Thalamocortical control of skilled motor behaviour

Motor control is a basic but fundamentally important aspect of human and animal behaviour and the only we way interact with the world is though movement. Thus, one of the most challenging problems in neuroscience is to understand how the brain generates and controls motor behaviour. Over the past century significant advances have been made in understanding how descending information from cortical and brainstem motor areas regulate spinal cord activity in order to execute a wide range of motor tasks from simple rhythmic behaviours to complex, dexterous tasks such as reaching and object manipulation. One pathway that is pivotal to the preparation and execution of a large repertoire of learned, dextrous movements is the basal ganglia-thalamcortical pathway. This pathway is thought to convey motivational and/or contextual information from the basal ganglia via thalamus to the primary motor cortex in order to select, prepare and execute different motor behaviours. Disruption to information transmission along this pathway leads to severe motor deficits and loss of motor control. Although we have an in-depth understanding of how basal ganglia-thalamocortical activity correlates with specific aspects of mammalian motor behaviour, the vast majority of these data have been generated using extracellular recording methods that preclude measurement of somatodendritic integration, input-output transformations, connection specific dynamics and spatiotemporal mapping of activity patterns across neuronal ensembles. This leads us to question, what are the spatiotemporal activity patterns of thalamocortical inputs in primary motor cortex (M1) during movement preparation/execution/suppression? How do these inputs shape somatodendritic integration in layer 5 projection neurons in M1 during behaviour? What is the causal link between activity along the basal ganglia-thalamocortical pathway, M1 output and behaviour?

To address these questions, we will investigate the neural representations of movement in M1 in mice trained to execute an auditory cued Go/NoGo forelimb push task developed in our lab. This behavioural paradigm is of particular interest as it provides an experimentally tractable model of complex motor control and facilitates the use of in vivo 2-photon calcium imaging, whole-cell patch-clamp electrophysiology and cell-selective opto-/chemogenetic manipulation techniques in head-restrained mice. By combining state-of-the-art cellular and circuit approaches in vivo, we will investigate the importance of the basal ganglia-thalamocortical input pathway in shaping M1 layer 5 projection neuron somatodendritic computations during behaviour. Given that axons from the basal ganglia-recipient area of motor thalamus (MThBG) primarily target the apical dendrites of layer 5 projection neurons in M1 and that behaviour-related MThBG activity precedes movement initiation, we will test the hypothesis that motor thalamocortical axons from MThBG (mTCBG) drive task context-specific modulation of dendritic activity and layer 5 output during movement preparation. We will also use cell- and pathway-specific opto-/chemogenetic manipulation strategies to determine the causal relationship between mTCBG activity, layer 5 somatodendritic computations and movement planning/execution. The overarching aim of the project is to provide new insights into the importance of M1 cellular and circuit computations during the execution of a learned, dextrous motor task, serving as an exemplar for the development of a more general mechanistic understanding of cortical motor control.

Motor control is the fundamental process by which humans and animals use their neuromuscular system to execute skilled motor behaviours, but how motor control emerges from interaction between cortical and subcortical structures remains unresolved. This project will investigate the importance of the basal ganglia-thalamocortical pathway in shaping somatodendritic computations of layer 5 projection neurons in primary motor cortex during the planning and execution of skilled motor behaviours. By combining novel, highly quantifiable behavioural paradigms, advanced methods in in vivo imaging, electrophysiology and molecular genetic manipulation techniques we will address 3 main objectives: 1) Determine the importance of dendritic activity for shaping motor cortical output and behaviour; 2) Determine the spatiotemporal activity patterns of basal ganglia-thalamocortical axons in M1 during the preparation/execution/suppression of learned movements; and 3) investigate whether modulation of basal ganglia-thalamocortical inputs affect dendritic activity patterns, M1 output and motor behaviour.

Specifically, we will combine in vivo 2-photon calcium imaging, whole-cell patch-clamp recordings and viral-based opto- / chemogenetic manipulation strategies in mice trained to perform repeated trials of an auditory cued Go/NoGo forelimb lever push task. The combination of in vivo 2-photon calcium imaging and membrane potential recordings will allow us to explore the principal mechanisms of somatodendritic integration in layer 5 projection neurons in M1 (Objective 1), activity patterns of corticothalamic inputs in L1 of motor cortex during motor behaviour (Objective 2), and effects of perturbing thalamocortical input on layer 5 output and behaviour (Objective 3). By employing a multi-level cellular and systems neuroscience approach our findings will provide new insights into the role of the basal ganglia-thalamocortical pathway in high-level motor control.

Economic:
Our bespoke behavioural solution(s) for investigating skilled motor control in mice will be of widespread interest to the biomedical science community and beyond. To ensure that our solution(s) are available to the widest audience, we will work closely with Edinburgh Research and Innovation (ERI) to explore marketing and dissemination options. We believe our versatile designs will be of interest to a wide variety of research disciplines and biotechnology/pharmaceutical companies so we expect high uptake both nationally and internationally. Commercialisation of our solutions would meet with the UK Government's current objective to promote the translation of world-class science to generate new business opportunities. In this case, we note that the primary goal of any commercialization process will be to disseminate our device to the broadest range of users. As an alternative approach, we may disseminate all necessary component and build information online via our website (www.DuguidLab.com) and/or neuroscience, neurotechnology & biomedical industry forums.

Developing our understanding of the neural underpinnings of cortical motor control will interest neurotechnologists focussed on the development of Brain-Machine-Interfaces (BMIs). Investment in basic science research is fundamental for driving collaborations and advances at the interface between neuroscience and neurotechnology. The development of assistive devices such as BMIs and Neuroprosthetics can enhance patient's quality of life, ensure an active independent life for a longer period of time and, therefore, also improve health. Consequently, such assistive devices will reduce the need for help from health care professionals, thereby keeping concomitant costs for society within reasonable limits.


Societal:
This research programme will promote the use of rodents as a viable and complimentary model system with which to elucidate the cellular and circuit mechanisms underlying cortical motor control. Given the significant advantages that rodent models provide (e.g. genetic tractability, ease of breeding, training and husbandry, low cost) and similarity to human and non-human primates in terms of basic motor repertoire, we hope to promote rodent use in developing novel pharmaceutical and surgical intervention methodologies that can be translated from bench to clinic. By highlighting the advantages and limitations of using rodent models of motor control we hope to contribute to the public and academic understanding of how animal research can lead to advances in human healthcare. Although this is a basic biomedical research programme it will serve as the foundation for more translational focussed research in the future.

Our long-term vision is to generate a 'blueprint' of the functional neuroanatomy of cortical motor control. This programme of research provides a significant step in this direction and will be helpful in identifying sites for pharmacological and/or surgical intervention aimed at alleviating many of the debilitating motor deficits associated with loss of motor control. As such, our data will be of interest to members of the pharmaceutical industry, clinicians and healthcare professionals alike. One specific example of where our research could help is in the treatment of Parkinson's disease which affects more than 10 million people worldwide. PD affects information transmission along the basal ganglia-thalamocortical pathway and this programme of research will focus on understanding how this pathway controls motor behaviour in the healthy brain, which is vital if we are to understand the mechanisms of cellular and circuit dysfunction in the diseased brain. We believe our findings will serve as a platform from which to identify new biomarkers and/or design, develop and optimise novel therapeutic interventions with the aim of enhancing patient quality of life.