Flexible specificity of memory in Drosophila depends on a comparison between choices
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Modi et al. investigate the question of how learned information guides behavior. They combine optogenetic conditioning in Drosophila to spatially restrict the formation of olfactory memory traces in mushroom bodies (MBs), where olfactory memory traces are formed during pavlovian olfactory conditioning and follow up with behavioral studies and physiological analysis to examine how flies use these 'minimal memories' during learned olfactory discrimination. They discover that MBONs' responses predict behavioral outcomes, with odor responses showing physiological differences under conditions where broadly similar odorants must be discriminated. Thus, flies use olfactory memory templates flexibly to suit their behavioral needs. Modi et al. conclude that a hitherto unknown mechanism downstream of mushroom body output neurons creates these context-specific responses at the MBONs. Overall, the experiments provide convincing physiological evidence for a neural mechanism that underlies a contextual basis for the precision of memory recall, which constitutes a fundamentally important advance in our understanding of the neurobiology of memory retrieval, however, the authors need to more deeply consider caveats to their arguments, more deeply discuss differences and similarities with prior publications and bolster their data by including a few controls that are currently missing.
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Abstract
Memory guides behavior across widely varying environments and must therefore be both sufficiently specific and general. A memory too specific will be useless in even a slightly different environment, while an overly general memory may lead to suboptimal choices. Animals successfully learn to both distinguish between very similar stimuli and generalize across cues. Rather than forming memories that strike a balance between specificity and generality, Drosophila can flexibly categorize a given stimulus into different groups depending on the options available. We asked how this flexibility manifests itself in the well-characterized learning and memory pathways of the fruit fly. We show that flexible categorization in neuronal activity as well as behavior depends on the order and identity of the perceived stimuli. Our results identify the neural correlates of flexible stimulus-categorization in the fruit fly.
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Author Response
Reviewer #1 (Public Review):
The paper addresses why and how odor discrimination ability achieved after learning occurs in select contexts. The finding is that two related odors trigger near identical Kenyon cell responses when tested in isolation, but trigger different responses to the second odor if these are experienced in sequence within a small temporal window. The authors argue that this template comparison requires some activity downstream of Kenyon cells, that is recruited by MBONs. Overall, the experiments provide very nice physiological evidence for a neural mechanism that underlies a contextual basis for the precision of memory recall.
The experiments were well designed and done. The findings are interesting, but the pitch (e.g. the last paragraph of the discussion and the title of the paper) seems to …
Author Response
Reviewer #1 (Public Review):
The paper addresses why and how odor discrimination ability achieved after learning occurs in select contexts. The finding is that two related odors trigger near identical Kenyon cell responses when tested in isolation, but trigger different responses to the second odor if these are experienced in sequence within a small temporal window. The authors argue that this template comparison requires some activity downstream of Kenyon cells, that is recruited by MBONs. Overall, the experiments provide very nice physiological evidence for a neural mechanism that underlies a contextual basis for the precision of memory recall.
The experiments were well designed and done. The findings are interesting, but the pitch (e.g. the last paragraph of the discussion and the title of the paper) seems to both ignore the main finding of the paper and overstate the novelty of the idea that memory recall can be flexibly regulated by context. There should be more space dedicated to clearly articulated statements/descriptions of hypotheses and candidate mechanisms to explain the interesting phenomenon described here. For instance, explaining "enhanced template mismatch detection" by potential " real-time and delay line summation" of MBON activity is not super useful for the reader as seems to use one abstraction to explain another. The authors cite Lin et al, 2014 from Miesenbock's lab which shows a key role for GABAergic APL neurons in discrimination. Is there increased activation of APL neurons when similar odourants are being compared and discrimination is required? This seems like a simple physically embodied mechanism that could/ should be examined.
Overall, I think the idea that memories are recalled with high precision (less generalisation) only when increased precision is demanded, is a fact that sure is well appreciated by behavioral biologists even beyond the two papers cited here (Campbell et al., J Neurosci 2013; Xu and Südhof, Science 2013). The new findings fill in a physiological gap in this phenomenology. I think the paper would be greatly improved if the authors highlighted what and focused on the physiological correlate uncovered, and tried to communicate (or test) possible mechanistic origins for this in more physically accessible terms.
