Complementary roles of basal ganglia and cerebellum in learning and motor control

The classical notion that the basal ganglia and the cerebellum are dedicated to motor control has been challenged by the accumulation of evidence revealing their involvement in non-motor, cognitive functions. From a computational viewpoint, it has been suggested that the cerebellum, the basal ganglia, and the cerebral cortex are specialized for different types of learning: namely, supervised learning, reinforcement learning and unsupervised learning, respectively. This idea of learning-oriented specialization is helpful in understanding the complementary roles of the basal ganglia and the cerebellum in motor control and cognitive functions.     

Altered expression of NCAM in hippocampus and cortex may underlie memory and learning deficits in rats with streptozotocin-induced diabetes mellitus

Neurological and structural changes are paralleled by cognitive deficits in diabetes mellitus. The present study was designed to evaluate the expression of neural cell adhesion molecules (NCAM) in the hippocampus, cortex and cerebellum and to examine cognitive functions in diabetic rats. Diabetes was induced in male albino rats via intraperitoneal streptozotocin injection. Learning and memory behaviors were investigated using a passive avoidance test and a spatial version of the Morris water maze test. NCAM expression was detected in the hippocampus, cortex and cerebellum by an immunoblotting method. The diabetic rats developed significant impairment in learning and memory behaviours as indicated by deficits in passive avoidance and water maze tests as compared to control rats. Expression of NCAM 180 and 120 kDa were found to be higher in hippocampus and cortex of diabetic rat brains compared to those of control, whereas expression of NCAM 140 kDa decreased in these brain regions. Our findings suggest that streptozotocin-induced diabetes impairs cognitive functions and causes an imbalance in expression of NCAM in those brain regions involved in learning and memory. Altered expression of NCAM in hippocampus may be an important cause of learning and memory deficits that occur in diabetes mellitus.     

Implications of different classes of sensorimotor disturbance for cerebellar-based motor learning models

The exact role of the cerebellum in motor control and learning is not yet fully understood. The structure, connectivity and plasticity within cerebellar cortex has been extensively studied, but the patterns of connectivity and interaction with other brain structures, and the computational significance of these patterns, is less well known and a matter of debate. Two contrasting models of the role of the cerebellum in motor adaptation have previously been proposed. Most commonly, the cerebellum is employed in a purely feedforward pathway, with its output contributing directly to the outgoing motor command. The cerebellum must then learn an inverse model of the motor apparatus in order to achieve accurate control. More recently, Porrill et al. (Proc Biol Sci 271(1541):789–796, 2004) and Porrill et al. (PLoS Comput Biol 3:1935–1950, 2007a) and Porrill et al. (Neural Comput 19(1), 170–193, 2007b) have highlighted the potential importance of these recurrent connections by proposing an alternative architecture in which the cerebellum is embedded in a recurrent loop with brainstem control circuitry. In this framework, the feedforward connections are not necessary at all. The cerebellum must learn a forward model of the motor apparatus for accurate motor commands to be generated. We show here how these two models exhibit contrasting yet complimentary learning capabilities. Central to the differences in performance between architectures is that there are two distinct kinds of disturbance to which a motor system may need to adapt (1) changes in the relationship between the motor command and the observed outcome and (2) changes in the relationship between the stimulus and the desired outcome. The computational distinction between these two kinds of transformation is subtle and has therefore often been overlooked. However, the implications for learning turn out to be significant: learning with a feedforward architecture is robust following changes in the stimulus-desired outcome mapping but not necessarily the motor command-outcome mapping, while learning with a recurrent architecture is robust under changes in the motor command-outcome mapping but not necessarily the stimulus-desired outcome mapping. We first analyse these differences theoretically and through simulations in the vestibulo-ocular reflex (VOR), then illustrate how these same concepts apply more generally with a model of reaching movements.     

