Function of the thalamo-cortical pathway in sensory-guided behaviour

The thalamus is a critical 'communications hub' at the heart of the brain. Almost all signals from the senses pass through the thalamus on the way on their way to the cerebral cortex. Thalamus is also crucial for communication between different parts of the cerebral cortex. Thus, when thalamus is damaged, for example by stroke, the consequences for the patient are devastating.

When we are awake, we actively control the sensory input to our eyes/hands using our muscles. Perception is thus an active process that integrates motor control with sensory input. Under anaesthesia, this motor control is inactive. Although we know a lot about how thalamus operates in the sleeping/anaesthetised brain, we still do not understand how it functions when we are awake and actively sensing the environment.

Here, we propose to investigate how thalamus operates in the awake, behaving animal. Fortunately, thalamic circuitry is remarkably similar in different mammalian species and across different neural systems, so it is possible to get insight into thalamic function that is applicable to human health by studying rats and mice. The whisker system of rats and mice is particularly well-suited to such research, since there is a modular structure whereby signals relating to a given whisker are primarily processed by discrete regions known, in thalamus, as 'barreloids'.

Due to technological progress, it is now feasible to perform experiments on the whisker system of mice that were not previously possible. In this project, we will use the new methods to study how the whisker-related thalamus operates when mice use their whiskers to solve a discrimination task (identifying the location of an object). We will first investigate how thalamic neurons represent object location and exactly what whisker movements it is that evoke activity in thalamic neurons. Finally, we will study how, during object localisation behaviour, thalamic neurons are modulated by feedback from the cerebral cortex.

In order to investigate the role of thalamus in whisker-guided behaviour, it is extremely helpful to be able to measure precisely how the whiskers are moving (whisker kinematics) whilst simultaneously measuring neuronal activity. Technical breakthroughs have now made this possible and the techniques are established in the Petersen lab in Manchester. We will train head-fixed mice to perform a go/no-go object localisation task: the object (a metal pole) is positioned in either a go location or a no-go location. The animal is rewarded for licking on go trials and punished for licking on no-go trials. A high speed camera (1000 frames/s) will be used to measure whisker kinematics and, simultaneously, we will use microelectrode arrays to record activity of thalamic neurons. Neuroinformatics plays a crucial role in this project. Will use algorithms developed by the PI to extract whisker kinematics from the video data and use clustering methods developed the co-PI to analyse the neuronal data.

To investigate how thalamus represents the location of an object (Obj 1,3), we will quantify how well alternative neural codes, involving either single neurons and populations of neurons, represent pole location; and we will test our hypothesis that neurons in the higher order POM nucleus correlate more closely with the mouse's decision than neurons in the first order VPM nucleus.

To investigate what kinematic features of whisker movement (e.g., angle to the snout, angular velocity) evoke thalamic activity (Obj 2,3), we will extract time series of these kinematic features from the high speed video record and correlate them with the spikes of individual thalamic neurons. We will test a computational model previously developed by the PI using anaesthetised data and, if necessary extend it.

To investigate the role of cortical feedback in modulating thalamic responses (Obj 4), we will make simultaneous recordings from barrel cortex and VPM/POM.

Our work programme is a basic sensory neuroscience project, whose purpose is to investigate how the somatosensory thalamus operates in the awake, behaving state. Due to the remarkable homology in thalamic organisation amongst different mammals, and the striking similarities across different sensory modalities, this awake, behaving animal model is exceptionally well-placed to further our understanding of human sensory function and deficits.

Short term (3 years), we expect the primary beneficiaries of our research to be experimental neuroscientists (detailed in 'Academic Beneficiaries'). Because we aim to address a major topic (how the thalamus works in the awake, behaving state) using cutting edge techniques, there is the potential for substantial impact on the broader neuroscientific community in terms of both the advances in understanding of thalamic function and in the innovative combination of methodological approaches (simultaneous awake in vivo recording and behaviour tracking; application of data-mining tools).

Longer term, our insights into the functioning of sensory thalamus will be beneficial to the development of neural prostheses, particularly those for replacement of sensory organs, such as retinal and cochlear implants. As the key route from the periphery to cortex in all sensory systems is through thalamus, and is in some cases only thalamus, so optimal design of implant outputs can only be achieved through deep knowledge of thalamic coding of sensory information. Within the time-frame of this project, therefore, a critical pathway to the public health and economic impact of this work will be through the intermediate step of maximising its impact in the neural engineering community.

The short-term (3-5 year) potential impact on the UK economy is through capacity building in a much-needed UK skill-base. In their joint report "Systems Biology: a vision for engineering and medicine" the Academy of Medical Sciences and The Royal Academy of Engineering recommended that establishing systems biology capacity in the UK was critical to its competitiveness at the forefront of science, public health initiatives, and economic potential. A major benefit of this project is thus that it will build UK capacity in systems biology within neurophysiology, offering an opportunity to establish a world-leading research group in a currently nascent field. Within the lifetime of the project, the immediate beneficiaries will be the research staff employed on the project, who will receive extensive cross-disciplinary experience, and the potential to establish their own groups in this area. The two PDRAs requested will receive excellent training in niche, in demand skill-sets: in vivo awake recording in animal models, and analytical and computational skills in machine-learning and informatics.