Actions of cerebellothalamocortical (CTC) networks on the musculature can be modified by associative conditioning in adult animals. During conditioning, electrical stimulation of a CTC network involved in forearm flexion movements results in either flexion or extension responses, depending on the somatosensory information given by the unconditioned stimulus (UCS). In the present work we attempt to determine what kind of neurobiological changes induced in the CTC pathways as a consequence of distinct somesthetic messages could lead to different conditioned motor responses. Two conditioning procedures in which distinct UCSs were successively applied to awake cats in chronic preparation. The conditioned stimulus (CS) was an electrical subthreshold stimulation of an interpositus nucleus (IN) site at the origin of CTC circuits controlling forelimb flexion movements. It was first paired with a UCS applied to the skin above the wrist, also producing a forearm flexion reflex, and second with a UCS applied more proximally on the forearm, producing a backward withdrawal reflex of the forelimb. The two procedures, termed "concordant" and "discordant," respectively, were carried out in a different order on the same cats, separated by 2 mo of rest. The effects of conditioning were assessed from the characteristics of the motor reponses induced by the CS and from the properties of the CTC transmission analyzed on the cortical field potentials induced by IN stimulation. The concordant procedure resulted in persistent enhancement of the amplitude and rate of occurrence of the forearm flexions induced by the CS. Concomitantly, an increase of the di- and/or trisynaptic excitatory negative component of the field potentials induced by the CS in layers III and V of the elbow motor cortical representation was observed. In contrast, during the discordant procedure, the forearm flexions initially induced by the IN stimulation were progressively abolished in favor of forearm extensions, and, in parallel, a depression of the excitatory negative component of the cortical responses and the appearance of a later large positive event were observed. The selectivity and the associative nature of the motor and synaptic changes were tested. The two kinds of events appeared to be linked. It was concluded that somesthetic information given by the UCS seems to be a critical factor in the determination of both the motor and synaptic CTC changes induced by associative conditioning. Alterations of cerebellocortical transmission appeared to constitute one of the neurobiological substrates for conditioned motor changes.

A simplified sensorimotor pathway was subjected to an associative conditioning in fully awake cats. It was defined by the location of electrodes for applying the conditional stimulation (CS) in the cerebellar interpositus nucleus (IN) and the unconditional stimulation (UCS) on the skin of the forelimb. Electrodes chronically implanted all along the pathway allowed the simultaneous study of the motor and the neurobiological effects of conditioning. Persistent motor changes were observed in parallel with interposito-rubral and thalamocortical synaptic efficiency changes. The two kinds of event evolved similarly and significant correlations were found between them. Changes appeared to be induced according to modalities similar to those underlying elementary mechanisms of neuronal plasticity. The modulations of thalamocortical synaptic efficiency inside the primary motor cortex (MI) determined a new pattern of distribution of cerebellar effects on musculature, indicating that in adult brains the functional organization of central motor pathways is not definitely rigid it can still be subject to adaptive modifications.

1. Some connections from the afferents to the magnocellular red nucleus (RNm), like the corticorubral synapses, have plastic properties that are thought to contribute to long-term changes such as functional readaptation, motor learning, and the establishment of conditioned responses. Because previous studies have focused on corticorubral synaptic reorganization after these events, we attempted to investigate cerebellorubral connections in intact adult cats during associative conditioning by pairing electrical stimulation of interpositus nucleus [the conditional stimulus (CS)] with electrical simulation of the forelimb [the unconditional stimulus (UCS)]. A large increase in the amplitude of the forelimb flexion (conditioned response) induced by the CS was observed after several days of paired CS-UCS presentations. 2. For this purpose, both behavioral and electrophysiological methods were used to correlate synaptic plasticity with changes in the motor responses. The somatotopically organized sensorimotor network functionally related to the control of the elbow joint movements was studied in awake adult cats. This circuit was defined on the basis of sites at which elbow flexions could be evoked both as a CS and a UCS. The CS was applied in the cerebellar interpositus nucleus (IN) site and the UCS was given to the skin on the dorsum of the distal part of the forepaw. Daily classical conditioning consisted of repetitive pairings of CS and UCS with an interstimulus interval (ISI) of 100 ms. 3. The transmission efficacy resulting from the conditioning was tested in various targets of the cerebellar efferent pathway, including the RNm. Electrophysiological responses evoked in these relay structures by the CS and the forelimb angular deviations were simultaneously recorded throughout each daily conditioning session. The surface areas of the rubral responses to CS and the percentage response rate, the angular deviation (amplitude), and the latency of the motor responses were systematically measured throughout the conditioning procedure. Test sessions were also performed before and after each period of conditioning. Quantification and statistical analysis were carried out to determine whether changes observed in interpositorubral synaptic transmission and in the motor responses evoked by the CS were correlated. 4. Daily repetition of paired CS and UCS according to a predefined and fixed temporal schedule led to an increase in the response rate and amplitude of the forelimb flexions. A procedure with repeated presentation of CS preceded by UCS was used to produce extinction of the enhanced motor responses. The associative nature of these changes was confirmed by the fact that the CS given alone for 11 days in a control condition failed to produce any modification of the motor response. 5. The changes in the flexion movements were accompanied by a nearly parallel increase of the amplitude of the "postsynaptic field potentials" evoked in the RNm by the CS (IN stimulation). Changes in the transmission efficacy of the interpositorubral synapses stayed stable even after several days of interruption and remained constant up the extinction period. Changes affecting both the motor and the central responses were significantly correlated, suggesting that modifications in the interpositorubral transmission efficacy might be one of the plastic correlates of forelimb flexion conditioning. 6. Examination of the neuronal excitability within either the IN or the RNm or in the spinal cord failed to show any evidence of facilitation suggesting that the increases in the postsynaptic rubral field potential were attributable to a plasticity of the interpositorubral connections. The long-lasting duration of the increase of cerebellorubral synaptic transmission suggests that structural changes were induced by conditioning in the intact animal. (ABSTRACT TRUNCATED)

