Dai Yanagihara

A mathematical model of adaptive behavior in quadruped locomotion

Abstract. Locomotion involves repetitive movements and is often executed unconsciously and automatically. In order to achieve smooth locomotion, the coordination of the rhythms of all physical parts is important. Neurophysiological studies have revealed that basic rhythms are produced in the spinal network called, the central pattern generator (CPG), where some neural oscillators interact to self-organize coordinated rhythms. We present a model of the adaptation of locomotion patterns to a variable environment, and attempt to elucidate how the dynamics of locomotion pattern generation are adjusted by the environmental changes. Recent experimental results indicate that decerebrate cats have the ability to learn new gait patterns in a changed environment. In those experiments, a decerebrate cat was set on a treadmill consisting of three moving belts. This treadmill provides a periodic perturbation to each limb through variation of the speed of each belt. When the belt for the left forelimb is quickened, the decerebrate cat initially loses interlimb coordination and stability, but gradually recovers them and finally walks with a new gait. Based on the above biological facts, we propose a CPG model whose rhythmic pattern adapts to periodic perturbation from the variable environment. First, we design the oscillator interactions to generate a desired rhythmic pattern. In our model, oscillator interactions are regarded as the forces that generate the desired motion pattern. If the desired pattern has already been realized, then the interactions are equal to zero. However, this rhythmic pattern is not reproducible when there is an environmental change. Also, if we do not adjust the rhythmic dynamics, the oscillator interactions will not be zero. Therefore, in our adaptation rule, we adjust the memorized rhythmic pattern so as to minimize the oscillator interactions. This rule can describe the adaptive behavior of decerebrate cats well. Finally, we propose a mathematical framework of an adaptation in rhythmic motion. Our framework consists of three types of dynamics: environmental, rhythmic motion, and adaptation dynamics. We conclude that the time scale of adaptation dynamics should be much larger than that of rhythmic motion dynamics, and the repetition of rhythmic motions in a stable environment is important for the convergence of adaptation.

Dual involvement of G-substrate in motor learning revealed by gene deletion.

In this study, we generated mice lacking the gene for G-substrate, a specific substrate for cGMP-dependent protein kinase uniquely located in cerebellar Purkinje cells, and explored their specific functional deficits. G-substrate–deficient Purkinje cells in slices obtained at postnatal weeks (PWs) 10–15 maintained electrophysiological properties essentially similar to those from WT littermates. Conjunction of parallel fiber stimulation and depolarizing pulses induced long-term depression (LTD) normally. At younger ages, however, LTD attenuated temporarily at PW6 and recovered thereafter. In parallel with LTD, short-term (1 h) adaptation of optokinetic eye movement response (OKR) temporarily diminished at PW6. Young adult G-substrate knockout mice tested at PW12 exhibited no significant differences from their WT littermates in terms of brain structure, general behavior, locomotor behavior on a rotor rod or treadmill, eyeblink conditioning, dynamic characteristics of OKR, or short-term OKR adaptation. One unique change detected was a modest but significant attenuation in the long-term (5 days) adaptation of OKR. The present results support the concept that LTD is causal to short-term adaptation and reveal the dual functional involvement of G-substrate in neuronal mechanisms of the cerebellum for both short-term and long-term adaptation.

Contributions of phase resetting and interlimb coordination to the adaptive control of hindlimb obstacle avoidance during locomotion in rats: a simulation study

Obstacle avoidance during locomotion is essential for safe, smooth locomotion. Physiological studies regarding muscle synergy have shown that the combination of a small number of basic patterns produces the large part of muscle activities during locomotion and the addition of another pattern explains muscle activities for obstacle avoidance. Furthermore, central pattern generators in the spinal cord are thought to manage the timing to produce such basic patterns. In the present study, we investigated sensory-motor coordination for obstacle avoidance by the hindlimbs of the rat using a neuromusculoskeletal model. We constructed the musculoskeletal part of the model based on empirical anatomical data of the rat and the nervous system model based on the aforementioned physiological findings of central pattern generators and muscle synergy. To verify the dynamic simulation by the constructed model, we compared the simulation results with kinematic and electromyographic data measured during actual locomotion in rats. In addition, we incorporated sensory regulation models based on physiological evidence of phase resetting and interlimb coordination and examined their functional roles in stepping over an obstacle during locomotion. Our results show that the phase regulation based on interlimb coordination contributes to stepping over a higher obstacle and that based on phase resetting contributes to quick recovery after stepping over the obstacle. These results suggest the importance of sensory regulation in generating successful obstacle avoidance during locomotion.

