Accessing and actuating specified neural circuits underlying motor function and dysfunction

Nerve cells in a brain region known as the basal ganglia are essential for making decisions and acting on them. This is shown by the main symptoms of Parkinson’s disease, in which the basal ganglia do not work properly.
Here, we aim to explain how nerve cells in the basal ganglia work together with their partner “motor circuits” to support purposeful movement. We will focus our efforts on discovering when, why and how different types of nerve cell use special patterns of electrical activity, genes and connections to control behaviour. As an important part of this, we will define how a lack of the chemical dopamine, as occurs in Parkinson’s disease, changes the ways in which these nerve cells interact and how they influence behaviour. This should help us better understand why people with Parkinson’s disease have difficulties with moving. These key issues cannot be addressed by studying humans alone, so we study the ways in which brain cells work in rodents (rats and mice).
This research will provide important new knowledge about how cells in the basal ganglia communicate with each other in health and disease. By defining the unique and complementary roles played by different types of nerve cell during movement, this research will put us in a stronger position to develop new therapies that are better able to manage brain activity and provide improved relief from symptoms in advanced Parkinson’s disease.

The design of new strategies for treating the symptoms of brain diseases must be tempered by a mature knowledge of how different nerve cell types fulfil their specialised roles to govern behaviour. The overarching goal of this Programme is to deliver high-resolution readouts and mechanistic explanations of brain motor circuit organization in the context of normal behaviours as well as impaired Parkinsonian behaviours. Focusing on the ‘motor domains’ of the neuronal circuits linking the basal ganglia, thalamus and cerebral cortex, we will harness cutting-edge technologies for identifying, accessing and manipulating neurons in vivo to provide fundamental new insights into the specific cellular substrates of the neuronal network dynamics therein. We will place special emphasis on defining how the interactions and activities of identified cell types in these motor circuits vary according to the temporal profile of dopamine release and movement. As a key corollary of this, we will define how a paucity of dopamine release, as occurs in Parkinson’s disease and its animal models, impacts on the neuronal encoding of behaviour in these motor circuits. To achieve our specific aims, we will couple novel and advanced analytical techniques with experimental interventions designed to probe causal interactions between specified circuit elements with high spatiotemporal precision. Our experiments will centre on the use of wild type and genetically-altered rodents with intact or comprised midbrain dopaminergic systems, the readouts from which will straddle multiple levels of function including molecular/genetic, structural, electrophysiological and behavioural. In capitalising on the new level of understanding of the dynamics of identified neurons that will be gained here, we will also exploit specified cell types and other circuit elements as novel points of entry for spatiotemporally-patterned interventions designed to correct circuit dysfunction and related behavioural deficits in advanced Parkinsonism.