Inhibitory columnar feedback neurons are required for motion processing in Drosophila
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eLife Assessment
This important article reports on the role of specific interneurons in the motion processing circuitry of the fruit fly, and marshals convincing evidence from neural recording, genetic manipulation, and behavioral analysis. A significant result ties the activity of C2/C3 neurons to the temporal resolution of the motion vision system. It remains unclear whether disrupting this pathway affects the dynamics of vision more generally.
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Abstract
Visual motion information is essential to guiding the movements of many animals. The establishment of direction-selective signals, a hallmark of motion detection, is considered a core neural computation and has been characterized extensively in primates, mice and fruit flies. In flies, the circuits that produce direction-selective signals rely on feedforward visual pathways that connect peripheral visual inputs to the dendrites of the ON and OFF-direction selective cells. Here we describe a novel role for feedback inhibition in motion computation. Two GABAergic neurons, C2 and C3, connect to neurons upstream of the direction-selective T4 and T5 cells and blocking C2 and C3 affects direction selectivity in T4/T5. In the ON pathway, this is likely achieved by C2-mediated suppression of responses in the major T4 input neuron Mi1. Together, C2 and C3 suppress responses to non-preferred stimuli in both T4 and T5. At the behavioral level, feedback inhibition temporally sharpens responses to ON stimuli, enhancing the fly’s ability to discriminate visual stimuli that occur in quick succession. GABAergic inhibitory feedback neurons thus constitute an essential component within the circuitry that computes visual motion.
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eLife Assessment
This important article reports on the role of specific interneurons in the motion processing circuitry of the fruit fly, and marshals convincing evidence from neural recording, genetic manipulation, and behavioral analysis. A significant result ties the activity of C2/C3 neurons to the temporal resolution of the motion vision system. It remains unclear whether disrupting this pathway affects the dynamics of vision more generally.
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Reviewer #1 (Public review):
Summary:
In this manuscript, Henning et al. examine the impact of GABAergic feedback inhibition on the motion-sensitive pathway of flies. Based on a previous behavioral screen, the authors determined that C2 and C3, two GABAergic inhibitory feedback neurons in the optic lobes of the fly, are required for the optomotor response. Through a series of calcium imaging and disruption experiments, connectomics analysis, and follow-up behavioral assays, the authors concluded that C2 and C3 play a role in temporally sharpening visual motion responses. While this study employs a comprehensive array of experimental approaches, I have some reservations about the interpretation of the results in their current form. I strongly encourage the authors to provide additional data to solidify their conclusions. This is …
Reviewer #1 (Public review):
Summary:
In this manuscript, Henning et al. examine the impact of GABAergic feedback inhibition on the motion-sensitive pathway of flies. Based on a previous behavioral screen, the authors determined that C2 and C3, two GABAergic inhibitory feedback neurons in the optic lobes of the fly, are required for the optomotor response. Through a series of calcium imaging and disruption experiments, connectomics analysis, and follow-up behavioral assays, the authors concluded that C2 and C3 play a role in temporally sharpening visual motion responses. While this study employs a comprehensive array of experimental approaches, I have some reservations about the interpretation of the results in their current form. I strongly encourage the authors to provide additional data to solidify their conclusions. This is particularly relevant in determining whether this is a general phenomenon affecting vision or a specific effect on motion vision. Knowing this is also important for any speculation on the mechanisms of the observed temporal deficiencies.
Strengths:
This study uses a variety of experiments to provide a functional, anatomical, and behavioral description of the role of GABAergic inhibition in the visual system. This comprehensive data is relevant for anyone interested in understanding the intricacies of visual processing in the fly.
Weaknesses:
(1) The most fundamental criticism of this study is that the authors present a skewed view of the motion vision pathway in their results. While this issue is discussed, it is important to demonstrate that there are no temporal deficiencies in the lamina, which could be the case since C2 and C3, as noted in the connectomics analysis, project strongly to laminar interneurons. If the input dynamics are indeed disrupted, then the disruption seen in the motion vision pathway would reflect disruptions in temporal processing in general and suggest that these deficiencies are inherited downstream. A simple experiment could test this. Block C2, C3, and both together using Kir2.1 and Shibire independently, then record the ERG. Alternatively, one could image any other downstream neuron from the lamina that does not receive C2 or C3 input.
(2) Figure 6c. More analysis is required here, since the authors claim to have found a loss in inhibition (ND). However, the difference in excitation appears similar, at least in absolute magnitude (see panel 6c), for PD direction for the T4 C2 and C3 blocks. Also, I predict that C2 & C3 block statistically different from C3 only, why? In any case, it would be good to discuss the clear trend in the PD direction by showing the distribution of responses as violin plots to better understand the data. It would also be good to have some raw traces to be able to see the differences more clearly, not only polar plots and averages.
(3) The behavioral experiments are done with a different disruptor than the physiological ones. One blocks chemical synapses, the other shunts the cells. While one would expect similar results in both, this is not a given. It would be great if the authors could test the behavioral experiments with Kir2.1, too.
