Reviewer #3 (Public review):
Summary
The authors set out to explore the potential relationship between adult neurogenesis of inhibitory granule cells in the olfactory bulb and cumulative changes over days in odor-evoked spiking activity (representational drift) in the olfactory stream. They developed a richly detailed spiking neuronal network model based on Izhikevich (2003), allowing them to capture the diversity of spiking behaviors of multiple neuron types within the olfactory system. This model recapitulates the circuit organization of both the main olfactory bulb (MOB) and the piriform cortex (PCx), including connections between the two (both feedforward and corticofugal). Adult neurogenesis was captured by shuffling the weights of the model's granule cells, preserving the distribution of synaptic weights. Shuffling of granule cell connectivity resulted in cumulative changes in stimulus-evoked spiking of the model's M/T cells. Individual M/T cell tuning changed with time, and ensemble correlations dropped sharply over the temporal interval examined (long enough that almost all granule cells in the model had shuffled their weights). Interestingly, these changes in responsiveness did not disrupt low-dimensional stability of olfactory representations: when projected into a low-dimensional subspace, population vector correlations in this subspace remained elevated across the temporal interval examined. Importantly, in the model's downstream piriform layer, this was not the case. There, shuffled GC connectivity in the bulb resulted in a complete shift in piriform odor coding, including for low-dimensional projections. This is in contrast to what the model exhibited in the M/T input layer. Interestingly, these changes in PCx extended to the geometrical structure of the odor representations themselves. Finally, the authors examined the effect of experience on representational drift. Using an STDP rule, they allowed the inputs to and outputs from adult-born granule cells to change during repeated presentations of the same odor. This stabilized stimulus-evoked activity in the model's piriform layer.
Strengths
This paper suggests a link between adult neurogenesis in the olfactory bulb and representational drift in the piriform cortex. Using an elegant spiking network that faithfully recapitulates the basic physiological properties of the olfactory stream, the authors tackle a question of longstanding interest in a creative and interesting manner. As a purely theoretical study of drift, this paper presents important insights: synaptic turnover of recurrent inhibitory input can destabilize stimulus-evoked activity, but only to a degree, as representations in the bulb (the model's recurrent input layer) retain their basic geometrical form. However, this destabilized input results in profound drift in the model's second (piriform) layer, where both the tuning of individual neurons and the layer's overall functional geometry are restructured. This is a useful and important idea in the drift field, and to my knowledge, it is novel. The bulb is not the only setting where inhibitory synapses exhibit turnover (whether through neurogenesis or synaptic dynamics), and so this exploration of the consequences of such plasticity on drift is valuable. The authors also elegantly explore a potential mechanism to stabilize representations through experience, using an STDP rule specific to the inhibitory neurons in the input layer. This has an interesting parallel with other recent theoretical work on drift in the piriform (Morales et al., 2025 PNAS), in which STDP in the piriform layer was also shown to stabilize stimulus representations there. It is fascinating to see that this same rule also stabilizes piriform representations when implemented in the bulb's granule cells.
The authors also provide a thoughtful discussion regarding the differential roles of mitral and tufted cells in drift in piriform and AON and the potential roles of neurogenesis in archicortex.
In general, this paper puts an important and much-needed spotlight on the role of neurogenesis and inhibitory plasticity in drift. In this light, it is a valuable and exciting contribution to the drift conversation.
Weaknesses
I have one major, general concern that I think must be addressed to permit proper interpretation of the results.
I worry that the authors' model may confuse thinking on drift in the olfactory system, because of differences in the behavior of their model from known features of the olfactory bulb. In their model, the tuning of individual bulbar neurons drifts over time. This is inconsistent with the experimental literature on the stability of odor-evoked activity in the olfactory bulb.
In a foundational paper, Bhalla & Bower (1997) recorded from mitral and tufted cells in the olfactory bulb of freely moving rats and measured the odor tuning of well-isolated single units across a five-day interval. They found that the tuning of a single cell was quite variable within a day, across trials, but that this variability did not increase with time. Indeed, their measure of response similarity was equivalent within and across days. In what now reads as a prescient anticipation of the drift phenomenon, Bhalla and Bower concluded: "it is clear, at least over five days, that the cell is bounded in how it can respond. If this were not the case, we would expect a continual increase in relative response variability over multiple days (the equivalent of response drift). Instead, the degree of variability in the responses of single cells is stable over the length of time we have recorded." Thus, even at the level of single cells, this early paper argues that the bulb is stable.