In awake chronically preparated cats with a neurotoxic lesion of the red nucleus, persistent thalamo-cortical and intracortical synaptic plasticity reinforcing the pre-established cerebello-thalamocortical (CTC) influences on the forelimb musculature was observed under associative alpha-conditioning. This plasticity occurs when the activation of the CTC circuits (conditioned stimulus, CS) producing a given motor response, was associated with somesthetic stimulation (unconditioned stimulus, UCS), producing the same movement. These CTC circuits are in fact liable to undergo modifications in two opposite ways depending on the motor responses induced by the UCS. A reinforcement of their action on the forearm flexor muscles was observed when the UCS produces elbow flexion reflex, whereas a depression of this action in favour of a potentiated cerebellar action on the forearm extensor muscles occurred when the UCS produces a shoulder retraction reaction. The mechanisms possibly underlying these changes, and their implications in motor learning processes are discussed in light of previous data.

1. In a previous study, using a chronic cat preparation subjected to an associative conditioning procedure, we described the plasticity of the thalamo-cortical pathway by qualitatively and quantitatively analyzing the motor responses induced by stimulating each of the relays on the cerebello-thalamo-cortical pathway. In the present study, it was proposed to analyze the effects on the synapses located between thalamic endings and cortical neurones, using a twofold behavioral and electrophysiological approach, with a view to correlating the patterns of synaptic plasticity with the changes in the motor responses recorded. 2. For this purpose, a reduced, functionally organized sensorimotor circuit, which can be taken to be a neuronal analog of associative conditioning, was studied in an awake chronic animal preparation. This circuit was defined on the basis of the sites at which conditioned (CS) and unconditioned stimuli (UCS) were applied: the CS was applied at a site on the cerebellar interpositus nucleus which activated the forepaw musculature so as to induce flexion movements and the UCS was applied to the skin of the distal part of that paw so as to induce reflex flexion movements. By repetitively activating the central nervous pathways by the associated CS and UCS according to a predefined temporal pattern, the efficiency of the thalamo-cortical pathway's contribution to the movement production was enhanced, and its capacity to convey the cerebellar inputs to neurons in the motor cortex increased. 3. The associative nature of the conditioning was tested using previously established criteria. The setting up of motor and central changes in response to the repetitive presentation of paired CS and UCS, the fact that these changes were reversible because they could be abolished by applying extinction procedures, and the consistency of their occurrence whenever the CS was applied repeatedly alone for several days to naive animals, all showed that the stimuli of both kinds (CS and UCS) had to be applied together for the plasticity of the thalamo-cortical pathway to be expressed. 4. By determining whether the waves constituting the cerebello-cortical responses were excitatory or inhibitory, the nature of the changes in the transmission of the cerebellar impulses to neurons in the motor cortex was established.(ABSTRACT TRUNCATED AT 400 WORDS)

