Zhang, Yuxin; (2025) Odour responses of sister projection neurons in the mouse olfactory bulb, revealed by correlative two-photon imaging and synchrotron X-ray holographic nano-tomography. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The mouse olfactory bulb (OB) conducts the first layer of olfactory information processing. It receives inputs from olfactory sensory neurons (OSNs) and outputs to a range of other brain regions which send feedback projections. The OB circuit architecture exhibits features of parallel processing where OSN inputs are spatially aggregated by olfactory receptor type into distinct glomeruli. Each glomerulus is associated with 10s of projection neurons (PNs) known as sister PNs, that receive similar OSN inputs. The bulb’s intricate inhibitory and centrifugal projection networks orchestrate various computations, transforming OSN inputs into a spatiotemporal representation of the odour environment encoded by PNs. Here, I aim to bring mechanistic insights into the understanding of OB input-output transformation, by studying odour responses of sister PNs. A combined structure-function approach brings valuable insights into how neural circuit structures relate to its functions. Here I established the use of two synchrotron X-ray tomography methods for fast, large volume and non-destructive structural imaging of OB and combined them with in vivo 2-photon (2P) imaging. Firstly, I established that sister PNs can be identified via apical dendrite tracings in the X-ray datasets. I then validated that functionally imaged PNs can be reliably identified in the X-ray datasets. I also optimised sample preparation to give homogeneous X-ray contrast throughout the sample. With the established correlative 2P and X-ray tomography workflow, I studied the responses of 289 sister PNs (mapped to 50 glomeruli) to 47 monomolecular odorants. I found striking similarity in the odour tuning of sister PNs, as well as consistent differences in their temporal response profiles. The findings were corroborated with two more biological replicates. In conclusion, sister PNs are not redundant and are likely used to increase the OB’s odour representation capacity, and X-ray tomography is an emerging tool to study neuronal circuits with a structure-function approach.

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