Motor skill learning enhances the expression of activity-regulated cytoskeleton-associated protein in the rat cerebellum

Motor skill learning is essential for environmental adaptations during everyday life. It has been shown that the cerebellum plays an important role in both the adaptation of eye movements and the motor skill learning. However, the neuronal substrates responsible for consolidation of complex motor skills rather than simple reflexes are still uncertain. Because the induction of immediate-early genes activity-regulated cytoskeleton-associated protein (Arc) and zinc finger binding protein clone 268 (Zif268) has been regarded as a marker for recent neuronal activity, therefore, in the present study, a rat paradigm of motor skill learning was used to investigate the protein expression of Arc and zif268 in the cerebellum after motor skill learning. Rats were trained to traverse the runway apparatus for 5 days. Protein samples were collected from the cerebellar cortices 1 hour after the training on days 1, 3, and 5, and analyzed by western blotting. The results showed that the expression of Arc, but not zif268, was significantly increased in the cerebellum following motor skill learning. These findings suggest that motor skill learning induces Arc expression in the cerebellum, which may play a role in acquiring complex motor skills.     

Expression of NR2B in cerebellar granule cells specifically facilitates effect of motor training on motor learning

It is believed that gene/environment interaction (GEI) plays a pivotal role in the development of motor skills, which are acquired via practicing or motor training. However, the underlying molecular/neuronal mechanisms are still unclear. Here, we reported that the expression of NR2B, a subunit of NMDA receptors, in cerebellar granule cells specifically enhanced the effect of voluntary motor training on motor learning in the mouse. Moreover, this effect was characterized as motor learning-specific and developmental stage-dependent, because neither emotional/spatial memory was affected nor was the enhanced motor learning observed when the motor training was conducted starting at the age of 3 months old in these transgenic mice. These results indicate that changes in the expression of gene(s) that are involved in regulating synaptic plasticity in cerebellar granule cells may constitute a molecular basis for the cerebellum to be involved in the GEI by facilitating motor skill learning.     

Are we ready for a natural history of motor learning?

Here we argue that general principles with regard to the contributions of the cerebellum, basal ganglia, and primary motor cortex to motor learning can begin to be inferred from explicit comparison across model systems and consideration of phylogeny. Both the cerebellum and the basal ganglia have highly conserved circuit architecture in vertebrates. The cerebellum has consistently been shown to be necessary for adaptation of eye and limb movements. The precise contribution of the basal ganglia to motor learning remains unclear but one consistent finding is that they are necessary for early acquisition of novel sequential actions. The primary motor cortex allows independent control of joints and construction of new movement synergies. We suggest that this capacity of the motor cortex implies that it is a necessary locus for motor skill learning, which we argue is the ability to execute selected actions with increasing speed and precision.     

Roles of the Caudate Nuclei, Cerebellum, and Caudato-Cerebellar Interconnections in the Control and Coordination of Ballistic Food-Procuring Movements

We studied the roles of the cerebellum and caudate nuclei in the programming and control of ballistic movements. An experimental model of operant food-procuring movements of the rats was used; the activity of single neurons of the above structures was recorded in the course of these motor performances. To evaluate the impact of the cerebellar–caudate interaction on the process of control of the ballistic (centrally programmed) components of food-procuring motor performance, we also recorded modifications of the neuronal activity in one of the above-mentioned structures induced by electrical extrastimulation of another structure in the course of realization of the above components. It is demonstrated that the cerebellum and, in particular, its dentate nuclei are involved in the programming of ballistic food-procuring movements. Neurons of the caudate nuclei play a significant role in the immediate preparation for and subsequent current control of stereotyped ballistic movements. The high plastic properties of the cerebellar neurons manifested in the process of control of ballistic food-procuring movements are proved.     

Moving, sensing and learning with cerebellar damage

The cerebellum is a subcortical brain structure that is essential for learning and controlling movement. Recent work shows that the cerebellum also plays a role in certain perceptual abilities, beyond what would be expected secondary to poor movement control. This review covers these and other recent advances, focusing on how cerebellar damage affects human abilities ranging from sensory perception to movement control and motor learning.     