We thank Reviewer #1 for their appreciation of our findings. We are grateful for this extremely constructive feedback on re-focussing the pitch of the paper and have extensively revised the manuscript along these lines, particularly changing the Title, Introduction and Discussion. As suggested, we now highlight how similar stimuli can be categorized together, or apart, depending on the stimulus choices animals are presented during recall.
Reviewer #2 (Public Review):
One of the key questions in circuit neuroscience is how learned information guides behavior. Modi et al. investigated this question in Drosophila's mushroom bodies (MBs), where olfactory memory traces are formed during pavlovian olfactory conditioning. They have used optogenetics to restrict the formation of memory traces in selective output compartments of the Kenyon cell (KC) axon terminals, the principal intrinsic neurons of the MB, and tested how flies use these 'minimal memories' during learned olfactory discrimination. They found that memory traces formed in some compartments support discrimination between similar odor pairs, whereas others do not. They then investigated the neural basis of this difference by comparing the responses of relevant output neurons (MBONs) to similar and dissimilar odor pairs. They discovered that MBONs' responses could predict behavioral outcomes if odor presentation profiles during calcium imaging mimic olfactory experience during behavior. This paper and previous works support the idea that flies use olfactory memory templates flexibly to suit their behavioral needs. However, one key difference between this paper and the previous works is the site of discrimination. While previous studies using intensity discrimination have pointed towards spike-latency and on and off responses of the KCs as the main mechanism behind discrimination, Modi et al. have not detected any response difference for similar odor pairs among the KCs. Therefore, they concluded that a hitherto unknown mechanism creates these context-specific responses at the MBONs. The findings will advance our understanding of how memories are recalled during behavior. However, the authors need to bolster their data by including some critical controls that are currently missing.
We thank Reviewer #2 for highlighting how our work contributes to the literature and for pointing out the gaps in our discussion of previous work, as well as the missing controls.
Reviewer #3 (Public Review):
This manuscript by Modi et al represents a novel and significant advance in the neurobiology of memory retrieval. The authors employ a novel behavioral paradigm in order to investigate memory generalization and discrimination. They investigate the role of two different populations of dopamine neurons (DANs) targeting different compartments involved in aversion learning, i.e. α3 (MB630B) and γ2α'1 (MB296B).
The behavioral platform is clear and convincing but lacks natural reinforcement comparisons. The entire paper uses optogenetic reinforcement of said DAN populations.
The authors identify that the gamma DANs can enable both easy and hard odor discrimination, while the alphas DANs can only do easy.
The odors can be separated by calcium imaging analysis of Kenyon cells. Subsequent calcium imaging of the gamma DANs themselves showed that a single training event was insufficient to enable easy odor discrimination at the gamma DAN level, but strangely not for the hard discrimination that gamma DANs can mediate. Seemingly, this is due to the lack of the temporal contiguity of odors (present in behavioral experiments but not in the initial imaging experiments. However, in gamma DANs, Odour transitions enabled discrimination of odors in hard discrimination, based on the depression of calcium activity in DANs after training that was odor-specific. The same was not true for alpha DANs, though the authors used natural electric shock pairings instead of optogenetic stimulation of DANs for the alpha experiment. However, statistical comparisons are done within group and need also be provided for between the groups for both pre and post-training. The authors persuasively show that hard discrimination can only happen in transitions. They also argue that the same engram can be read in two different ways. This is convincing overall, but they claim it is happening downstream of the Kenyon cells just because they do not see it in the Kenyon cells, and I cannot comment on the modeling in Figure 5 (expertise).
Experimental methods used are appropriate, as are data analysis strategies.
The manuscript itself is well written in parts, though at times paragraphs are quite patchy, especially in the discussion. There are also a visible number of typos. The figures are well constructed, and generally well organized. The overall document is concise and has sufficient detail.
We appreciate the reviewer’s comments on the novelty and significance of our study.
