Lecture 12 The cerebellum.pdf

LECTURE 13 – The Cerebellum The circuit The cerebellum has a modular structure, in that it presents an elementary circuit repeated innumerable times. The most superficial layer of the cortex is constituted by parallel fibres (molecular layer). The big somas of Purkinje neurons are aligned one behind...

LECTURE 13 – The Cerebellum The circuit The cerebellum has a modular structure, in that it presents an elementary circuit repeated innumerable times. The most superficial layer of the cortex is constituted by parallel fibres (molecular layer). The big somas of Purkinje neurons are aligned one behind the other just below this layer. Purkinje neurons are inhibitory neurons that project to the deep nuclei and constitute the only output path from the cerebellar cortex. They have an enormous, fan shaped spread of dendritic ramifications that extends in the molecular layer on a plane perpendicular to the parallel fibres and receives tens of thousands of synapses from them. The granule cells – which have their bodies in a layer deeper than Purkinje cells – send their axons to the molecular layer, where the axon splits in a T shape, generating the parallel fibres; each parallel fibre contacts thousands of Purkinje cells. Granule cells receive ipsilateral inputs from most structures in the brainstem and contralateral inputs from the cortex, through mossy fibres; Golgi (inhibitory) interneurons contact the dendrites of several granule cells where they are contacted by mossy fibres, thereby favouring coordinated activity in the granular layer. This way, each Purkinje cell collects quite a complex set of data from sensory as well as descending systems, largely (not fully) shared with other Purkinje neurons aligned with it. It looks as if everything is connected with everything... an exasperated pattern of divergence and convergence. This way, each Purkinje cell presumably responds to a number of patterns of cerebral+brainstem activity and, as a consequence, inhibits its deep nuclei target neurons. Each Purkinje neuron also receives a strong input from a climbing fibre that comes from the contralateral inferior olivary complex in a mostly one-to-one connection. The inferior olivary complex is a large medullar structure that collects information form both ascending (state of the body) and descending (commands from the brain) systems, compares them, and informs the cerebellum about possible discrepancies between commands and their results. Both the mossy fibres and the climbing fibres leave collaterals to the deep nuclei, that are therefore activated by both the direct information about the state of the nervous system (mossy fibres) and the consistency between command and results (climbing fibres). The resulting activity in the deep nuclei is modulated by the cerebellar control (Purkinje neurons). As a result, the deep nuclei tend to produce reflex and instinctual responses to any situation that arises in the central nervous system, and in doing so they are strongly affected by the reaction of the inferior olive to possible errors in the outcome. When the olivary complex detects an inconsistency between descending commands and ascending sensory information climbing fibres are activated and reach the deep nuclei, to correct the movement, and simultaneously the dendrites of the corresponding Purkinje cells. This produces a strong, prolonged and complex activation of multiple synapses on the dendrites of the target Purkinje cell, that induces long-term depression of all parallel-toPurkinje synapses that are simultaneously active: as a result, when the deep nuclei are activated by the olivary output, the response of Purkinje cells is concurrently modified. This system is particularly fast and allows the brain to correct ongoing movements if they tend to depart from the desired path, without the need for the cortex to reprogram them. Precision and coordination The rapidity and efficiency of the inferior olive + cerebellum system in supervising the correct execution of movements il largely based on the very efficient handling of (1) time intervals and (2) graded modulation of descending motor system. Even the “simplest” movement (e.g. moving a hand from the sternum straight forward) actually involves activating a large number of muscular groups in a perfectly timed way: the hand initially accelerates in the appropriate direction, moves due to continuously changing contributions of the muscles acting on shoulder, elbow and wrist, is stopped at precisely the right place by concerted inhibition of the active muscles and activation of the antagonists; no overshoot or wavering. Disturbances of this precisely timed coordination of several muscle groups produce imprecise, badly temporized, disordered movements (lack of order, ataxia). In summary, the cerebellum is a input-output system that provides feedback to the cortex and the brainstem so that it can correct procedures and possibly take control; in particular, four input-output “lines” go through the cerebellar circuits. 1. The simplest circuit is the direct connection of the input through collaterals of the mossy fibres to the deep nuclei, which essentially sustain reflex and instinctual responses. 2. A second, similar circuit is constituted by the climbing fibres; these also send collaterals to the deep nuclei, which produce appropriate correction of the responses when the inferior olivary complex detects inconsistency between descending commands and sensory feedback 3. The most complex circuit is the hugely convergent/divergent processing by the {granule cells + Purkinje neuron} circuitry, that modulates the action of the deep nuclei on the basis of all the information arriving from the cortex (through the pontine nuclei) and the descending and ascending systems in the brainstem. This system is able to modify motor, visceral and cognitive responses and to correct them to compensate for external conditions or stimuli, or concomitant behaviours or internal tasks, that may interfere. A salient feature of this system is the very refined control of timing, intensity and contrast in the modulation of the direct circuits (1 and 2 above). Inhibitory Golgi cells receive input from granule cells both at the dendrites and at the parallel fibres, thereby producing a rapid inhibitory shut-down of the activity of the granule cells; since Golgi cells are interconnected through gap junctions, the shutting off is extended to a number of other granule cells, thereby defining a very narrow time window for temporal summation of inputs (if an input arrives with a slight delay its action is inhibited by the Golgi neuron feedback). Stellate and basket cells, on the other hand, are inhibitory neurons in the molecular layer that provide lateral inhibition by inhibiting neighbouring Purkinje neurons when one of them is activated; this increases contrast and spatial precision, making it possible to activate specific Purkinje neurons in the face of the vast divergence of mossy inputs. 