Learning to predict the future: the cerebellum adapts feedforward movement control

The role of the cerebellum in motor control and learning has been largely inferred from the effects of cerebellar damage. Recent work shows that cerebellar damage produces greater impairment of movements that require predictive as opposed to reactive control. This dissociation is consistent across many different types of movement. Predictive control is crucial for fast and ballistic movements, but impaired prediction can also affect slow movements, because of increased reliance on time-delayed feedback signals. The new findings are compatible with theories of cerebellar function, but still do not resolve whether the cerebellum operates by predicting the optimal motor commands or future sensory states. Prediction mechanisms must be learned and maintained through comparisons between predicted and observed outcomes. New results show that not all such error information is equivalent in driving cerebellar learning.     

Proteome profile of whole cerebellum of the mature rat

Cerebellum is an important brain region involved in motor, cognition, learning and memory functions. Proteome mapping of the 21 days old rat cerebellum identified total 285 proteins, out of which 76 proteins were not reported earlier from rat brain. This includes 49 neuronal activity-specific proteins, 7 of which are reported for the first time from the cerebellum in this study. The protein sequence data for 31 proteins reported here have been integrated in the UniProt Knowledgebase.     

Cerebellar long-term depression: a mechanism for learning and memory

It is commonly thought that a persistent change in the efficacy of the synaptic transmission is the basic mechanism underlying learning and memory. The cerebellum, key structure of the motor function, exhibits a synaptic plasticity named cerebellar long-term depression or LTD. This phenomenon appears in the Purkinje cell when the two main excitatory inputs (one consists of the parallel fibers which relay information on the task to accomplish and the other one includes the climbing fiber which conveys error signals) are activated in combination, resulting in a persistent decrease of the efficacy of the parallel fiber-Purkinje cell synapse. Studies made in the last 20 years show that activation of ionotropic and metabotropic glutamate receptors triggers complex signal transduction processes, leading to the phosphorylation and the internalization of AMPA receptors, a subtype of glutamatergic receptors. The aim of this paper is firstly to present mechanisms involved in LTD induction and maintenance. The second part introduces briefly experimental data that show that LTD is indeed strongly associated with motor learning. Recent studies on the involvement of the cerebellum in cognitive tasks also suggest that LTD may play some role other than that in the sole motor learning.     

Recovery of Motor Deficit,Cerebellar Serotonin and Lipid Peroxidation Levels in the Cortex of Injured Rats

The sensorimotor cortex and the cerebellum are interconnected by the corticopontocerebellar (CPC) pathway and by neuronal groups such as the serotonergic system. Our aims were to determine the levels of cerebellar serotonin (5-HT) and lipid peroxidation (LP) after cortical iron injection and to analyze the motor function produced by the injury. Rats were divided into the following three groups: control, injured and recovering. Motor function was evaluated using the beam-walking test as an assessment of overall locomotor function and the footprint test as an assessment of gait. We also determined the levels of 5-HT and LP two and twenty days post-lesion. We found an increase in cerebellar 5-HT and a concomitant increase in LP in the pons and cerebellum of injured rats, which correlated with their motor deficits. Recovering rats showed normal 5-HT and LP levels. The increase of 5-HT in injured rats could be a result of serotonergic axonal injury after cortical iron injection. The LP and motor deficits could be due to impairments in neuronal connectivity affecting the corticospinal and CPC tracts and dysmetric stride could be indicative of an ataxic gait that involves the cerebellum.     

Cerebellar function: coordination, learning or timing?

Theories of cerebellar function have largely involved three ideas: movement coordination, motor learning or timing. New evidence indicates these distinctions are not particularly meaningful, as the cerebellum influences movement execution by feedforward use of sensory information via temporally specific learning.     

