NMDA receptors in visual cortex are necessary for normal visuomotor integration and skill learning
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Evaluation Summary:
This study examined the mechanism underlying the development of prediction-error related responses of neurons in the primary visual cortex (V1) evoked by the mismatch between self-generated locomotor movement and visual feedback. The authors show that unilateral gene knockout of NMDA receptors or CaMKII in the primary visual cortex impaired the mismatch-related responses in V1. The experiments are well thought out and the paper is well presented. The results suggesting a role for local plasticity in V1 will be of great interest to those researchers interested in neural circuit development as well as cortical functions.
(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. The reviewers remained anonymous to the authors.)
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Abstract
The experience of coupling between motor output and visual feedback is necessary for the development of visuomotor skills and shapes visuomotor integration in visual cortex. Whether these experience-dependent changes of responses in V1 depend on modifications of the local circuit or are the consequence of circuit changes outside of V1 remains unclear. Here, we probed the role of N -methyl- d -aspartate (NMDA) receptor-dependent signaling, which is known to be involved in neuronal plasticity, in mouse primary visual cortex (V1) during visuomotor development. We used a local knockout of NMDA receptors and a photoactivatable inhibition of CaMKII in V1 during the first visual experience to probe for changes in neuronal activity in V1 as well as the influence on performance in a visuomotor task. We found that a knockout of NMDA receptors before, but not after, first visuomotor experience reduced responses to unpredictable stimuli, diminished the suppression of predictable feedback in V1, and impaired visuomotor skill learning later in life. Our results demonstrate that NMDA receptor-dependent signaling in V1 is critical during the first visuomotor experience for shaping visuomotor integration and enabling visuomotor skill learning.
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Evaluation Summary:
This study examined the mechanism underlying the development of prediction-error related responses of neurons in the primary visual cortex (V1) evoked by the mismatch between self-generated locomotor movement and visual feedback. The authors show that unilateral gene knockout of NMDA receptors or CaMKII in the primary visual cortex impaired the mismatch-related responses in V1. The experiments are well thought out and the paper is well presented. The results suggesting a role for local plasticity in V1 will be of great interest to those researchers interested in neural circuit development as well as cortical functions.
(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. The reviewers …
Evaluation Summary:
This study examined the mechanism underlying the development of prediction-error related responses of neurons in the primary visual cortex (V1) evoked by the mismatch between self-generated locomotor movement and visual feedback. The authors show that unilateral gene knockout of NMDA receptors or CaMKII in the primary visual cortex impaired the mismatch-related responses in V1. The experiments are well thought out and the paper is well presented. The results suggesting a role for local plasticity in V1 will be of great interest to those researchers interested in neural circuit development as well as cortical functions.
(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. The reviewers remained anonymous to the authors.)
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Reviewer #1 (Public Review):
Widmer and Keller investigate the role of NMDAR-dependent plasticity in mouse V1 in the development of proper motor-sensory mismatch detection. To control motor-visual experience, the authors reared mice in the dark and then controlled their only motor-visual experience in a VR corridor. Using in vivo 2p imaging of L2/3 excitatory neurons, the authors find that unilateral inactivation of V1 NMDARs led to a decrease in mismatch signals when optic flow is halted; a decrease in visually evoked responses; and abnormal integration of sensory and motor signals at locomotion onset. These findings required NMDAR inactivation during the mouse's first motor-visual experiences. NMDAR-inactivated mice also showed an inability to adjust their behavior in a motor-visual task. Finally, the authors show that inhibiting …
Reviewer #1 (Public Review):
Widmer and Keller investigate the role of NMDAR-dependent plasticity in mouse V1 in the development of proper motor-sensory mismatch detection. To control motor-visual experience, the authors reared mice in the dark and then controlled their only motor-visual experience in a VR corridor. Using in vivo 2p imaging of L2/3 excitatory neurons, the authors find that unilateral inactivation of V1 NMDARs led to a decrease in mismatch signals when optic flow is halted; a decrease in visually evoked responses; and abnormal integration of sensory and motor signals at locomotion onset. These findings required NMDAR inactivation during the mouse's first motor-visual experiences. NMDAR-inactivated mice also showed an inability to adjust their behavior in a motor-visual task. Finally, the authors show that inhibiting CAMKII function in excitatory neurons partially recapitulates the effect of V1-wide NMDAR inactivation, while inhibiting CaMKII function in SST neurons has some opposite effects. The authors conclude by suggesting that plasticity of excitatory synapses onto SST neurons is important for learning motor-visual expectations.
