Connectivity of olfactory bulb dopaminergic interneurons

Olfaction is unique amongst sensory systems because it bypasses the thalamus. Perhaps to compensate for this lack of an intermediate computational hub between periphery and cortex, a vast amount of local processing happens in the olfactory bulb, where the olfactory signal enters the brain. As such, the olfactory bulb is home to a large and diverse population of inhibitory interneurons that greatly outnumber the excitatory neurons. These are responsible for processing the incoming sensory signal in accordance with the wider sensory context, prior experience, and internal state, to shape its eventual perception and influence on behaviour. My thesis begins by characterising this interneuron population, specifically that of the olfactory bulb glomerular layer, where the synapse between the sensory neurons and output neurons is located. Calretinin-positive interneurons were the most numerous, followed by parvalbumin-positive, calbindin-positive, anaxonic dopaminergic and finally axon-bearing dopaminergic interneurons. Adding to the unusual features of olfaction, all of these interneurons, except the axon-bearing dopaminergic subtype, undergo continuous neurogenesis throughout life, yet their ratios remained stable across adolescence, early adulthood, and late adulthood. Dopaminergic interneurons co-release GABA and dopamine and are particularly important in shaping olfactory signals. They both enhance and suppress the activity of other cell types, including the terminals of olfactory sensory neurons coming from the nose, so modulate the gain of incoming olfactory signals. Additionally, the axon-bearing subtype projects laterally through the glomerular layer, allowing them to control signal contrast between different odour channels. As such, previous work has demonstrated their importance for olfactory discrimination and olfactory-driven social behaviours. Despite their significant impact on olfactory processing, these and other results showed that dopaminergic interneurons comprise a small fraction of glomerular interneurons. To understand their disproportionate influence on circuitry and behaviour, the rest of my thesis aimed to characterise their connectivity. A broad anatomical screening of the inputs to dopaminergic interneurons using rabies tracing revealed presynaptic partners across the olfactory bulb and higher olfactory areas, suggesting they act as an integration point for olfactory activity across multiple odour channels as well as top-down information, which could include memory of past experiences and internal states. To investigate this functionally, I employed patch-clamp electrophysiology, which also has the benefit of facilitating clear classification of the two subtypes—axon-bearing and anaxonic—as they have distinct electrophysiological signatures. The two subtypes showed differences in the inputs received and how they were processed. Finally, I explored how dopaminergic interneurons use this information to modulate olfactory output. With further patch clamp electrophysiology, coupled with optogenetics, I assessed whether they directly influence the output neurons of the olfactory bulb. Together, these results underscore that the dopaminergic interneurons of the olfactory bulb may be few but are powerful. My thesis shows that they integrate multiple sources of information and provides the first evidence for how their inputs differ between subtypes. Coupled with their distinct morphology, their distinct connectivity patterns facilitate two parallel dopaminergic processing streams, supporting a hypothesis whereby the two dopaminergic subtypes have distinct roles to play in olfactory processing.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2025

Author dc:creator

• McWhinnie, Ailie

Advisor dc:contributor.advisor

• Galliano, Elisa

• Dopamine
• Neuroscience
• Olfaction

Licence

• https://www.repository.cam.ac.uk/bitstreams/03b5e2da-89b0-42cf-94b3-dfc3ad3e8c81/download
• https://creativecommons.org/licenses/by/4.0/

Language dc:language

eng

Author Identifier

0009-0007-7359-0178

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/399488