Fear conditioning biases olfactory sensory neuron frequencies across generations

Background

The mammalian olfactory system provides a powerful model to study how sensory experience shapes neural circuits. In mice, the main olfactory epithelium (MOE) encodes odors through a large repertoire of ~1400 olfactory receptor genes ¹, with each olfactory sensory neuron (OSN) expressing a single receptor via a largely stochastic gene selection process ². This organization allows precise mapping between receptor identity and odor detection.

A central question in neuroscience is how experience-dependent plasticity influences not only neural circuits, but potentially future generations. Previous studies have shown that olfactory fear conditioning increases the number of OSNs responsive to a conditioned odor in adult mice. Remarkably, similar increases have been observed in unconditioned offspring, suggesting that sensory experiences may be transmitted across generations ^3,4.

This phenomenon is linked to intergenerational epigenetic inheritance, where information is passed without changes to the DNA sequence. While such mechanisms are well established in organisms such as plants ⁵ and invertebrates ^6,7, their existence and mechanisms in mammals remain controversial. The olfactory system offers a unique opportunity to address this gap, as changes in OSN populations can be directly quantified and linked to defined sensory experiences.

In this preprint ⁸, the authors investigated how olfactory fear conditioning alters OSN populations in both parents and offspring, and whether these changes are associated with behavioral adaptations. They combined transgenic mouse models, cellular imaging, and machine learning-based behavioral analysis to test the hypothesis that experience-dependent sensory plasticity can be inherited and may influence behavior in a subtle, context-dependent manner.

Key findings

Odor-specific sensory plasticity can be induced and inherited

Applying olfactory fear conditioning with two different odors (acetophenone or lyral), the authors demonstrated that olfactory fear conditioning increased the number of olfactory sensory neurons (OSNs) responsive to the conditioned odor. Strikingly, this increase was observed in both conditioned parents (F0) and their naïve offspring (F1), demonstrating intergenerational inheritance. More importantly, this effect was odor-specific, rather than reflecting a global increase in OSN number.

Learning biases neurogenesis toward specific receptor identities

Using EdU labeling, the authors showed that fear conditioning increased the proportion of newly generated OSNs expressing receptors for the conditioned odor, despite differences in subtype differentiation rates. This indicated that learning biases stem cell differentiation, rather than simply prolonging the survival of existing neurons.

Sensory cell adaptations are dissociated from avoidance behavior

Based on the results from the Trichamber Assay and the approach-avoid index that the authors developed, the increase in odor-responsive OSNs persisted for at least 9 weeks, despite extensive epithelial turnover. However, avoidance behavior did not persist over time, indicating that changes in sensory neuron composition were not sufficient to drive behavioral responses. This revealed a dissociation between peripheral sensory plasticity and behavioral output.

Machine learning reveals subtle, odor-specific behavioral modulation in offspring

Although F1 offspring did not exhibit overt avoidance of the conditioned odor, they displayed odor-specific behavioral changes. Using pose tracking and unsupervised machine learning (Keypoint-MoSeq), the authors identified fine-scale behavioral “syllables.” This approach uncovered subtle, condition-dependent differences in movement patterns in F1 offspring that were not detectable with traditional metrics. These odor-specific differences supported the idea that inherited sensory changes lead to context-dependent behavioral modulation, rather than explicit fear behavior.

Future directions

Despite these findings, the cellular mechanisms underlying intergenerational olfactory plasticity remain incompletely understood. In particular, it is unclear whether the increase in odor-responsive OSNs arises from enhanced survival of existing neurons or from biased neurogenesis. Furthermore, the mechanisms linking peripheral sensory changes to behavioral outcomes and their potential transmission to the germline remain unresolved.

Why we highlight this preprint

We chose this preprint because it touches on a broader question in neuroscience: how flexible is the boundary between experience and biology? More specifically, it challenges the idea that neural systems are only shaped within an individual’s lifetime; by suggesting that experience-dependent changes could extend across generations.

What we found particularly interesting is how this work connects sensory plasticity with mechanisms like neurogenesis and epigenetic regulation. It raises the idea that environmental experiences might bias the development of specific neural populations, which is relevant to how we think about circuit formation and stabilization, for example, in processes involving structures like perineuronal nets.

At the same time, the dissociation between neural changes and behavior highlights the complexity of linking cellular-level plasticity to functional outcomes. Overall, this paper stood out for opening new perspectives on how experience, neural development, and inheritance might interact to shape the brain.

Questions for the authors

Question 1: The results showed that the increase in olfactory neurons is inherited, but the mechanism remains unclear. Do you have any hypotheses about how this information is transmitted to the germline?

Question 2: Since the unpaired group also showed an intermediate increase in newborn odor-responsive OSNs, how do you disentangle the relative contributions of odor exposure versus associative fear learning in driving this effect?

Question 3: If unconditioned offspring F1 were to go through the same odor-fear conditioning as the F0 parent, how would the cellular composition of the olfactory epithelium change, and would the fear-related behavior be potentiated in comparison to the F0 parent?

References

1. Buck L, Axel R. A novel multigene family may encode odorant receptors: A molecular basis for odor recognition. Cell. 1991;65(1):175-187. doi:https://doi.org/10.1016/0092-8674(91)90418-x
2. Jones SV, Choi DC, Davis M, Ressler KJ. Learning-Dependent Structural Plasticity in the Adult Olfactory Pathway. Journal of Neuroscience. 2008;28(49):13106-13111. doi:https://doi.org/10.1523/jneurosci.4465-08.2008
3. Aoued HS, Sannigrahi S, Doshi N, et al. Reversing Behavioral, Neuroanatomical, and Germline Influences of Intergenerational Stress. Biological Psychiatry. 2019;85(3):248-256. doi:https://doi.org/10.1016/j.biopsych.2018.07.028
4. Aoued HS, Soma Sannigrahi, Hunter SC, et al. Proximate causes and consequences of intergenerational influences of salient sensory experience. Genes Brain & Behavior. 2020;19(4). doi:https://doi.org/10.1111/gbb.12638
5. Schmitz RJ, Schultz MD, Lewsey MG, et al. Transgenerational Epigenetic Instability Is a Source of Novel Methylation Variants. Science. 2011;334(6054):369-373. doi:https://doi.org/10.1126/science.1212959
6. Greer EL, Maures TJ, Ucar D, et al. Transgenerational Epigenetic Inheritance of Longevity in C. elegans. Nature. 2011;479(7373):365-371. doi:https://doi.org/10.1038/nature10572
7. Rechavi O, Houri-Ze’evi L, Anava S, et al. Starvation-Induced Transgenerational Inheritance of Small RNAs in C. elegans. Cell. 2014;158(2):277-287. doi:https://doi.org/10.1016/j.cell.2014.06.020
8. Liff CW, Ayman YR, Jaeger ECB, et al. Fear conditioning biases olfactory stem cell receptor fate. bioRxiv (Cold Spring Harbor Laboratory). Published online February 23, 2023. doi:https://doi.org/10.1101/2023.02.23.529692

Tags: behavior, epigenetic inheritance, fear conditioning, intergenerational inheritance, learning and memory, mouse model, neurogenesis, neuroplasticity, neuroscience, olfaction, olfactory epithelium, olfactory sensory neurons, sensory neuroscience, stem cells, transgenerational effects

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