The lack of coordination in cerebellar patients is due to deficits affecting both the programming and the execution of motor activity. The aspects of motor performance which are most severely affected are the chronology, the time course and the distribution of the activatory inputs to the muscles. The cerebellar control of motor synergies partly depends on the intrinsic organization of the cerebellar cortex, but interconnections between the cerebellum and the cortex, as well as the organization of the cerebello-spinal outputs are also involved. All these elements take part in different ways in the various aspects of motor synergy control. Depending on the type of sensory signals involved in the triggering of coordinations, different cortico-cerebello-cortical connections take part in their programming. Those synergies which are initiated by external sensory signals are triggered by inputs from the dentate and interposed nuclei and transmitted to parietal associative areas 5 and 7. The programming of the synergies induced by internal signals or motivational states involves projections from the dentate nucleus to prefrontal area 9 as well as to the supplementary motor (SMA) and premotor (PM) areas. The distribution of the cerebellar outputs to the muscles participating in motor synergies depends on the organization of the cerebellar circuits projecting to PM and M1 neurones at the origin of the descending pathways. The fastigial and dentate nuclei give off projections to the PM whereby they activate both axial and proximal muscles via bilateral reticulo-spinal pathways, and these nuclei are therefore responsible for synergies which provide for the necessary postural adjustments when limb movements are performed. When voluntary movements are to be performed, the cerebellar efferents from the three cerebellar nuclei to the motor cortex (M1) are able to trigger all the necessary synergies. Since the motor cortex can be subdivided into several representation areas dealing with elementary unidirectional movements performed by a single joint, activating the requisite coordinations requires particular patterns of cerebello-thalamocortical activation. With these networks, which can be said to constitute the morphological basis of motor synergies, several body representation cortical areas can be activated simultaneously. These networks seem to be partly set up before birth; but they may also be shaped during the early stages of life. They are still adaptable during adult-hood, and they can undergo synaptic and functional changes in response to the sensory constraints imposed by the environment.

1. The ability of somaesthetic sensory inputs to produce structural changes in the connectivities of the central nervous structures involved in motor activity was tested with an alpha type of classical conditioning in chronically prepared adult cats. Repetitive sensory stimulation was applied at constant intervals after the activation of the motor circuits originating in the neurons or efferent axons of the cerebellar nuclei. A conditional stimulation (CS) applied to interpositus neurons was consistently paired with an unconditional stimulation (UCS) applied to the dorsal skin of the forelimb extremity to induce associative sensorimotor conditioning. The sites at which the conditional and unconditional stimuli were applied set up a simplified sensorimotor circuit including pathways transmitting both these stimuli and others mediating the expression of the conditioned responses. 2. To test the changes resulting from the conditioning, electrodes were implanted into the various relay structures on the cerebellar efferent pathways (ventrolateral nucleus motor cortex). The forelimb motor responses elicited by stimulating these relay structures were recorded with a potentiometer placed at the elbow joint. The angular displacement (amplitude) and latency of the responses and the percentage response rates were systematically quantified throughout the conditioning procedure and at test sessions carried out after the daily conditioning routines. 3. It was observed that daily repetition of paired CS-UCS led to an increase in the response rates and amplitudes of the forelimb flexions, which already began to occur very slightly on the first 4 or 5 days in response to the alpha conditioning, whereas the CS when applied alone failed to produce any changes in this initial response. Likewise, after the acquisition phase, repeated presentation of either the CS alone or the CS preceded by the UCS led to the extinction of the conditioned response, thus indicating that the observed changes were of an associative nature and that they depended on interactions between the motor and sensory inputs occurring somewhere in the CNS. In fact, the effects of conditioning were not generalized, but involved only a circumscribed circuit originating in the cerebellar neurons stimulated by the CS, which were activated concomitantly with the sensory pathways. 4. The conditioned response amplitudes were enhanced by 2.5-3 times their initial value. This enhancement persisted at the end of acquisition or after several days of consolidation, even when the paired CS-UCS sessions were interrupted for a period of 15 days to 2 mo.(ABSTRACT TRUNCATED AT 400 WORDS)

Single biceps motor units were recorded in two awake monkeys (Macaca fascicularis) during the preparation for and execution of a forearm flexion movement. The motor sequence was organized as follows: after a control period lasting 500 ms, the animal was informed that a preparatory period (PP) was beginning by a preparatory signal (PS) consisting of diffuse sound and light. One to 1.5 s later, the animal was instructed by a bright light response signal (RS) to perform a rapid forearm flexion movement. Two hundred motor sequences were run during each daily session. The single motor units (MU) were recorded and their discharges analysed. In both monkeys, two extreme groups were found to exist on the basis of their pattern of activity during the preparatory and movement execution phases. 56% of the MUs were silent during the PP and showed a brief burst of discharge after the RS, which was strictly correlated to the movement execution. Their high recruitment threshold and their firing frequency during resting and movement periods suggested that these MUs associated with the movement execution could be called presumed fast or phasic MUs. Among the remaining MUs (44%), 15% were active as early as the beginning of the PP (about 300 ms after the PS) and showed a progressively increasing discharge, which stopped just after the beginning of the movement execution. These MUs associated with the preparatory phase had low recruitment thresholds and firing frequencies, which is compatible with the possibility that they might be slow or tonic MUs. Two functional hypotheses can be proposed on the basis of these results. The first is that the presumed slow MUs associated with the preparatory period might modify the physiological state of the muscle, increasing its stiffness and thus enhancing the efficiency of the “fast phasic MUs” activated during the triggering of rapid movements. This would shorten the reaction time and make it possible to perform the fast movements required in these experiments. The second hypothesis is that the slow MUs may contribute to building up the nervous activity responsible for the forthcoming movement; and more specifically, to controlling the excitability of central neurons producing a phasic discharge which might activate the presumed fast MUs.

