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Functions of plasticity in adult-born neurons

Periodic Reporting for period 2 - FUNCOPLAN (Functions of plasticity in adult-born neurons)

Reporting period: 2018-12-01 to 2020-05-31

The problem being addressed by this project is the functional role played by adult-generated brain cells, or neurons, in information processing in the nervous system. It has been known for decades that, although the majority of neurons in the brain are generated before birth, a few areas of the brain continue to generate new neurons throughout life, in a process known as adult neurogenesis. One key outstanding question is: why? Why, when this capacity has been lost in almost all parts of the adult brain, do some areas still produce newborn neurons? One major hypothesis is that these adult-generated neurons bring something different to the circuits into which they integrate. In particular, immature neurons tend to be more plastic than their mature counterparts – they are more able to change their properties in response to alterations in the inputs they receive. This project aims to determine whether this is the case for a particularly interesting population of adult-born cells which are involved in processing information about the sense of smell, and which release the neurotransmitter dopamine. We will ask whether these ‘dopaminergic’ adult-born neurons are more plastic when they are immature, and then determine the influence of any extra plastic capacity on information-processing in their host circuits.

This question is important because it pertains to new cells being added to old brain networks. This is precisely the kind of scenario that occurs in many attempts to repair the brain after injury or disease, where new brain cells are added to dysfunctional networks. By studying a phenomenon where such addition of new neurons happens naturally in the brain, we hope to learn lessons that will prove useful when trying to add new neurons to damaged brains in a clinical setting.

Our overall objectives are to: 1) Describe whether adult-born dopaminergic cells in the olfactory bulb are especially plastic when they are immature; 2) Characterise the effects of any such plasticity on the sensory response properties of adult-born dopaminergic neurons – i.e. does their plasticity change the way that they respond to smell stimuli? And finally 3) Precisely control activity in adult-born dopaminergic cells to understand how their plasticity might change the way that whole networks process sensory information. Are extra-plastic immature adult-born neurons crucial to the way in which the brain detects smells?
Work performed in the first 30 months of the project has made good progress towards achieving our three Key Objectives. Crucial steps have been taken to get the right personnel employed on the project, including a dedicated PhD student, three talented Post-doctoral Research Associates, and a superbly supportive Technician. All hiring for the project has now been successfully completed. All necessary infrastructure has also now been put in place to enable us to carry out the planned work. Chiefly, we have procured, purchased, installed and optimised a highly specialised microscope that is crucial to the success of the project. In terms of the project’s research and its Key Objectives, we are now in the final stages of data collection and analysis for Key Objective 1, which will describe activity-dependent plasticity in dopaminergic neurons in the olfactory bulb, both in terms of gene expression and functional properties. Importantly, work on this part of the project contributed to a key paper published by the laboratory in 2018 (Galliano et al., eLife), which provides data that will be used for baseline comparisons in all three Key Objectives. Despite some recent technical setbacks which are now very close to resolution (see Problems and Difficulties), we have also begun data collection for Key Objective 2. For Key Objective 3 key preparatory experiments are well underway.
This project is already going beyond the state-of-the-art in its study of plasticity in a single, distinct, and genetically-defined population of adult-born neurons in the mammalian brain. Our aims for the rest of the project remain as described in the original proposal and DoA: to fully characterise the plastic potential of newborn dopaminergic neurons in the adult mouse brain, to determine the implications of any such plasticity on those cells’ ability to encode information about the sense of smell, and to test how such plasticity might impact on the olfactory system as a whole. At the end of the project, we hope to have a much fuller understanding of the unique functional role(s) played by newly-generated neurons in the adult brain.