Cerebellar circuitry: from synapse to behaviour

Many diseases ? stroke, multiple sclerosis or cancer ? can make a brain structure called the cerebellum fail. When the cerebellum goes wrong, patients can suffer from impairment of balance and coordination, disordered eye movements, and severe tremor. The cerebellum (or ?little brain?) is found at the back of the brain, just above the brain stem. Often the cerebellar aspect of these diseases is the thing that forces patients into the wheelchair. There is no good treatment for any cerebellar disease. The neurons die and cannot be replaced. But it may eventually be possible to build an artificial cerebellar-like device which could, at least partially, carry out some realistic functions at natural (high) speeds. This could help patients with cerebellar damage. To get such a device to work with the full ability of the real cerebellum, we need a deep knowledge of how the natural circuit works. This is what we research: how the cerebellum helps the body make movements. To do this research we use special types of mice (genetically engineered) that have specific parts of their cerebellum altered. We will then study how the chemicals that pass information between the brain cells in the cerebellum make the circuit work. The cerebellum has five different types of brain cell which are wired up to each other in a clear way. We are working on one of these types, a Purkinje cell. Using a special method which we invented, we can turn the activity of the Purkinje cells up and down, and find out how this alters the behaviour of the mice. For example, we film how well the mice can walk. This will tell us what the Purkinje cells do.

The cerebellum makes motor adjustments and sensorimotor predictions essential for any kind of active life. Cerebellar disorders have severe effects: impairment of balance (ataxia) and extremity coordination (dysmetria), disordered eye movements (nystagmus), dysarthria and intentional tremor. The cerebellum offers an opportunity for understanding how neuronal networks produce and store memories. Three outstanding advantages are: (i), the well defined circuit; (ii) the ability for precise cell-type specific targeting using gene promoters; (iii) a new pharmaco-genetic technique that we have invented for fast cell-type specific modulation of neurons in vivo. This enables dynamic analysis of individual circuit components and how they relate to, or produce, behaviour. We wish to: (i) investigate how feed-forward inhibition of the Purkinje cells shapes cerebellar memories, in particular the consolidation process; (ii) explore the possibilities of cell-type selective bidirectional modulation of Purkinje cells ? can we increase or decrease memory performance; (iii) explore the role of the timing component of inhibition (phasic inhibition) onto granule cells using specific modulation of the Golgi-granule cell synapse using newly engineered mice; (iv) explore the role of mossy fibre input to granule cells by specifically ablating either the AMPA or the NMDA receptor component. We will study these questions using slice and in vivo electrophysiology as well as behavioural assays.