The experiments are well thought out, the paper is well presented, and this is an important contribution to our understanding of where in the brain plasticity happens as animals learn how their actions influence the world. There are a couple of small caveats in interpreting these results, many of which the authors go through in detail in their Discussion section. The authors focus their neuronal readout on the activity of excitatory neurons in L2/3. While there is precedent for focusing on these cells, the perturbations that the authors induce in their experiments are not limited to L2/3 cells. Therefore it remains to be tested at exactly which synaptic sites plasticity matters. Second, the two plasticity manipulations don't lead to exactly the same phenomenology in L2/3 excitatory neurons, leading to some residual questions about exactly how plasticity in V1 contributes to motor-sensory learning. Third, the magnitude of mismatch signals in their various control mice varies quite a bit, meaning that what looks like a big effect in one experimental group might actually be an artifact of the control condition.
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Reviewer #2 (Public Review):
Authors and others previously showed that coupling of motor output and visual sensory feedback is necessary to establish proper visuomotor integration in visual cortex. Here, authors investigated the roles of NMDA receptor and related CaMK2 activity in primary visual cortex to establish visuomotor integration during the first visual experience, and visuomotor skill learning later in life. They found that conditional knock out of NMDA receptor within V1 from juvenile period reared in dark from birth (but not in adult knock out) show diminished V1 mismatch onset response, suggesting a key role for visuomotor integration. The same manipulations also impaired visuomotor skill learning later in life. To gain insight into the cellular/circuit mechanism, authors also employed photoactivable inhibitor of CaM2K in …
Reviewer #2 (Public Review):
Authors and others previously showed that coupling of motor output and visual sensory feedback is necessary to establish proper visuomotor integration in visual cortex. Here, authors investigated the roles of NMDA receptor and related CaMK2 activity in primary visual cortex to establish visuomotor integration during the first visual experience, and visuomotor skill learning later in life. They found that conditional knock out of NMDA receptor within V1 from juvenile period reared in dark from birth (but not in adult knock out) show diminished V1 mismatch onset response, suggesting a key role for visuomotor integration. The same manipulations also impaired visuomotor skill learning later in life. To gain insight into the cellular/circuit mechanism, authors also employed photoactivable inhibitor of CaM2K in cell-type specific manner, and found changes in the correlation of V1 activity and visual flow when manipulating CaMK2 activity in SST interneurons consistent with the known role of this cell type in regulating visuomotor integration. Overall, these findings support a key role for NMDA receptor and associated CaMK2 signaling in V1 neurons (especially SST interneurons) in shaping visuomotor integration during the first visual experience. These findings are significant to the field as it provides the first molecular mechanism supporting the role of visuomotor integration in V1. Use of photoactivatable peptide to inhibit CaMK2 in cell type and temporally selective manner is especially elegant.
While the questions and findings are overall interesting, there are some issues with 1) the interpretation of the data related to plasticity, and 2) insufficient integration of data analysis and interpretation between Grin KO (Fig1) and CaMK2 manipulations (Fig5).
Regarding the data interpretation, authors interpreted that it is the "plasticity" which is necessary for visuomotor integration through the study of conditional manipulations of NMDA receptor or CaMK2 activity in mouse V1. However, data do not convincingly support this claim. Given that not only the response to mismatch onset response, but also grating onset response was reduced by juvenile V1 NMDAR knock-out, it is totally possible that diminished mismatch response may not directly require plasticity mechanism for visuomotor integration (bottom up/top-down integration) per se, but can be secondary to diminished visual response due to plasticity deficits of bottom-up visual input connectivity only. This possibility was not considered well in the current manuscript. Similar concerns on interpretations apply to CaMK2 manipulations which also led to changes in both mismatch onset response and grating onset response.
There is also a challenge in conceptually putting together the findings from Grin and CaMK2 manipulations. While manipulations of Grin and CaMK2 led to consistent changes at the level of activity correlation with visual flow, these manipulations led to very different V1 responses especially for grating onset response (Fig1F vs Fig5DG). It would be helpful if authors can attempt to better explain why this discrepancy does not contradict to the authors' model. It would be informative to consider the possibility that manipulation in single cell type (Fig5) vs multiple cell types (Fig1 uses non-cell type selective promotor for cre expression) leads to a different outcome. This possibility can be experimentally supported and/or discussed to enhance the integration of the study.
Other weaknesses, which are minor, include 1) lack of quantification of Grin KO, 2) lack of control experimental groups for better interpretation, 3) lack of consideration of dark rearing to delay the maturation program, and 4) insufficient descriptions of animal number for each figure. Some of these issues can be addressed with more description or experimentally. Otherwise, unaddressed issues need to be discussed thoroughly.
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