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eLife assessment
Modi et al. investigate the question of how learned information guides behavior. They combine optogenetic conditioning in Drosophila to spatially restrict the formation of olfactory memory traces in mushroom bodies (MBs), where olfactory memory traces are formed during pavlovian olfactory conditioning and follow up with behavioral studies and physiological analysis to examine how flies use these 'minimal memories' during learned olfactory discrimination. They discover that MBONs' responses predict behavioral outcomes, with odor responses showing physiological differences under conditions where broadly similar odorants must be discriminated. Thus, flies use olfactory memory templates flexibly to suit their behavioral needs. Modi et al. conclude that a hitherto unknown mechanism downstream of mushroom body output neurons …
eLife assessment
Modi et al. investigate the question of how learned information guides behavior. They combine optogenetic conditioning in Drosophila to spatially restrict the formation of olfactory memory traces in mushroom bodies (MBs), where olfactory memory traces are formed during pavlovian olfactory conditioning and follow up with behavioral studies and physiological analysis to examine how flies use these 'minimal memories' during learned olfactory discrimination. They discover that MBONs' responses predict behavioral outcomes, with odor responses showing physiological differences under conditions where broadly similar odorants must be discriminated. Thus, flies use olfactory memory templates flexibly to suit their behavioral needs. Modi et al. conclude that a hitherto unknown mechanism downstream of mushroom body output neurons creates these context-specific responses at the MBONs. Overall, the experiments provide convincing physiological evidence for a neural mechanism that underlies a contextual basis for the precision of memory recall, which constitutes a fundamentally important advance in our understanding of the neurobiology of memory retrieval, however, the authors need to more deeply consider caveats to their arguments, more deeply discuss differences and similarities with prior publications and bolster their data by including a few controls that are currently missing.
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Reviewer #1 (Public Review):
The paper addresses why and how odor discrimination ability achieved after learning occurs in select contexts. The finding is that two related odors trigger near identical Kenyon cell responses when tested in isolation, but trigger different responses to the second odor if these are experienced in sequence within a small temporal window. The authors argue that this template comparison requires some activity downstream of Kenyon cells, that is recruited by MBONs. Overall, the experiments provide very nice physiological evidence for a neural mechanism that underlies a contextual basis for the precision of memory recall.
The experiments were well designed and done. The findings are interesting, but the pitch (e.g. the last paragraph of the discussion and the title of the paper) seems to both ignore the main …
Reviewer #1 (Public Review):
The paper addresses why and how odor discrimination ability achieved after learning occurs in select contexts. The finding is that two related odors trigger near identical Kenyon cell responses when tested in isolation, but trigger different responses to the second odor if these are experienced in sequence within a small temporal window. The authors argue that this template comparison requires some activity downstream of Kenyon cells, that is recruited by MBONs. Overall, the experiments provide very nice physiological evidence for a neural mechanism that underlies a contextual basis for the precision of memory recall.
The experiments were well designed and done. The findings are interesting, but the pitch (e.g. the last paragraph of the discussion and the title of the paper) seems to both ignore the main finding of the paper and overstate the novelty of the idea that memory recall can be flexibly regulated by context. There should be more space dedicated to clearly articulated statements/descriptions of hypotheses and candidate mechanisms to explain the interesting phenomenon described here. For instance, explaining "enhanced template mismatch detection" by potential " real-time and delay line summation" of MBON activity is not super useful for the reader as seems to use one abstraction to explain another. The authors cite Lin et al, 2014 from Miesenbock's lab which shows a key role for GABAergic APL neurons in discrimination. Is there increased activation of APL neurons when similar odourants are being compared and discrimination is required? This seems like a simple physically embodied mechanism that could/ should be examined.
Overall, I think the idea that memories are recalled with high precision (less generalisation) only when increased precision is demanded, is a fact that sure is well appreciated by behavioral biologists even beyond the two papers cited here (Campbell et al., J Neurosci 2013; Xu and Südhof, Science 2013). The new findings fill in a physiological gap in this phenomenology. I think the paper would be greatly improved if the authors highlighted what and focused on the physiological correlate uncovered, and tried to communicate (or test) possible mechanistic origins for this in more physically accessible terms.
