Friday, May 9, 2025
5/9/2025
Transcriptional adaptation and sensory function in the olfactory system - Abstract Adaptation is fundamental to the function of all sensory systems. In the olfactory system, the olfactory sensory neurons (OSNs) that detect odors undergo a form of rapid adaptation that evolves over milliseconds to seconds, is mediated by post-translational mechanisms, and is thought to reshape responses to highly dynamic odor plumes. In addition, central neurons adapt to odors on timescales of minutes, which is thought to help distinguish salient cues from background. However, it is not yet clear how olfactory sensory neurons adapt at the longer timescales over which animals traverse different environments — and therefore encounter different background stimuli — as is common during a typical circadian cycle. We have recently developed single cell sequencing (scSeq) data that demonstrate that every OSN subtype (as identified by its OR) expresses a distinguishable transcriptome. We show that transcriptional variation among OSNs is systematically organized through a bidirectional, rheostat-like mechanism (akin to a balance control on a stereo) whose setting in each OSN is defined by OR-environment interactions. This transcriptional rheostat is composed of more than 70 genes relevant to OSN function, whose expression levels vary continuously across OSNs in an OR-dependent manner. Because activity patterns in each OSN reflect the combined influence of its OR and the environment, the position of the rheostat is different in each OSN subtype, and dynamically varies as mice traverse distinct environments. Critically, we also show that the specific position adopted by this rheostat (i.e., the OR-specific pattern of functional gene expression) predicts the odor response amplitude of a given OSN (as assessed by a transcriptional metric called the activation score). Thus, rather than faithfully reporting the extent of odor-OR interactions, the peripheral olfactory system dynamically uses gene expression to instantiate expectation, thereby building odor codes that are continuously personalized (over hours-long timescales) by each animal’s experience. Here we propose several Aims to further characterize the relationship between experience-dependent transcriptional adaptation and olfactory function. In Aim 1 we will combine scSeq, Act-Seq, functional imaging and spatial transcriptomics to ask how OSN-specific ES scores relate to acute odor-driven glomerular responses. We will also assess how faithfully odor-driven activation scores relate to acute odor responses as assessed by functional imaging, which will further validate Act-Seq as a powerful method for odor receptor deorphanization. In Aim 2 we will characterize the signaling and transcriptional mechanisms that couple OSN activity to long-term expression patterns for functional genes and changes in neural odor codes. Finally, in Aim 3 we will ask whether environment-dependent changes in peripheral odor codes impact odor perception and behavior. Together these Aims will reveal how odors are translated into adaptive patterns of gene expression, and how these patterns in turn influence odor processing; addressing the questions posed by these Aims is essential for a full account of olfactory system function.
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