A large number of projections from cerebellar nuclei converge onto individual neurones in the thalamic relay to the motor cortex. Among the thalamic cells receiving cerebellar inputs, 75 out of 153 (50%) were found to be influenced by monosynaptic inputs from at least two cerebellar nuclei and 2 (1.5%) from three nuclei (the interpositus, dentate and fastigial nuclei). The pathways of the inputs converging on the same unit were found to be monosynaptic in 67 thalamic neurons, and disynaptic in the eight others. The monosynaptic nature of the majority of the pathways was proved by analysing the synaptic delay and the spatial and temporal summation. The 67 thalamic neurons receiving direct convergent influences were found to be distributed within the central portion of the VL. Forty-four of them give off projections to all the cortical areas, although a slightly higher proportion is to be found within the motor cortex shoulder area than elsewhere (medial part of area 4). Consequently, the specific function of the neurons receiving direct, convergent cerebellar inputs is not to control one particular part of the musculature but on the contrary, to transmit reciprocal facilitatory effects between the interpositus and dentate nuclei to all the cortical motor subdivisions. Maps summarizing monosynaptic responses obtained with semi-chronic preparations were drawn at thalamic and cortical levels. Each VL neuron was found to be a point where the two cerebellar circuits converge and may interact: the cerebrocerebellar circuit, which passes through the dentate nucleus, generates a feedward motor command: this can either modify or be modified by the feedback peripheral loop, which passes through the interpositus nucleus.

The extent of thalamic projections from punctate sites in the cerebellar nuclei was examined in 22 acutely prepared cats by mapping monosynaptic field potentials evoked in the ventrolateral (VL) nucleus by stimulation of the interpositus and dentate nuclei (IN and DN). The monosynaptic field potentials were evoked in the VL by low current stimulating pulses applied at high frequency to these cerebellar nuclei. Quantification of the projections was possible since the conditions of stimulation and recording were strictly controlled. The incoming volley recorded in the brachium conjunctivum caudally to the VL was also analysed. It was composed of two amplitude peaks with different latencies, corresponding to two groups of fibres conducting at 60-90 m/s and 20-25 m/s respectively. The negative field potentials in VL also showed two amplitude peaks and different latencies. The differences in latency between the first and second peaks in the presynaptic and postsynaptic field potentials are compatible with the possibility that both groups of afferent fibres may be monosynaptically connected to VL relay cells. The cerebello-thalamic projections were mapped and their density gradient was established. Two or three small thalamic strips of dense projections surrounded by a large zone of weaker projections were observed to emerge from each punctate cerebellar site. In the discussion of the functional significance of these findings, it is suggested that this organization might constitute a modulatable morphological support for a mechanism focalizing the cerebello-cortical inputs.

Thalamic nuclei constitute the diencephalic relay system between different afferent systems and the telencephalon. The "motor" thalamus links cerebellar and pallidal afferents with the motor and pre-motor cortical regions. Separation of pallido-thalamo-cortical and cerebello-thalamo-cortical pathways is relatively complete: afferents of pallidal origin are relayed by thalamic nuclei VA, VLo and VLm and are projected onto prefrontal and supplementary motor areas whereas afferents of cerebellar origin are relayed in the VL and VPLo and then projected onto motor areas 4.6 and parietal areas 5 and 7. This report is concerned mainly with the analysis of the motor thalamus as a relay system for afferents of cerebellar origin. The anatomofunctional organization of the cerebello-thalamo-cortical tract possesses a topographic arrangement and also wide convergences and appears able to participate in the realization, through the motor cortex, of motor synergies and of co-ordinating postures and movements. The cerebello-cortical tract apparently plays a different role during learning of a movement and executing an automatized movement. For the latter, it is involved in their onset and in their completion. Its contribution to fine control of temporal parameters of motor commands or control of peripheral afferent messages is not decisive. During learning of a movement the cerebello-cortical tract plays a predominant role. According to Ito, the cerebellum is involved in the process of automatization of a movement, organized initially entirely by the cortex and then becoming progressively subcortical. Plasticity of cerebellar microcircuits could be the basis for these automatization processes expressed through the cerebello-thalamo-cortical tract.