An integrative study of neural coding in the vestibular cerebellum: from cellular physiology to models of network behaviour

We form representations of our surroundings using our primary senses: seeing, hearing, smelling, tasting and touching the world around us. To process this vast array of information brains have evolved specialized regions dedicated to specific types of sensory modalities. In mammals including humans we know when this information reaches the brain it is placed in context through multimodal integration within and between these different regions. The success of this kind of integration is highlighted, for example, by our ability to compute the location of an auditory or visual stimulus relative to head position. Vestibular information, the so-called sixth sense has perhaps the most dramatic and yet underappreciated influence throughout the central nervous system, contributing to functions such as vision, hearing, movement, cognition, sleep, digestion and even learning and memory. More specifically it is presumed to underlie an internal gravity model in humans as well as an intrinsic spatial coordinate system. Defects of the vestibular system result in impaired spatial perception and memory as well as failure to perceive self-motion. In fact disequilibrium affects almost half of the population by age 60 and is as prevalent as hypertension and angina. Recent clinical studies have reported that isolated cortical lesions in humans can cause recurrent episodes of vertigo and imbalance that are consistent with extracellular electrophysiological studies in primates and cats showing vestibular contributions to cortical activity. In this project we will elucidate the neural mechanisms of vestibular representation in the cerebellum- the primary structure know to be involved in maintaining balance, posture and the control of movement. We will combine cellular studies in brain slices that allow us to examine the microscopic mechanisms involved in regulating single cell excitability with a systems approach that uses natural stimulation in the intact animal. Computer simulations will allow us to explore the mechanisms of vestibular signalling on the large scale that the cerebellum is known to operate on. Findings from this provide an understanding of the neural basis of balance and movement and shed light on the underlying causes of disequilibrium and vertigo.

Organised as networks of interconnected modules, cortices are the parallel distributed processors of the brain. We propose here to take a systems biology approach to breaking the cerebellar code, that is to use the power of systems neuroscience, computation and modelling to infer the properties of the cerebellar microcircuit from the properties of its parts. To reach this goal our consortium includes cellular neurophysiologists with a long-lasting interest in cerebellar microcircuits, in vivo electrophysiologists, specialists of neuronal computing and of statistical physics. By bringing together scientists with this broad spectrum of competence, we aim at developing an explicit model of the cerebellar cortex that will be tightly constrained by detailed morphological and physiological data. Because its anatomically well-defined and natural sensory stimuli (ie in the input stimuli) are readily quantifiable we will focus on signal processing in the vestibular cerebellum. To address this question we record intracellularly from cerebellar mossy fibers (input), uniploar brush cells (UBCs) and granule cells (GCs) in vivo during vestibular stimulation. We will then use analysis methods derived from information theory to quantify the amount of information that is transferred to GCs. We will then analyse and model information transfer synapse by synapse in vitro to understand how UBCs and GCs might integrate mossy fibers inputs. These data will serve to construct an explicit model of the granular layer in 3D using neuroConstruct. We will then use an in vitro model of triggered activity to constrain computer modelling by comparing patterns of activity evoked single cell activation in silico and in the slice. Gradually additional components of network processing such as inhibition and transmitter spillover will be added to generate a comprehensive model of vestibular cerebellum computation.