile cues. By forming distinct input and output connections with other brain areas, these neuronal subtypes independently mediated behaviors of predator avoidance and prey capture. Our results reveal that, in the midbrain, sensorimotor transformation for different behaviors may be performed by separate circuit modules that are molecularly defined by distinct transcriptomic codes.
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Evaluation Summary:
This excellent manuscript combines molecular, anatomical and behavioral methods to characterize neuron types in the mouse superior colliculus. It will likely be a significant resource to those who study how these circuits integrate sensory information to promote motor output. A diverse set of experiments supports the conclusion that the superior colliculus includes separate circuit modules involved in distinct behaviors: prey capture and predator escape.
(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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Reviewer #1 (Public Review):
The authors performed high-throughput sequencing and performed transctiptome analysis of neurons in the adult superior colliculus (SC). This revealed that there are potentially 19 molecularly distinct neural cell types in the SC. Genes enriched is specific types have lamina specific expression patterns as do SC neurons that project to the LPTN and ZI. From this analysis two Cre-lines were chosen that express in the LPTN (Cbln2) or ZI (Pitx2) SC neurons. Using these lines and a number of tracing/recording techniques and behavioral assays they show that these two populations of neurons are involved in different circuits with the Cbln2 neurons responding to visual stimuli and necessary for the looming response, and the Pitx2 neurons responding to touch stimuli and involved in predator detection. This work will …
Reviewer #1 (Public Review):
The authors performed high-throughput sequencing and performed transctiptome analysis of neurons in the adult superior colliculus (SC). This revealed that there are potentially 19 molecularly distinct neural cell types in the SC. Genes enriched is specific types have lamina specific expression patterns as do SC neurons that project to the LPTN and ZI. From this analysis two Cre-lines were chosen that express in the LPTN (Cbln2) or ZI (Pitx2) SC neurons. Using these lines and a number of tracing/recording techniques and behavioral assays they show that these two populations of neurons are involved in different circuits with the Cbln2 neurons responding to visual stimuli and necessary for the looming response, and the Pitx2 neurons responding to touch stimuli and involved in predator detection. This work will be of wide interest to researchers who aim to understand the relationship between molecular identity and function.
The strengths of the paper are the identification of genes in the SC that are likely to be cell type specific, the characterization of two such cell types, and the finding that different cell type are used for specific behaviorally relevant tasks. There is also a large number of independent techniques used to validate the hypothesis.
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Reviewer #2 (Public Review):
This work presents an integrated characterization of neuron types in the mouse superior colliculus, using the combination of molecular, anatomical and functional methods. This midbrain area is involved in sensorimotor processing in a wide range of behavioral contexts including predator escape and prey capture. Like the cerebral cortex, the superior colliculus is organized in layers with specialized input-output connectivity. Neural circuits engaging these layers have been studied extensively in the past. However, neuron types in the superior colliculus had never been characterized systematically with molecular data.
This paper is an initial step towards the complete multimodal characterization of neural types in this important brain area. The study is based on an impressive array of challenging experiments, …
Reviewer #2 (Public Review):
This work presents an integrated characterization of neuron types in the mouse superior colliculus, using the combination of molecular, anatomical and functional methods. This midbrain area is involved in sensorimotor processing in a wide range of behavioral contexts including predator escape and prey capture. Like the cerebral cortex, the superior colliculus is organized in layers with specialized input-output connectivity. Neural circuits engaging these layers have been studied extensively in the past. However, neuron types in the superior colliculus had never been characterized systematically with molecular data.
This paper is an initial step towards the complete multimodal characterization of neural types in this important brain area. The study is based on an impressive array of challenging experiments, including single-cell RNAseq, patch-seq, high-resolution viral tracing, calcium imaging and behavioral experiments. Using single-cell RNA seq as an entry point, the authors identify two types of glutamatergic neurons expressing distinct markers, including Cbln2 and Pitx2. These types localize to distinct layers of the superior colliculus, and have distinct input-output connectivity. Behavioral and manipulation experiments indicate that these two types are part of two distinct circuit modules, involved in predator avoidance and prey capture, respectively.
From these data, the general conclusion proposed is that transcriptomically-defined neuron types in the superior colliculus belong to neural circuits engaged in distinct behaviors.
The paper is well written and the data support the main conclusions.
Strengths:
The wide range of methods used in this paper is impressive. This is a complete story that truly embraces the multidisciplinary spirit of modern neuroscience. With the multimodal characterization of neuron types, the authors achieve several goals. First, they go beyond a simple description of cell clusters in the single-cell transcriptomic space, and corroborate the conclusion that these clusters are distinct cell types using orthogonal lines of evidence. Second, the multimodal data are key to bridge molecular data to physiology and behavior. Using the single-cell RNA sequencing data as an entry point, the authors were able to identify cell-type specific marker genes and transgenic lines which were instrumental for precise circuit mapping and manipulation experiments.
This paper will be an important reference for researchers interested in the superior colliculus because it introduces new resources. Single-cell RNA sequencing data from the mouse superior colliculus are not new, but this dataset is larger and analyzed thoroughly. Furthermore, the paper reports the generation and characterization of a new transgenic line, the Cbln2-IRES-Cre line, created by CRISPR knock in.
Weaknesses:
The choice of experimental breadth comes with the cost of depth, perhaps unavoidably. The size of the single-cell RNA sequencing dataset is still relatively modest, and the true diversity of neuron types in the superior colliculus might have been underestimated.
The combination of tracing and Patch-Seq experiments indicates that Cbln2 and Pitx2 are expressed in neurons projecting to the LPTN and to the ZI, respectively. However, the present data do not exclude the possibility that other neuron types in the superior colliculus, that do not express those markers, are projecting to LPTN or ZI.
The circuit model proposed in Figure 7L appears oversimplified. The model proposes that predator escape and prey capture behaviors are associated to the projections of Cbln2 and Pitx2 neurons to LPTN and ZI, respectively. However, as Figure S6 shows, Cbln2 and Pitx2 neurons project to many other brain areas. This is consistent with previous literature. Presumably several of these downstream brain areas, besides LPTN and ZI, are engaged in those behaviors.
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