Effect of rice-expressed amyloid β in the Tg2576 Alzheimer's disease transgenic mouse model.

One of the main hallmarks of Alzheimers disease (AD) is senile plaques composed of amyloid β (Aβ). We developed a new edible vaccine: rice expressing GFP-Aβ42. In a previous report, we described the production of anti-Aβ antibodies in B6 mice fed Aβ rice mixed with cholera toxin B subunit (CTB). In this report, we investigated whether Aβ rice had therapeutic effects in the Tg2576 AD model mice. The anti-Aβ antibody titer was increased and levels of intracerebral Aβ (soluble and insoluble) and serum Aβ decreased. Because the value of IgG1/IgG2a in the Aβ feeding group was >1, immunization via Aβ rice may induce a non-inflammatory Th2 reaction. We also found that the Aβ vaccine improved memory, as assessed in a Y-maze test. The number of arm entries in the Y-maze test was lower in the Aβ feeding group than in the control group. These results suggest that the new edible vaccine Aβ rice may have therapeutic effects in AD.

Progressive impairment of cerebellar mGluR signalling and its therapeutic potential for cerebellar ataxia in spinocerebellar ataxia type 1 model mice

Spinocerebellar ataxia type 1 (SCA1) is a progressive neurodegenerative disease caused by a gene defect, leading to movement disorder such as cerebellar ataxia. It remains largely unknown which functional defect contributes to the cerebellar ataxic phenotype in SCA1. In this study, we report progressive dysfunction of metabotropic glutamate receptor (mGluR) signalling, which leads to smaller slow synaptic responses, reduced dendritic Ca2+ signals and impaired synaptic plasticity at cerebellar synapses, in the early disease stage of SCA1 model mice. We also show that enhancement of mGluR signalling by a clinically available drug, baclofen, leads to improvement of motor performance in SCA1 mice. SCA1 is an incurable disease with no effective treatment, and our results may provide mechanistic grounds for targeting mGluRs and a novel drug therapy with baclofen to treat SCA1 patients in the future.

Ultrasound-enhanced delivery of Morpholino with Bubble liposomes ameliorates the myotonia of myotonic dystrophy model mice

Phosphorodiamidate morpholino oligonucleotide (PMO)-mediated control of the alternative splicing of the chloride channel 1 (CLCN1) gene is a promising treatment for myotonic dystrophy type 1 (DM1) because the abnormal splicing of this gene causes myotonia in patients with DM1. In this study, we optimised a PMO sequence to correct Clcn1 alternative splicing and successfully remedied the myotonic phenotype of a DM1 mouse model, the HSALR mouse. To enhance the efficiency of delivery of PMO into HSALR mouse muscles, Bubble liposomes, which have been used as a gene delivery tool, were applied with ultrasound exposure. Effective delivery of PMO led to increased expression of Clcn1 protein in skeletal muscle and the amelioration of myotonia. Thus, PMO-mediated control of the alternative splicing of the Clcn1 gene must be important target of antisense therapy of DM1.