-
Reviewer #2 (Public Review):
One of the key questions in circuit neuroscience is how learned information guides behavior. Modi et al. investigated this question in Drosophila's mushroom bodies (MBs), where olfactory memory traces are formed during pavlovian olfactory conditioning. They have used optogenetics to restrict the formation of memory traces in selective output compartments of the Kenyon cell (KC) axon terminals, the principal intrinsic neurons of the MB, and tested how flies use these 'minimal memories' during learned olfactory discrimination. They found that memory traces formed in some compartments support discrimination between similar odor pairs, whereas others do not. They then investigated the neural basis of this difference by comparing the responses of relevant output neurons (MBONs) to similar and dissimilar odor …
Reviewer #2 (Public Review):
One of the key questions in circuit neuroscience is how learned information guides behavior. Modi et al. investigated this question in Drosophila's mushroom bodies (MBs), where olfactory memory traces are formed during pavlovian olfactory conditioning. They have used optogenetics to restrict the formation of memory traces in selective output compartments of the Kenyon cell (KC) axon terminals, the principal intrinsic neurons of the MB, and tested how flies use these 'minimal memories' during learned olfactory discrimination. They found that memory traces formed in some compartments support discrimination between similar odor pairs, whereas others do not. They then investigated the neural basis of this difference by comparing the responses of relevant output neurons (MBONs) to similar and dissimilar odor pairs. They discovered that MBONs' responses could predict behavioral outcomes if odor presentation profiles during calcium imaging mimic olfactory experience during behavior. This paper and previous works support the idea that flies use olfactory memory templates flexibly to suit their behavioral needs. However, one key difference between this paper and the previous works is the site of discrimination. While previous studies using intensity discrimination have pointed towards spike-latency and on and off responses of the KCs as the main mechanism behind discrimination, Modi et al. have not detected any response difference for similar odor pairs among the KCs. Therefore, they concluded that a hitherto unknown mechanism creates these context-specific responses at the MBONs. The findings will advance our understanding of how memories are recalled during behavior. However, the authors need to bolster their data by including some critical controls that are currently missing.
-
Reviewer #3 (Public Review):
This manuscript by Modi et al represents a novel and significant advance in the neurobiology of memory retrieval. The authors employ a novel behavioral paradigm in order to investigate memory generalization and discrimination. They investigate the role of two different populations of dopamine neurons (DANs) targeting different compartments involved in aversion learning, i.e. α3 (MB630B) and γ2α'1 (MB296B).
The behavioral platform is clear and convincing but lacks natural reinforcement comparisons. The entire paper uses optogenetic reinforcement of said DAN populations.
The authors identify that the gamma DANs can enable both easy and hard odour discrimination, while the alphas DANs can only do easy.
The odours can be separated by calcium imaging analysis of Kenyon cells. Subsequent calcium imaging of the …
Reviewer #3 (Public Review):
This manuscript by Modi et al represents a novel and significant advance in the neurobiology of memory retrieval. The authors employ a novel behavioral paradigm in order to investigate memory generalization and discrimination. They investigate the role of two different populations of dopamine neurons (DANs) targeting different compartments involved in aversion learning, i.e. α3 (MB630B) and γ2α'1 (MB296B).
The behavioral platform is clear and convincing but lacks natural reinforcement comparisons. The entire paper uses optogenetic reinforcement of said DAN populations.
The authors identify that the gamma DANs can enable both easy and hard odour discrimination, while the alphas DANs can only do easy.
The odours can be separated by calcium imaging analysis of Kenyon cells. Subsequent calcium imaging of the gamma DANs themselves showed that a single training event was insufficient to enable easy odor discrimination at the gamma DAN level, but strangely not for the hard discrimination that gamma DANs can mediate. Seemingly, this is due to the lack of the temporal contiguity of odors (present in behavioral experiments but not in the initial imaging experiments.
However, in gamma DANs, Odour transitions enabled discrimination of odours in hard discrimination, based on the depression of calcium activity in DANs after training that was odour-specific. The same was not true for alpha DANs, though the authors used natural electric shock pairings instead of optogenetic stimulation of DANs for the alpha experiment. However, statistical comparisons are done within group and need also be provided for between the groups for both pre and post-training. The authors persuasively show that hard discrimination can only happen in transitions. They also argue that the same engram can be read in two different ways. This is convincing overall, but they claim it is happening downstream of the Kenyon cells just because they do not see it in the Kenyon cells, and I cannot comment on the modelling in Figure 5 (expertise).
Experimental methods used are appropriate, as are data analysis strategies.
The manuscript itself is well written in parts, though at times paragraphs are quite patchy, especially in the discussion. There are also a visible number of typos. The figures are well constructed, and generally well organized. The overall document is concise and has sufficient detail.
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