Distinct connectivity of newly-generated dopaminergic neurons in the adult brain?

A healthy brain requires its constituent cells, or neurons, to be properly connected to each other. These connections can involve thousands of different inputs arriving onto a single cell, before that cell integrates the incoming information and sends an output signal to a range of highly specific downstream partners. In this way, neuronal networks transform input information into a suitably-processed output signal, so that sensory experience, for example, can control our behaviour. Understanding the way in which neurons are connected, then, is crucial in understanding their function. This is particularly true for a unique type of neuron: those born in the adult brain. These cells are in the great minority, because most of our neurons are generated before birth and lack the ability to regenerate after injury or disease. However, in a few specialised zones of the mature mammalian brain, new neurons are continually produced throughout life in a process known as adult neurogenesis. This generates entirely new neurons which must integrate into existing networks, receiving inputs and sending outputs to contribute to circuit function.

The goal of our proposal is to study these newly-formed connections made by a particular type of adult-generated neuron. In the olfactory bulb - the first part of the brain to process smell information arriving from the nose - dopaminergic neurons play a key role in modulating sensory signals at their earliest stages, and these cells can be generated throughout life. However, it is entirely unknown whether the input and output connections, and therefore the circuit function of these neurons, is unique to dopaminergic cells produced in adulthood. By using a combination of cutting-edge approaches, we will ask whether adult neurogenesis produces cells with unique connectivity in this sensory-processing circuit.

In addressing this important basic biological question, our work has the potential to impact on healthcare in the UK. Our study of the olfactory system may inform future approaches to treat debilitating smell disorders such as anosmia and hyposmia, which have a huge impact on quality of life and affect at least 20% of the population. Our focus on dopaminergic neurons may inform treatments for disorders where these cells are lost in later life, such as Parkinson's Disease. And our study of new neurons in old circuits has the wider promise of informing any attempt to repair brain damage by adding freshly-generated cells to perturbed networks.

Adult neurogenesis generates newborn neurons in specialised regions of the mature mammalian brain. These newly-generated cells integrate into existing circuitry, where their functional role is determined to a large extent by their patterns of input and output connectivity. But is this connectivity, and therefore function, unique to adult-born cells? Do they provide connections that are missing in existing mature circuits? We aim to address these questions by studying the connectivity of a unique population of adult-generated neurons: dopaminergic neurons in the olfactory bulb. Our approach involves the synthesis of multiple state-of-the-art techniques for uncovering anatomical and functional connectivity, including morphological reconstructions of sparsely-labelled individual neurons in intact cleared brain tissue, rabies virus-mediated monosynaptic tracing of input populations, and electrophysiological recordings coupled with targeted optogenetic photostimulation to reveal functional connectivity. By combining these parallel approaches we will compare and contrast the connectivity of dopaminergic neurons that are born in embryonic development versus those generated in adulthood, and will ask whether adult neurogenesis produces a specialised pool of new cells with distinct contributions to functional circuit architecture.

Although the proposed project is primarily one of basic scientific research, there are a number of potential non-academic beneficiaries from the data, results, and knowledge we will produce. These beneficiaries can be divided into 2 broad groups: 1) public sector, commercial enterprises and policy makers with a stake in the provision of healthcare, and 2) the general public.

1) The proposed research has the potential to contribute to the nation's health and wellbeing, directly meeting the BBSRC's Key Strategic Research Priority of 'Bioscience for Health'. By studying the functional implications of new cells in old circuits, our work directly impacts on therapeutic attempts to repair damaged or diseased brain tissue through the replacement of newly-generated neurons. By studying the novel circuit-level function(s) associated with new neurons generated in the adult brain, and thereby uncovering the full plastic potential of mature neuronal networks, we also address the Council's specific priority of 'Healthy ageing across the lifecourse'. And, as well as providing basic knowledge which can then be applied to a broad range of issues surrounding normal ageing and mental health, the proposed work will also impact on research aiming to treat specific disorders. Our study of dopaminergic neuron function and plasticity may influence attempts to treat disorders based on dopaminergic cell malfunction such as Parkinson's Disease, while novel insights into the function of olfactory bulb networks could impact on attempts to improve recovery rates and quality of life in the significant proportion of the population - 20% of us, rising to >50% in over-75s - that suffers from debilitating smell dysfunction. Finally, the potential benefits for public health produced by the proposed project can also lead to advances in evidence-based policy making, if, for example, eventual effective treatments can be included in NICE guidelines. In the more immediate term, we additionally hope that our findings can contribute to efforts to persuade policy makers that basic bioscience research is a just, important, and profitable use of public funds.

2) Our research also has the potential to benefit the UK public, by generating openly-available novel data on brain function and plasticity, and by public engagement in our discoveries. The brain is a fascinating organ, and our research into its inner workings could benefit, amongst others, school students deciding where to take their careers, patient and carer groups interested in the implications for particular disorders, and adults with well-honed scientific curiosity.