Activity-Dependent Plasticity in the Murine Olfactory Bulb Neurons

Abstract

Neurons are equipped with the striking ability to adapt their structure and function in response to different stimuli, allowing for learning, memory, and homeostasis of the neural circuit. In sensory systems, adaptive neuronal plasticity is recruited to combat dynamic changes in sensory input – such as its sudden loss - and maintain circuit homeostasis. Adaptive neuronal plasticity can be induced and expressed at different cellular spatial scales, and is heavily modulated by the duration of activity perturbation (Wen and Turrigiano, 2024). This thesis aimed to investigate how different neuron types and subtypes in mammalian pre-cortical sensory circuits are modulated by sensory deprivation in a cell-type-specific and temporally-distinct manner, with a specific focus on the olfactory system. To understand whether there are common plasticity themes amongst sensory systems, we conducted a systematic review of the literature describing sensory-deprivation-induced plasticity mechanisms at the first pre-cortical brain region receiving sensory input in the olfactory (olfactory bulb, OB), visual (lateral geniculate nucleus & superior colliculus) and auditory (ventral and dorsal cochlear nuclei) system. Despite significant heterogeneity in reporting and experimental methods, we found common temporally-defined plasticity mechanisms engaged by all three circuits. Brief (1 day or shorter) deprivation reduced activity and increased disinhibition, medium-term deprivation (1 day to a week) led to glial changes and synaptic remodelling, and long-term deprivation (over a week) primarily caused structural alterations. As described above, the OB is the first central station of olfactory sensing and is particularly well-suited for the study of activity-dependent plasticity. To understand how different murine bulbar cell types respond to odour deprivation of physiologically relevant duration, I characterised the changes in activity level and axon initial segment (AIS) morphology of the main cell types in the OB after up to 7 days of olfactory deprivation using immunohistochemistry. I found that while excitatory principal neurons and interneurons in the OB undergo minimal changes in activity levels and AIS morphology, a population of dopamine (DA) -expressing inhibitory interneurons significantly down-regulated their activity. In addition, the axon-bearing subtype of these DA interneurons also significantly shortened their AIS after a week of olfactory deprivation, a change typically associated with decreased intrinsic excitability. This finding is in line with past work showing that these axon-bearing DA neurons are capable of downregulating their intrinsic excitability and AIS length after just 1 day of olfactory deprivation (Galliano et al., 2021). It is unknown, however, how the synaptic properties of these cells, and other bulbar neurons, are changed by 1 day olfactory deprivation. Using patch-clamp electrophysiology, I found that the axon-bearing DA neurons undergo synaptic upscaling at their inhibitory synapses. While potential compensatory synaptic plasticity were also observed at the other subpopulation of anaxonic DA neurons and in the excitatory interneurons, I found that the excitatory principal neurons were unchanged in their measured synaptic properties. By studying presynaptic neurotransmitter release properties at the afferent sensory fibre from the nose, I found that there was a trend for compensatory increases in their neurotransmitter release. In summary, using the mouse OB as a model system, I found that bulbar neurons of different classes differentially undergo functional and structural adaptations in response to medium- and short-lived olfactory deprivation. Overall, the results of this thesis suggest that there are foundational principles shared across sensory systems when faced with activity deprivation.