Frequency modulation of organelle calcium-dependent voltage oscillations: an essential memory trace produced by operant conditioning in Aplysia
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eLife Assessment
This important work substantially advances our understanding of non-synaptic biophysical mechanisms underpinning associative learning. The evidence supporting the conclusions is convincing, with rigorous behavioural assays and state-of-the-art electrophysiology. The work will be of broad interest to neurobiologists and biophysicists.
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Abstract
Spontaneous voltage oscillations in neuronal ensembles play a critical role in memory formation and storage. Although oscillatory activities arising endogenously within central pattern-generating (CPG) networks underlie many rhythmic motor behaviors, the contribution of such autonomous signals to motor learning and memory remains poorly understood. Previously, we found that the buccal CPG network driving food-seeking behavior in Aplysia contains a subset of electrically-coupled neurons that produces spontaneous, variable-amplitude voltage oscillations instigating infrequent and irregular cycles of patterned motor output. This pattern-initiating activity originates from organelle-derived, inositol triphosphate (IP3) receptor-dependent calcium oscillations in a pair of identified decision-making neurons (B63) within the CPG subset (Bédécarrats et al., 2021). Here, we show that the cycle frequency of this spontaneous pacemaker mechanism based on intracellular calcium store release is persistently increased by operant reward-learning, and in association with increased B63 excitability, constitutes a fundamental memory trace for accelerated and stereotyped rhythmic food-seeking movements.
Article activity feed
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eLife Assessment
This important work substantially advances our understanding of non-synaptic biophysical mechanisms underpinning associative learning. The evidence supporting the conclusions is convincing, with rigorous behavioural assays and state-of-the-art electrophysiology. The work will be of broad interest to neurobiologists and biophysicists.
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Reviewer #1 (Public review):
Summary:
This manuscript presents some interesting results that further delineate and characterize the origins of rhythmicity in a paradigmatic model system, the Aplysia feeding network.
Strengths:
The manuscript writing is clear and concise. The figures present the data well (with one exception noted below), and the mathematical and statistical analyses are rigorously done. The results support most of the authors' conclusions, except for three Discussion points as noted below. This manuscript does make a significant contribution to our understanding of how rhythmic motor patterns are generated in a relatively simple, widely used animal model, thus, these results are of considerable importance.
Weaknesses:
There is one significant data inconsistency the authors need to address. Three of the Discussion points …
Reviewer #1 (Public review):
Summary:
This manuscript presents some interesting results that further delineate and characterize the origins of rhythmicity in a paradigmatic model system, the Aplysia feeding network.
Strengths:
The manuscript writing is clear and concise. The figures present the data well (with one exception noted below), and the mathematical and statistical analyses are rigorously done. The results support most of the authors' conclusions, except for three Discussion points as noted below. This manuscript does make a significant contribution to our understanding of how rhythmic motor patterns are generated in a relatively simple, widely used animal model, thus, these results are of considerable importance.
Weaknesses:
There is one significant data inconsistency the authors need to address. Three of the Discussion points are not supported and need removal or revision, and I have a few minor comments.
Major Comments:
(1) In Figure 3A, for the noncontingent (NC) group, the plotted mean rate of BMPs is highly discrepant from the rate of BMPs in Figure 2A1, assuming the stated 10 min trace duration is accurate. More importantly, that mean rate is discrepant from the 89 sec spectral density peak in 2A2. However, that mean rate does appear consistent with the rate of NC fast oscillations in Fig. 2A1 and with the 57 sec peak in 2A2. Thus, it appears the fast oscillation rate was actually plotted in 3A. For the contingent (C) group, the rates are about the same, so I can't tell if the same issue is present. Check if this inconsistency is also an issue for Figure 3B. Revise these figures as needed. Revise any manuscript text as needed to account for, or explain, this inconsistency.
(2) Page 10, lines 210-214. The presented data do not establish that IP3 removed the memory trace. Instead, IP3 could have obscured the trace without removing it. To really establish that the trace was removed, IP3 would have to be removed to see if the trace returned or not. This caveat should be noted in the Discussion.
(3) Discussion, lines 452-454. This statement about replay is completely unwarranted because nothing in your preceding text deals, specifically, with replay of activity patterns. Replay is a specific term as occurs, for example, when rats spontaneously replay a sequence of neural activations that previously occurred when they were running along a track. If you want to discuss replay, you have to add some more references and discussion that spell out any link between oscillations and replay.
(4) Discussion, lines 460-463, and 590-592. I am highly skeptical that the relatively small subthreshold oscillations, as opposed to the much larger voltage bursts, can propagate through gap junctions to an extent that would initiate electrical activity in neighboring cells. It would appear that the subthreshold oscillations would be attenuated to be negligible, after going through gap junctions. I could envision, instead, that the effect of voltage bursts, propagated through gap junctions, can suffice to initiate activity in neighboring cells. Please discuss further and revise as necessary.
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Reviewer #2 (Public review):
Summary:
This study demonstrates that low-voltage oscillations in neuronal ensembles can contribute to learning and memory. The authors identify long-lasting plasticity in the dynamics of oscillatory intracellular calcium store release in key neurons of Aplysia's food-seeking network, serving as a subcellular substrate for operant-reward learning that leads to the rhythmic expression of motor output producing compulsive-like behavior.
Strengths:
The study used a combination of well-designed and rigorously executed behavioural and electrophysiological experiments in an extremely well-defined nervous system to test the hypothesis that spontaneous voltage oscillations in neuronal ensembles play a critical role in memory formation and storage.
Weaknesses:
I was unable to identify any major weakness in this …
Reviewer #2 (Public review):
Summary:
This study demonstrates that low-voltage oscillations in neuronal ensembles can contribute to learning and memory. The authors identify long-lasting plasticity in the dynamics of oscillatory intracellular calcium store release in key neurons of Aplysia's food-seeking network, serving as a subcellular substrate for operant-reward learning that leads to the rhythmic expression of motor output producing compulsive-like behavior.
Strengths:
The study used a combination of well-designed and rigorously executed behavioural and electrophysiological experiments in an extremely well-defined nervous system to test the hypothesis that spontaneous voltage oscillations in neuronal ensembles play a critical role in memory formation and storage.
Weaknesses:
I was unable to identify any major weakness in this study. The authors fully achieved their aims, and the results support their conclusions.
Conclusion:
This is a potentially impactful study that supports the notion that non-synaptic subcellular mechanisms make an important contribution to neuronal ensemble plasticity underpinning associative learning. I regard the utility value of the methods and data to the community as high.
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Frequency modulation of organelle calcium-dependent voltage oscillations: an essential memory trace produced by operant conditioning in Aplysia https://www.biorxiv.org/content/10.64898/2026.07.30.741715v1
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Frequency modulation of organelle calcium-dependent voltage oscillations: an essential memory trace produced by operant conditioning in Aplysia https://www.biorxiv.org/content/10.64898/2026.07.30.741715v1
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