Melatonin is Involved in Regulation of the Expression of Neural Cell Adhesion Molecules in the Rat Brain

Cell adhesion molecules play a diverse role in neural development, signal transduction, structural linkage to extracellular and intracellular proteins, synaptic stabilization, neurogenesis, and learning. Neural cell adhesion molecules (NCAM) are members of the immunoglobulin superfamily and are involved in synaptic rearrangements in the mature brain. There are three major NCAM isoforms: NCAM 180, NCAM 140, and NCAM 120. Several studies reported that NCAM play a central role in memory formation. We investigated the effects of melatonin on the expression of NCAM in the hippocampus, cortex, and cerebellum of rats. The levels of NCAM isoforms were determined by Western blotting. After administration of melatonin for 7 days, the expression of NCAM 180 increased both in the hippocampus and in the cortex, as compared with the control. In contrast, in rats exposed to constant illumination for 7 days (a procedure that inhibits endogenous production of melatonin), levels of NCAM 180 dropped in the hippocampus and became undetectable in the cortex and cerebellum. Levels of NCAM 140 in the hippocampus of light-exposed rats also decreased. There was no change in the expression of NCAM 120 in any brain region. This is the first report indicating that melatonin exerts a modulatory effect on the expression of NCAM in brain areas related to realization of cognitive functions. Melatonin may be involved in structural remodeling of synaptic connections during memory and learning processes.     

芬太尼经中间神经元减弱吹风刺激诱发的小鼠小脑分子层场电位反应

芬太尼作为一种合成的阿片类药物,可与μ型阿片受体(mu-opioid receptor,MOR)结合产生镇痛、镇静及奖赏相关的行为.小脑的功能不仅局限于对躯体平衡、肌张力和随意运动的调节,还有情绪调节、认知和学习记忆等功能.有研究表明,小脑中广泛分布着功能性的MOR,但其对小脑功能的影响还未见报道.本文旨在采用在体电生...     

Motor control and learning in altered dynamic environments

Dynamic perturbations of reaching movements are an important technique for studying motor learning and adaptation. Adaptation to non-contacting, velocity-dependent inertial Coriolis forces generated by arm movements during passive body rotation is very rapid, and when complete the Coriolis forces are no longer sensed. Adaptation to velocity-dependent forces delivered by a robotic manipulandum takes longer and the perturbations continue to be perceived even when adaptation is complete. These differences reflect adaptive self-calibration of motor control versus learning the behavior of an external object or 'tool'. Velocity-dependent inertial Coriolis forces also arise in everyday behavior during voluntary turn and reach movements but because of anticipatory feedforward motor compensations do not affect movement accuracy despite being larger than the velocity-dependent forces typically used in experimental studies. Progress has been made in understanding: the common features that determine adaptive responses to velocity-dependent perturbations of jaw and limb movements; the transfer of adaptation to mechanical perturbations across different contact sites on a limb; and the parcellation and separate representation of the static and dynamic components of multiforce perturbations.     

Changes in the cannabinoid receptor binding, G protein coupling, and cyclic AMP cascade in the CNS of rats tolerant to and dependent on the synthetic cannabinoid compound CP55,940

