Back to front: importance of cerebro-cerebellar interactions in goal-directed behaviour.

A substantial part of animal, including human behaviour is goal-directed. Learning how to achieve a defined goal requires the interplay between higher brain centres involved in planning and decision making, and subcortical structures that co-ordinate the desired movement. The prefrontal areas of the cerebral cortex are thought to be especially concerned with the planning and decision making aspects of such tasks, while the cerebellum is heavily involved in co-ordinating the desired action. However, recent studies in humans and patients are challenging this division of labour and it is increasingly being recognised that the contribution of the cerebellum goes beyond movement control to include many other aspects of brain function, including a contribution to cognitive processes.

The cerebellum is linked to structures throughout the central nervous system, from the spinal cord to prefrontal cortex. An important organizational principle of the cerebellum for understanding these widespread connections is a division into a series of anatomical/functional units called modules. How individual modules contribute to goal-directed behaviour remains far from clear. Individual cerebellar modules are thought to contain representations (internal models) of predictable behaviour that allow us, through practice, to execute tasks more rapidly and with increased accuracy. The current project uses the modular organization of the cerebellum combined with the computational capability of internal models as a structural and theoretical framework to study prefrontal-cerebellar network interactions during goal-directed behaviour.

An important gap in our understanding of prefrontal-cerebellar interactions is investigation in animal models of large scale brain networks in terms of information processing at the level of recording neural population activity and spike trains of individual neurones; and also interventionist work to dissect out the functional importance of the interactions. Linking the study of higher centres to movement control also has the advantage that 'cognition' is constrained in the sense that it is being studied in relation to well defined behavioural outputs. In collaboration with our industrial partner (Takeda Cambridge Ltd) we will therefore use the combined power of multichannel electrophysiological recording, stimulation, functional anatomical and behavioural techniques at the systems level of analysis to advance our understanding of the function of brain circuits involved in goal-directed behaviour.

Choice of experimental model: cerebellar network architecture and patterns of connectivity are highly conserved across mammalian species, including human. However, adult rats are the experimental animal of choice because our understanding of the basic neuroanatomy and physiology is most complete in this species. Importantly, our experiments will include study of neural network interactions during behavioural situations that have been well characterized in rats and that correlate to human cognitive performance. We will study neural network dynamics in prefrontal-cerebellar circuits during cognitive task performance before and after transcranial stimulation of the cerebellum. The latter has been shown in human studies to improve cognitive task performance but the underlying neurobiology is unknown. In complementary functional anatomical studies our industry partner will chart the pattern of neural network activation produced by transcranial cerebellar stimulation.

The results of our project aim to provide fundamental new insights into how neural circuits within the brain give rise to our ability to modify our actions to achieve a particular goal.

Goal-directed movements involve a distributed network of linked brain regions that includes the prefrontal cortex (PFC) and the cerebellum. The PFC is involved in the decision making and planning of such movements whereas the cerebellum ensures that the resulting movements are performed in a co-ordinated manner. However, the distinction between cognitive and motor structures may not be as clear cut as this would imply. An emerging concept is that the cerebellum, which has traditionally been thought to be exclusively concerned with motor control, may also be involved with cognition. The current study will examine this possibility directly by recording the interaction between the PFC and the cerebellum during goal-directed behaviours that engage higher order processes.

Together with our industrial partner (Takeda Cambridge) we will test the related hypothesis that: 1) during cognitive tasks co-activation of the PFC and cerebellum will occur; 2) that the level of co-activation will differ according to cognitive load; And 3) as cognitive demand decreases once the cognitive task is solved and becomes automatic, information flow between the two structures will shift from top down (PFC to cerebellum) to bottom up (cerebellum to PFC).

To test these hypotheses in vivo experimental approaches in adult rats will combine cognitive behavioural tests (delayed matched to sample and attentional set shifting) with simultaneous multichannel electrophysiological recording of neural activity within the cerebellum and PFC. In addition, the effects of transcranial DC stimulation of the cerebellum on PFC - cerebellar interactions during task performance will be studied, and complementary functional anatomical experiments will determine the key brain structures activated by the cerebellar stimulation. Overall, these experiments will provide new insights into the way the PFC interacts with the cerebellum during goal-directed behaviours that engage cognitive processes.

Goal-directed behaviours require higher order processes to plan and decide which strategies to use to achieve the desired outcome. These mental processes are impaired in healthy ageing and in neurodegenerative diseases such as Alzheimer's and Parkinson's, and in neuropsychiatric disorders such as schizophrenia and autism spectrum disorder, and therefore contribute substantially to a wide burden of symptoms that remain largely refractory to conventional drug-based therapies.

The research will be of benefit to:
(i) The academic research team;
(ii) The industry collaborator;
(iii) The academic community;
(iv) Members of the general public with an interest in cognition and its link to behaviour;
(v) The Pharmaceutical Industry as a whole;
(vi) Patients suffering from cognitive disorders, their families, charities and organizations seeking to support patients.

How will they benefit from this research?
(i) The research co-I will develop expertise in highly novel and state-of-the-art research techniques that will aid her future career. There is a worldwide skills shortage of researchers with experimental animal in vivo research expertise. By taking a lead role in the research programme the research co-I will also develop her management, communication, team working and other transferable skills. The active involvement of the Industrial Collaborator will also help to inform and educate the academic research team as a whole (academic staff as well as postgraduate and undergraduate research students) to allow a better understanding of the needs and focus of Industry, helping to breakdown barriers to partnerships.

(ii) Takeda Cambridge will benefit considerably through interactions with Bristol University and the academic research team involved in the project. Building good working relationships with researchers in areas of active scientific interest is of great importance to inform strategy and provide opinion for drug discovery. Skills, technical capabilities and specialist knowledge will be shared between the company and the academic researchers, helping broaden individual personal strengths.

(iii) International academia in the fields of preclinical and clinical psychiatry, as well as basic scientists in the fields of sensorimotor, cognitive and behavioural neuroscience are likely to benefit from the scientific progress made by this research.

(iv) Members of the general public. The findings from this project are applicable to understanding human mental health and ageing. Such knowledge is of wide interest to the general public. The findings will therefore be appropriate to disseminate through public engagement activities.

(v) Pharmaceutical Industry. Worldwide clinical and preclinical drug research will benefit from advances in understanding of basic brain biology and its relevance to areas of major human disease that cause a substantial burden on society.

(vi) Patients suffering from cognitive disorders. At present there are no satisfactory treatments. In large part this is because the underlying neurobiology of these disorders is unknown. By providing insights into normal brain circuit function associated with cognitive behaviours, the research will enable charities to realise their mission of providing education and help to patients and their carers. Progress in understanding network dysfunction that leads to cognitive disorders requires a global perspective on brain function i.e. it is not sufficient to study one brain region in isolation. The network analysis we seek to provide will offer a more accurate picture of the neurobiology involved. The impact of the research on patient groups and their families will be in terms of identifying potential new targets for therapies; insights into the neurobiology of transcranial stimulation as a potential treatment; and being able to provide a better understanding of the brain circuitry that underpins cognitive disorders.