Cell and circuit substrates of normative and impaired motor operations

Nerve cells in a brain region called the basal ganglia are important for making decisions and acting on them. The basal ganglia do not work properly in Parkinson’s disease, leading to difficulties with moving.
Here, we aim to explain how nerve cells in the basal ganglia work together 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, connections and chemical messengers to control behaviour. As an important part of this, we will define how changes to signalling with the chemical dopamine, as occurs in Parkinson’s, changes the ways these nerve cells interact and influence behaviour. This should help us better understand why people with Parkinson’s have difficulties with moving. These important issues cannot be tackled by studying humans alone, so we study the ways in which brain cells work in mice, which have basal ganglia similar to humans.
This research will provide important new knowledge about how cells in the basal ganglia communicate with each other in health and disease. This new knowledge will in turn put us in a stronger position to develop new therapies that are better able to manage brain activity and provide improved relief from the symptoms of Parkinson’s.

The burden of disease is not borne evenly across all cell types in the brain. As such, it is imperative that the design of new strategies for treating disease progression and symptoms is informed by a mature knowledge of how different cell types fulfil their specialised roles to govern behaviour. The overall aim of this new Programme is to deliver high-resolution mechanistic explanations of the brain cell and circuit substrates of normative movement as well as impaired Parkinsonian behaviour. Focusing on the ‘motor domains’ of basal ganglia circuits in the brain, we will harness cutting-edge technologies for monitoring and manipulating neurons in vivo to provide essential new insights into how the activities and interactions of identified cell types are configured in their host circuits according to the temporal dynamics of dopaminergic signalling as well as action. As a key corollary, we will define how dopaminergic signalling arises in the basal ganglia and to what extent it is altered by factors of high relevance for early and sustained manifestations of Parkinson’s disease. We will also define how profound deficits in dopamine release, as occur in advanced Parkinsonism, impact on the cell-type-dependent encoding of behaviour in these circuits. To achieve our specific research objectives, 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 mice, with intact or comprised midbrain dopaminergic systems, the readouts from which will straddle multiple levels of function including molecular/genetic, structural, electrophysiological, neurochemical and behavioural. In capitalising on the new understanding of the activity dynamics of identified neurons gained here, we will also exploit specified cell types as novel points of entry for spatiotemporally-patterned interventions designed to not only dissect circuit function but also to correct circuit dysfunction and related behavioural impairments in advanced Parkinsonism.