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Reviewer #2 (Public review):
Summary:
The work by Henning et al. explores the role of feedback inhibition in motion vision circuits, providing the first identification of inhibitory inheritance in motion-selective T4 and T5 cells of Drosophila. This work advances our current knowledge in Drosophila motion vision and sets the way for further exploring the intricate details of direction-selective computations.
Strengths:
Among the strengths of this work is the verification of the GABAergic nature of C2 and C3 with genetic and immunohistochemical approaches. In addition, double-silencing C2&C3 experiments help to establish a functional role for these cells. The authors holistically use the Drosophila toolbox to identify neural morphologies, synaptic locations, network connectivity, neuronal functions, and the behavioral output.
Weaknesses:
Reviewer #2 (Public review):
Summary:
The work by Henning et al. explores the role of feedback inhibition in motion vision circuits, providing the first identification of inhibitory inheritance in motion-selective T4 and T5 cells of Drosophila. This work advances our current knowledge in Drosophila motion vision and sets the way for further exploring the intricate details of direction-selective computations.
Strengths:
Among the strengths of this work is the verification of the GABAergic nature of C2 and C3 with genetic and immunohistochemical approaches. In addition, double-silencing C2&C3 experiments help to establish a functional role for these cells. The authors holistically use the Drosophila toolbox to identify neural morphologies, synaptic locations, network connectivity, neuronal functions, and the behavioral output.
Weaknesses:
The authors claim that C2 and C3 neurons are required for direction selectivity, as per the publication's title; however, even with their double silencing, the directional T4 & T5 responses are not completely abolished. Therefore, the contribution of this inherited feedback in direction-selective computations is not a prerequisite for its emergence, and the title could be re-adjusted.
Connectivity is assessed in one out of the two available connectome datasets; therefore, it would make the study stronger if the same connectivity patterns were identified in both datasets.
The mediating neural correlates from C2 & C3 to T4 & T5 are not clarified; rather, Mi1 is found to be one of them. The study could be improved if the same set of silencing experiments performed for C2-Mi1 were extended to C2 &C3-Tm1 or Tm4 to find the T5 neural mediators of this feedback inhibition loop. Stating more clearly from the connectomic analysis, the potential T5 mediators would be equally beneficial. Future experiments might also disentangle the parallel or separate functions of C2 and C3 neurons.
Finally, the authors' conclusions derive from the set of experiments they performed in a logical manner. Nonetheless, the Discussion could benefited from a more extensive explanation on the following matters: why do the ON-selective C2 and C3 neurons control OFF-generated behaviors, why the T4&T5 responses after C2&C3 silencing differ between stationary and moving stimuli and finally why C2 and not C3 had an effect in T5 DS responses, as the connectivity suggests C3 outputting to two out of the four major T5 cholinergic inputs.
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Reviewer #3 (Public review):
Summary:
This article is about the neural circuitry underlying motion vision in the fruit fly. Specifically, it regards the roles of two identified neurons, called C2 and C3, that form columnar connections between neurons in the lamina and medulla, including neurons that are presynaptic to the elementary motion detectors T4 and T5. The approach takes advantage of specific fly lines in which one can disable the synaptic outputs of either or both of the C2/3 cell types. This is combined with optical recording from various neurons in the circuit, and with behavioral measurements of the turning reaction to moving stimuli.
The experiments are planned logically. The effects of silencing the C2/C3 neurons are substantial in size. The dominant effect is to make the responses of downstream neurons more sustained, …
Reviewer #3 (Public review):
Summary:
This article is about the neural circuitry underlying motion vision in the fruit fly. Specifically, it regards the roles of two identified neurons, called C2 and C3, that form columnar connections between neurons in the lamina and medulla, including neurons that are presynaptic to the elementary motion detectors T4 and T5. The approach takes advantage of specific fly lines in which one can disable the synaptic outputs of either or both of the C2/3 cell types. This is combined with optical recording from various neurons in the circuit, and with behavioral measurements of the turning reaction to moving stimuli.
The experiments are planned logically. The effects of silencing the C2/C3 neurons are substantial in size. The dominant effect is to make the responses of downstream neurons more sustained, consistent with a circuit role in feedback or feedforward inhibition. Silencing C2/C3 also makes the motion-sensitive neurons T4/T5 less direction-selective. However, the turning response of the fly is affected only in subtle ways. Detection of motion appears unaffected. But the response fails to discriminate between two motion pulses that happen in close succession. One can conclude that C2/C3 are involved in the motion vision circuit, by sharpening responses in time, though they are not essential for its basic function of motion detection.
Strengths:
The combination of cutting-edge methods available in fruit fly neuroscience. Well-planned experiments carried out to a high standard. Convincing effects documenting the role of these neurons in neural processing and behavior.
Weaknesses:
The report could benefit from a mechanistic argument linking the effects at the level of single neurons, the resulting neural computations in elementary motion detectors, and the altered behavioral response to visual motion.
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