Temporal dissection of the grasping circuit

An ultimate goal of systems neuroscience is to explain human behaviour based on brain activity. It is becoming increasingly clear that in order to do this we need to understand how different brain areas talk and interact with each other. This is especially true for the brains of primates (including humans), which have many more distinct areas compared to lower mammals, such as the mouse. Moreover, understanding how different brain areas interact is likely to be important in the future for the diagnosis and treatment of human brain disorders. New experimental techniques that allow simultaneous monitoring of the activity of thousands of individual neurons in different brain areas during behaviour combined with novel and sophisticated analysis provide an unprecedented opportunity to advance our understanding of how interactions between brain areas contribute to behaviour.
In this project, we will investigate interactions in the brain network controlling visually guided grasping. The grasp network is an ideal model system to examine wider issues of interactions between different brain areas. We can achieve exquisite, millisecond-precise control of this system's input (vision of an object to be grasped), and can likewise easily characterise the network output (hand kinematics and muscle activity). Understanding visual control of grasp is important because hand function is fundamental to daily life, for our technology, communication, culture and social interaction, and loss of hand function is devastating. We will focus our attention on three key nodes of the brain network responsible for grasping: the primary motor cortex and the secondary motor cortices in both hemispheres (premotor areas) which are all critically involved and interact during visually guided grasp. To the best of our knowledge, interactions between these areas have never been investigated simultaneously. Therefore, there is still a lack of understanding of how precisely grasping unfolds in time, from the first sight of an object through hand pre-shaping to the actual grasp and how it is influenced by interactions between grasping brain areas.
We will record the activity of thousands of individual neurons during grasp and apply state-of-the-art analysis techniques to discover how brain areas talk to each other to enable this complex motor behaviour. To understand the causal role of brain interactions in grasping behaviour, we will manipulate behaviour and brain activity using a specifically designed behavioural task and pharmacological and optogenetic interference techniques.
In this project, we will reveal fundamental principles of how multiple, spatially distributed areas in the primate brain collaborate to achieve a specific behaviour, this is critical for theories of neural communication. We will provide insights into neural mechanisms controlling our hands during grasp, with important implications for understanding brain control of human hand function in health and disease.

The feedforward and feedback connections between spatially distributed cortical areas in the primate brain provide an anatomical scaffolding for interareal neural communication, however, we still lack a detailed understanding of how these communications contribute to the behaviour.
Here, I propose to investigate interareal communications within the cortical grasping network enabling skilled hand function. Hand control is fundamental for our daily life and its loss is devastating. However, it is still unknown how moment-by-moment neuronal activity controlling visually guided grasp is shaped by interareal communications.
We will record neuronal activity using high-density probes simultaneously in three major nodes of the cortical grasping network: M1 and bilateral F5, all of which are densely anatomically interconnected. We will identify the specific roles of ipsiF5 and contraF5 in shaping M1 neuronal activity to resolve the apparent paradox that ipsiF5 and contraF5 have similar neuronal activity but different contributions to motor output.
Large-scale recording datasets are challenging to interpret. Therefore, we will apply state-of-the-art population-level analysis based on the dimensionality reduction techniques, specifically designed for large-scale neuronal recordings, to reveal 'communication subspaces' within the grasping network. In addition, we will physiologically identify pyramidal tract neurons and their subset, corticomotoneuronal neurons to reveal their contribution to interareal communication.
To uncover the time-resolved directionality and causality of the communication we will perturb the system behaviourally with task manipulations and neuronally using pharmacological and optogenetic techniques.
The project will reveal fundamental principles of how multiple, spatially distributed cortical areas in the primate brain collaborate to achieve a computational goal.