4. The fourth circuit is driven by error detection by the inferior olive and correction through climbing fibres. In addition to directly correct in the presence of an error (circuit 2 above), climbing fibres produce a large, prolonged and complex depolarization of the dendrites of the target Purkinje neuron, determining long-term depression of the parallelto-Purkinje synapses concurrently active, thus also modifying the circuit (3) so that it becomes able to intervene and correct even before the error occurs. From correcting to learning The plastic changes produced by the climbing fibres on the parallel-to-Purkinje system of synapses bring about an important change in the cerebellar function: the cerebellum learns how to correct the movement during the execution itself, based on the information it receives from cortex and brainstem through the granule cells. This is the circuital basis of conditioning: a certain situation (unconditioned stimulus, US) produces a response (unconditioned response, UR). A concurrent stimulus would produce a different response, activate a number of granule cells and thus elicit the inhibitory action of a number of Purkinje neurons; this may interfere with the UR. The olivary detection of improper response will act on the circuit so that the deep nuclei respond correctly (UR) and the interfering Purkinje cells are excluded (long-term depression of the active parallel-Purkinje synapses); Purkinje neurons will thus learn to modulate the deep nuclei so to facilitate – rather than interfere with – the UR. As a result, the cerebellum will learn to produce the same response (no more UR, but now conditioned response, CR) in the absence of the US and in response to the new (conditioned) stimulus (CS). It can be noted that the just described classical (Pavlovian) conditioning allows the CNS to produce sequences of movements in an automatic way: the momentary situation constitutes the conditioned stimulus for the next movement (hitting one key on the piano elicit the movement of hitting the next one in the sonata). This way the cerebellum can take control, in performing sequences of actions that have been repetitively practiced, and thanks to the rapidity of these circuits, make it possible to perform them at a greater speed and without the need to intentionally supervise them (which would actually break the sequence). Non-motor functions of the cerebellum A very general rule, as regards the various circuits and areas of the brain, is that each of them can be looked at as a computational system, with its own specialization in elaborating information in the appropriate way to perform its function. Given the particular organization of the cerebellar circuits, that offers (1) the possibility of a real-time correction of ongoing procedures, on the fly, and (2) the possibility of learning to correct errors before they occur and (3) to favour the next step in a procedure based on the current situation, it would be a shame to use such a powerful servo-system only for the control of motor behaviour by the cortex. It should be clear that this function of the cerebellum – supervision on the fly + automatic guidance of a procedure – is not limited to motor behaviour, but extends to cognitive behaviour. When a poem or a prayer has been learnt by heart, repeating it becomes an automatic task; if one gets stuck in repeating it the best way to proceed is by restarting from the beginning; it might not even be easy to perform the task correctly if one tries to “think” and intentionally supervise what they are saying. Language is a domain in which this kind of automated control of cognitive behaviour plays a paramount role: when we speak we continuously check the consistency of desinences with singular/plural (possibly gender) of nouns and tenses of verbs, the correct word ordering in the sentence, and the compliance with grammatical and syntactic rules, but after we learn to do so, in infancy, we certainly we do not intentionally supervise these aspects any more. Defects in cerebellar function Neurons in deep cerebellar nuclei are tonically active. ✓ Lesions will produce a decrease in muscular tone (cerebellar hypotonia) Defects in cerebellar function: ✓ increased errors in timing the components of movements ✓ systematic errors in direction and extent (dysmetria) ✓ poor coordination of joint motions (ataxia): curved (not straight) hand motions ✓ attempts to correct and new errors → hand irregular oscillation (terminal tremor) ✓ stretch reflexes are present, but the limb tends to oscillate (pendular reflexes). Lesions of the Cerebro-cerebellum disrupt motor planning and prolong reaction time Lateral cerebellar lesions disrupt the timing of the various components of movement; they appear to take place sequentially rather than being coordinated smoothly: → “decomposition of movement” Medial cerebellar lesions interfere only with accurate execution of the response, whereas lateral cerebellar lesions interfere with the timing of serial events (timing defect not limited to motor events → inability to judge elapsed time and speed) Please note (also in reference to the discussion of basal nuclei and their function): here we are talking about movement decomposition (each movement is a complex timed sequence of muscle activations), but not about coordinating distinct movements or conciliating them or harmonizing subsequent movements and blending them into a complex fluid behaviour. Also, note that subcortical reflexes can be modulated and modified, but in that case learning is produced by the cerebellum by temporarily modifying synaptic efficiencies in the subcortical circuits (examples are adaptation of nystagmus speed when wearing magnifying glasses) and not by long-term changes in the cerebellar cortex. These modifications are rapidly reversed.