This basic result has since been replicated by several groups. Kato et al. (2012) used chronic two-photon calcium imaging of mitral cells in awake, head-fixed mice and likewise found that, while odor responses could be modulated by recent experience (odor exposure leading to transient adaptation), the underlying tuning of individual cells remained stable. While experience altered mitral cell odor responses, those responses recovered to their original form at the level of the single neuron, maintaining tuning over extended periods (two months). More recently, the Mizrahi lab (Shani-Narkiss et al., 2023) extended chronic imaging to six months, reporting that single-cell odor tuning curves remained highly similar over this period. These studies reinforce Bhalla and Bower's original conclusion: despite trial-to-trial variability, olfactory bulb neurons maintain stable odor tuning across extended timescales, with plasticity emerging primarily in response to experience. (The Yamada et al., 2017 paper, which the authors here cite, is not an appropriate comparison. In Yamada, mice were exposed daily to odor. Therefore, the changes observed in Yamada are a function of odor experience, not of time alone. Yamada does not include data in which the tuning of bulb neurons is measured in the absence of intervening experience.)
Therefore, a model that relies on instability in the tuning of bulbar neurons risks giving the incorrect impression that the bulb drifts over time. This difference should be explicitly addressed by the authors to avoid any potential confusion. Perhaps the best course of action would be to fit their model to Mizrahi's data, should this data be available, and see if, when constrained by empirical observation, the model still produces drift in piriform. If so, this would dramatically strengthen the paper. If this is not feasible, then I suggest being very explicit about this difference between the behavior of the model and what has been shown empirically. I appreciate that in the data there is modest drift (e.g., Shani-Narkiss' Figure 8C), but the changes reported there really are modest compared to what is exhibited by the model. A compromise would be to simply apply these metrics to the model and match the model's similarity to the Shani-Narkiss data. Then the authors could ask what effect this has on drift in piriform.
The risk here is that people will conclude from this paper that drift in piriform may simply be inherited from instability in the bulb. This view is inconsistent with what has been documented empirically, and so great care is warranted to avoid conveying that impression to the community.
Major comments (all related to the above point)
(1) Lines 146-168: The authors find in their model that "individual M/T cells changed their responses to the same odor across days due to adult-neurogenesis, with some cells decreasing the firing rate responses (Fig.2A1 top) while other cells increased the magnitude of their responses (Fig. 2A2 bottom, Fig. S2)" they also report a significant decrease in the "full ensemble correlation" in their model over time. They claim that these changes in individual cell tuning are "similar to what has been observed by others using calcium imaging of M/T cell activity (Kato et al., 2012 and Yamada et al., 2017)" and that the decrease in full ensemble correlation is "consistent with experimental observations (Yamada et al., 2017)." However, the conditions of the Kato and Yamada experiments that demonstrate response change are not comparable here, as odors were presented daily to the animals in these experiments. Therefore, the changes in odor tuning found in the Kato and Yamada papers (Kato Figure 4D; Yamada Figure 3E) are a function of accumulated experience with odor. This distinction is crucial because experience-induced changes reflect an underlying learning process, whereas changes that simply accumulate over time are more consistent with drift. The conditions of their model are more similar to those employed in other experiments described in Kato et al. 2012 (Figure 6C) as well as Shani-Narkiss et al. (2023), in which bulb tuning is measured not as a function of intervening experience, but rather as a function of time (Kato's "recovery" experiment). What is found in Kato is that even across two months, the tuning of individual mitral cells is stable. What alters tuning is experience with odor, the core finding of both the Kato et al., 2012 paper and also Yamada et al., 2017. It is crucial that this is clarified in the text.
(2) The authors show that in a reduced-space correlation metric, the correlation of low-dimensional trajectories "remained high across all days"..."consistent with a recent experimental study" (Shani-Narkiss et al., 2023). It is true that in the Shani-Narkiss paper, a consistent low-dimensional response is found across days (t-SNE analysis in Shani-Narkiss Figure 7B). However, the key difference between the Shani-Narkiss data and the results reported here is that Shani-Narkiss also observed relative stability in the native space (Shani-Narkiss Figure 8). They conclude that they "find a relatively stable response of single neurons to odors in either awake or anesthetized states and a relatively stable representation of odors by the MC population as a whole (Figures 6-8; Bhalla and Bower, 1997)." This should be better clarified in the text.
(3) In the discussion, the authors state that "In the MOB, individual M/T cells exhibited variable odor responses akin to gain control, altering their firing rate magnitudes over time. This is consistent with earlier experimental studies using calcium-imaging." (L314-6). Again, I disagree that these data are consistent with what has been published thus far. Changes in gain would have resulted in increased variability across days in the Bhalla data. Moreover, changes in gain would be captured by Kato's change index ("To quantify the changes in mitral cell responses, we calculated the change index (CI) for each responsive mitral cell-odor pair on each trial (trial X) of a given day as (response on trial X - the initial response on day 1)/(response on trial X + the initial response on day 1). Thus, CI ranges from −1 to 1, where a value of −1 represents a complete loss of response, 1 represents the emergence of a new response, and 0 represents no change." Kato et al.). This index will capture changes in gain. However, as shown in Figure 4D (red traces), Figure 6C (Recovery and Odor set B during odor set A experience and vice versa), the change index is either zero or near zero. If the authors wish to claim that their model is consistent with these data, they should also compute Kato's change index for M/T odor-cell pairs in their model and show that it also remains at 0 over time, absent experience.