Involvement of Cholinergic System in Hyperactivity in Dopamine-Deficient Mice

Dopaminergic systems have been known to be involved in the regulation of locomotor activity and development of psychosis. However, the observations that some Parkinson’s disease patients can move effectively under appropriate conditions despite low dopamine levels (eg, kinesia paradoxia) and that several psychotic symptoms are typical antipsychotic resistant and atypical antipsychotic sensitive indicate that other systems beyond the dopaminergic system may also affect locomotor activity and psychosis. The present study showed that dopamine-deficient (DD) mice, which had received daily L-DOPA injections, could move effectively and even be hyperactive 72 h after the last L-DOPA injection when dopamine was almost completely depleted. Such hyperactivity was ameliorated by clozapine but not haloperidol or ziprasidone. Among multiple actions of clozapine, muscarinic acetylcholine (ACh) activation markedly reduced locomotor activity in DD mice. Furthermore, the expression of choline acetyltransferase, an ACh synthase, was reduced and extracellular ACh levels were significantly reduced in DD mice. These results suggest that the cholinergic system, in addition to the dopaminergic system, may be involved in motor control, including hyperactivity and psychosis. The present findings provide additional evidence that the cholinergic system may be targeted for the treatment of Parkinson’s disease and psychosis.

Characteristics of gait ataxia in δ2 glutamate receptor mutant mice, ho15J.

The cerebellum plays a fundamental, but as yet poorly understood, role in the control of locomotion. Recently, mice with gene mutations or knockouts have been used to investigate various aspects of cerebellar function with regard to locomotion. Although many of the mutant mice exhibit severe gait ataxia, kinematic analyses of limb movements have been performed in only a few cases. Here, we investigated locomotion in ho15J mice that have a mutation of the δ2 glutamate receptor. The cerebellum of ho15J mice shows a severe reduction in the number of parallel fiber-Purkinje synapses compared with wild-type mice. Analysis of hindlimb kinematics during treadmill locomotion showed abnormal hindlimb movements characterized by excessive toe elevation during the swing phase, and by severe hyperflexion of the ankles in ho15J mice. The great trochanter heights in ho15J mice were lower than in wild-type mice throughout the step cycle. However, there were no significant differences in various temporal parameters between ho15J and wild-type mice. We suggest that dysfunction of the cerebellar neuronal circuits underlies the observed characteristic kinematic abnormality of hindlimb movements during locomotion of ho15J mice.

Gait modification during approach phase when stepping over an obstacle in rats

Stepping over obstacles to avoid tripping is an essential component in safe and smooth locomotion. Obstacle avoidance during locomotion is completed in several steps during the approach phase toward the obstacle and stepping over the obstacle. The purpose of this study was to investigate gait modification during the approach phase when stepping over obstacles of different heights in rats. In all four limbs, the toe height when the toe was just above the obstacle increased depending on the obstacle height, leaving a safe margin. However, the horizontal distance between toe and obstacle just prior to stepping over was not influenced by obstacle height. In the fore- and hindlimbs that served as trailing limbs, it was found that the stride length and its related swing phase duration in the final step were significantly shorter than those in both the penultimate step and overground locomotion. These results suggest that adjustment of trailing limb in the final step during the approach phase is important in preparation for the stepping movement over an obstacle.

Lesion in the lateral cerebellum specifically produces overshooting of the toe trajectory in leading forelimb during obstacle avoidance in the rat

During locomotion, stepping over an obstacle under visual guidance is crucial to continuous safe walking. Studies of the role of the central nervous system in stepping movements have focused on cerebral cortical areas such as the primary motor cortex and posterior parietal cortex. There is speculation that the lateral cerebellum, which has strong anatomical connections with the cerebral cortex, also plays a key role in stepping movements over an obstacle, although this function of the lateral cerebellum has not yet been elucidated. Here we investigated the role of the lateral cerebellum during obstacle avoidance locomotion in rats with a lateral cerebellar lesion. A unilateral lesion in the lateral cerebellum did not affect limb movements during overground locomotion. Importantly, however, the lesioned animals showed overshooting of the toe trajectory specific to the leading forelimb ipsilateral to the lesion when stepping over an obstacle, and the peak toe position, in which the toe is maximally raised during stepping, shifted away from the upper edge of the obstacle. Recordings of EMG activity from elbow flexor and extensor muscles suggested that the overshooting toe trajectory in the ipsilateral leading forelimb possibly resulted from sustained elbow flexion and delayed elbow extension following prolonged activity of the biceps brachii. These results suggest that the lateral cerebellum specifically contributes to generating appropriate toe trajectories in the ipsilateral leading forelimb and to controlling related muscle activities in stepping over an obstacle, especially when accurate control of the distal extremity is achieved under visual guidance.