Cerebellar Physiology Richard M. Costanzo, Ph.D. OBJECTIVES After studying the material of this lecture, the student should be able to: 1. Name the three functional subdivisions of the cerebellum. 2. Compare and contrast the mossy and climbing fiber systems. 3. Give examples of inhibitory interneurons located in the cerebellar cortex. 4. Describe how the cerebellar cortex influences the activity of the deep cerebellar nuclei. 5. Describe the cerebellar abnormality referred to as "ataxia". I. FUNCTIONAL SUBDIVISIONS OF THE CEREBELLUM The cerebellum receives information from most sensory modalities including information about body position, muscle length and muscle tension and provides continuous feedback control over movement. One of its major functions is to regulate the rate, range, force, and direction of movement (synergy). The cerebellum is responsible for the coordination of movement. In addition to the anatomical divisions of the cerebellum (cerebellar hemispheres, vermis, and the anterior, posterior, and flocculonodular lobes), the cerebellum has three functional subdivisions. They are the cerebrocerebellum (also called pontocerebellum), vestibulocerebellum, and the spinocerebellum. Figure 1: (From Netter- CIBA collection, 1983) A. Cerebrocerebellum (neocerebellum) The cerebrocerebellum helps to coordinate movement by continuously monitoring and adjusting motor commands. It receives input from different areas of the cerebral cortex (e.g., sensory and motor areas) by way of the pontine nuclei (cortico-ponto- cerebellar system) and thereby is continuously updated about ongoing movements being executed by the motor cortex. Efferents from the cerebrocerebellum project via the dentate nucleus to the thalamus and then motor (area 4), and premotor (area 6), areas of cortex, where they provide important information needed to prepare for movement. Efferents also project to a region of the red nucleus. Lesions to the cerebrocerebellum can result in delays in initiation of movement and distortions in coordination (ataxia). B. Vestibulocerebellum (archicerebellum) The vestibulocerebellum plays an important role in controlling balance and compensatory eye movements that occur with changing vestibular signals (vestibuloocular reflexes and optokinetic reflexes). It receives input primarily from the vestibular apparatus and its output projects back to the vestibular nuclei, bypassing the deep cerebellar nuclei. The vestibulocerebellum has its primary influence over the axial motor neurons (medial systems) that control balance and posture. C. Spinocerebellum (paleocerebellum) The spinocerebellum is primarily comprised of the anterior lobe vermis and hemisphere (although some spinocerebellar input also reaches the pyramis and uvula of the posterior lobe vermis). It receives sensory information (e.g., proprioception) from the spinal cord (via spinocerebellar tracts) as well as auditory and visual. The spinocerebellum uses this sensory information to continuously monitor movement and provide feedback signals to control muscle tone and adjust ongoing movement. II. CEREBELLAR CORTEX (3 layers) A. Molecular Layer (outer layer) 1. Stellate and basket cells 2. Dendrites of Purkinje and Golgi II cells 3. Parallel fibers (axons of granule cells) B. Purkinje Cell Layer (middle layer) 1. Purkinje cells C. Granule Layer (innermost layer) 1. Granule cells 2. Golgi type II cells 3. Glomeruli - axons of mossy fibers forming synaptic modules on dendrites of granular and golgi II cells. III. CEREBELLAR AFFERENTS (INPUTS) There are two excitatory fiber systems that provide input to the cerebellum. They are the climbing and mossy fiber systems. Both systems send collateral branches to the deep cerebellar nuclei in addition to their projections to cerebellar cortex. These excitatory collateral projections make up the primary cerebellar circuit. Projections to the cerebellar cortex activate secondary modulatory circuits that in turn regulate the output of the cerebellar nuclei via the inhibitory action of Purkinje cells. Purkinje cells which are driven (directly or indirectly) by the inputs from climbing and mossy fibers provide the only output pathway for activity in the cerebellar cortex. Purkinje cell efferents are always inhibitory and provide the modulatory control signals for the primary (excitatory) cerebellar circuit. Figure 2: Primary and modulatory cerebellar circuits A. Climbing Fibers Climbing fibers originate from a single region of the medulla (the inferior olive) and have direct projections to Purkinje cells. The term climbing fiber refers to the way that these fibers make multiple synaptic connections along the dendrites of Purkinje cells. A single fiber can make up to 2000 or 3000 synaptic contacts along the dendritic tree of