Chronic exposure to CP55,940 produced a significant down-regulation of cannabinoid receptors in the striatum, cortex, hippocampus, and cerebellum of rat brain. At 24 h after SR141716-precipitated withdrawal, we observed a tendency to return to basal levels in the striatum and cortex, whereas the specific binding remained lower in the hippocampus and cerebellum. When we surveyed cannabinoid receptor-activated G proteins, in chronic CP55,940-treated rats the guanosine 5'-O:-(3-[(35)S]thiotriphosphate) ([(35)S]GTPgammaS) binding assay revealed a decrease of activated G proteins in the striatum, cortex, and hippocampus, whereas no significant changes were seen in the cerebellum. At 24 h after the SR141716-precipitated withdrawal, [(35)S]GTPgammaS binding increased compared with that of rats chronically exposed to CP55,940, attaining the control level except for cerebellum, where we observed a trend to overcome the control amounts. Concerning the cyclic AMP (cAMP) cascade, which represents the major intracellular signaling pathway activated by cannabinoid receptors, in the cerebral areas from rats chronically exposed to CP55,940 we found alteration in neither cAMP levels nor protein kinase A activity. In the brain regions taken from CP55, 940-withdrawn rats, we only observed a significant up-regulation in the cerebellum. Our findings suggest that receptor desensitization and down-regulation are strictly involved in the development of cannabinoid tolerance, whereas alterations in the cAMP cascade in the cerebellum could be relevant in the mediation of the motor component of cannabinoid abstinence.     

The negative cell cycle regulator, Tob (transducer of ErbB-2), is involved in motor skill learning

Tob (transducer of ErbB-2) is a negative cell cycle regulator with anti-proliferative activity in peripheral tissues. Our previous study identified Tob as a protein involved in hippocampus-dependent memory consolidation (M.L. Jin, X.M. Wang, Y.Y. Tu, X.H. Zhang, X. Gao, N. Guo, Z.Q. Xie, G.P. Zhao, N.H. Jing, B.M. Li, Y.Yu, The negative cell cycle regulator, Tob (Transducer of ErbB-2), is a multifunctional protein involved in hippocampus-dependent learning and memory, Neuroscience 131 (2005) 647-659). Here, we provide evidence that Tob in the central nervous system is engaged in acquisition of motor skill. Tob has a relatively high expression in the cerebellum. Tob expression is up-regulated in the cerebellum after rats receive training on a rotarod-running task. Rats infused with Tob antisense oligonucleotides into the 4th ventricle exhibit a severe deficit in running on a rotating rod or walking across a horizontally elevated beam.     

Central mechanisms of motor skill learning

Recent studies have shown that frontoparietal cortices and interconnecting regions in the basal ganglia and the cerebellum are related to motor skill learning. We propose that motor skill learning occurs independently and in different coordinates in two sets of loop circuits: cortex-basal ganglia and cortex-cerebellum. This architecture accounts for the seemingly diverse features of motor learning.     

Adaptive Robotic Control Driven by a Versatile Spiking Cerebellar Network

The cerebellum is involved in a large number of different neural processes, especially in associative learning and in fine motor control. To develop a comprehensive theory of sensorimotor learning and control, it is crucial to determine the neural basis of coding and plasticity embedded into the cerebellar neural circuit and how they are translated into behavioral outcomes in learning paradigms. Learning has to be inferred from the interaction of an embodied system with its real environment, and the same cerebellar principles derived from cell physiology have to be able to drive a variety of tasks of different nature, calling for complex timing and movement patterns. We have coupled a realistic cerebellar spiking neural network (SNN) with a real robot and challenged it in multiple diverse sensorimotor tasks. Encoding and decoding strategies based on neuronal firing rates were applied. Adaptive motor control protocols with acquisition and extinction phases have been designed and tested, including an associative Pavlovian task (Eye blinking classical conditioning), a vestibulo-ocular task and a perturbed arm reaching task operating in closed-loop. The SNN processed in real-time mossy fiber inputs as arbitrary contextual signals, irrespective of whether they conveyed a tone, a vestibular stimulus or the position of a limb. A bidirectional long-term plasticity rule implemented at parallel fibers-Purkinje cell synapses modulated the output activity in the deep cerebellar nuclei. In all tasks, the neurorobot learned to adjust timing and gain of the motor responses by tuning its output discharge. It succeeded in reproducing how human biological systems acquire, extinguish and express knowledge of a noisy and changing world. By varying stimuli and perturbations patterns, real-time control robustness and generalizability were validated. The implicit spiking dynamics of the cerebellar model fulfill timing, prediction and learning functions.