a single Purkinje cell. Although a single climbing fiber may contact between 1-10 Purkinje cells, each Purkinje cell receives synaptic connections from only one climbing fiber. Synaptic connections formed by climbing fibers are some of the most powerful in the nervous system. A single action potential from a climbing fiber can elicit a gigantic excitatory high frequency burst in Purkinje cell dendrites and is referred to as a "complex spike". It is thought that climbing fibers act to condition Purkinje cells so as to modulate there response to mossy fiber input. It has also been suggested that they play a role in cerebellar or motor learning. Figure 3: Neural circuits of the cerebellar cortex (From Costanzo, 2006, Fig. 3-33) B. Mossy Fibers Mossy fibers make up the majority of cerebellar afferents. They include: pontocerebellar, spinocerebellar, reticulocerebellar and vestibulocerebellar afferents. Mossy fibers project to excitatory interneurons (granule cells) and form morphologically distinct synaptic structures referred to as cerebellar glomeruli. The axons from granule cells ascend to the molecular layer where they bifurcate and give rise to parallel fibers. The parallel fibers of the granule cells contact numerous Purkinje cell dendrites and produce a "beam" of excitation along row of Purkinje cells. The dendritic tree of each Purkinje cell can receive input from as many as 250,000 parallel fibers and therefore has access to a lot of information. IV. CEREBELLAR INTERNEURONS With the exception of granule cells, interneurons within the cerebellar cortex are all inhibitory. Granule cells have an excitatory influence of basket cells, stellate cells, golgi type II cells and on Purkinje cells via parallel fibers. Basket cells and stellate cells inhibit Purkinje cells. Golgi type II cells inhibit granule cells which in turn reduces their excitatory effect on Purkinje cells. The primary function of cerebellar interneurons is to modulate Purkinje cell output. V. CEREBELLAR CORTICAL EFFERENTS (Output) Purkinje cell axons provide the only output signals from the cerebellar cortex. Purkinje cells are GABAergic inhibitory neurons and project to the deep cerebellar nuclei (dentate, interpositus and fastigius) and the vestibular nucleus. These inhibitory projections serve to modulate the primary cerebellar circuit (excitatory stream of activity from mossy and climbing fiber collaterals projecting to cerebellar nuclei) and play an important role in the control of rate, range and direction of movement. VI. CEREBELLAR EFFERENTS The deep cerebellar nuclei (fastigial, interposed, dentate) give rise to all of the cerebellar efferent projections that leave the cerebellum. In general, cerebellar efferents are excitatory on their targets, e.g., thalamus, red nucleus, basilar pons, inferior olive. VII. FUNCTIONS OF THE CEREBELLUM The location of the cerebellum adjacent to the brainstem provides it with the unique opportunity to monitor (listen in on) sensory and motor activity. The lateral portion of the cerebellum (cerebrocerebellum) receives information form sensory and motor areas of cortex and plays an important role in the planning and preparation for movement. The cerebrocerebellum sends plan and program information to the premotor and motor cortex which in turn executes these plans by generating motor control signals. The spinocerebellum (vermis and intermediate region) participates in the execution of movement by monitoring sensory and proprioceptive feedback signals and making adjustments to the motor control signals. This assures that the programmed movement is coordinated and carried out as planned. VIII. DISEASES (LESIONS) OF THE OF THE CEREBELLUM Most abnormalities due to cerebellar lesions are observed during movement. Abnormalities of movement resulting from cerebellar lesions are referred to as "ataxia" (also called "asynergia" or "dyssynergia"). Cerebellar ataxia is the lack of coordination due to errors in rate, range, force and direction of movement. Asynergia can be manifested in a number of different ways. There could be a delay in the onset of movement, or the movement could be a poor execution of a sequence of movement so that it appears unsmooth and uncoordinated (decomposition of movement). A limb can overshoot its target (hypermetria or past pointing) or can stop before reaching its goal (hypometria). These disturbances of trajectory or placement of a body part during movement are called "dysmetrias". The inability to perform rapid alternating movements is referred to as "dysdiadochokinesia". Intention tremors are tremors that occur perpendicular to the direction of movement and increase in magnitude near the end of the movement. This is the result of a disturbance of temporal coordination of contraction