Symposium
New understanding of functions of basal ganglia in health and disease
シンポジウム
大脳基底核の機能の新たな理解:正常と疾患 |
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| 7月27日（土）16:30～16:54 第2会場（朱鷺メッセ 2F メインホールA）
3S02e-1
連続運動のリズムによる制御と線条体機能
Takashi Kitsukawa（木津川 尚史）
大阪大学大学院生命機能研究科
Rhythmic movements are critical to many activities, ranging from running, speaking to playing musical instruments. Such rhythmic behaviors consist of timed sequences of individual actions of multiple body parts like arms, legs, fingers and so on, and thus precise spatial and temporal coordination of each body part is required for continuous, skilled performance of the sequences. To study how those continuous timed action sequences are coordinated, we have used a complex stepping task, the step-wheel, that permits control of the stepping patterns of mice. The step-wheel is a motor-driven wheel in which mice run for water as a reward. The running surface for mice was made of ladder-like pegs. The step pattern of mice can be changed by the arrangement of the pegs, which can be readily changed. When right and left pegs are alternately arranged, mice run with the walk gait; when the pegs are arranged face to face, they run with the gallop gait. While mice run following the pegs in these peg-patterns above, they run according not only to the peg-pattern but also to their physical running state in complex peg-patterns, in which pegs are arranged pseudo-randomly. Actually, we found that there were several blocks of a few steps in a peg-pattern in which the relative position of right and left forelimbs (phase) was conserved. Inside such blocks, the variance of touch intervals was low compared with that of between-blocks, which indicates that the speed of limb movements was kept relatively constant within blocks. These results suggest that mice adjusted their stepping so that they could keep steady phase and cycle in a block. Controlling phase and cycle may be an easy and efficient strategy for organizing concurrent repetitive movements. To understand how such coordination of movements is shaped in the brain, we recorded spike activity from the dorsal striatum as mice performed the step-wheel task. We found neurons responding to touches of forelimb to pegs. Even with complex peg-patterns, the touch responding neurons showed phasic responses correlated with the touches. Interestingly the responses were not uniform to each touch. By aligning the spikes to right or left touches, we found that those neurons responded to certain touch-to-touch intervals and/or right-left timing of limbs. This result indicates that the striatal neurons may encode the cycle and phase, which are critical parameters of the rhythm, serving the coordination of concurrent repetitive movements. | | 7月27日（土）16:54～17:18 第2会場（朱鷺メッセ 2F メインホールA）
3S02e-2
パーキンソン病における大脳皮質－大脳基底核経路の情報伝達異常
Satomi Chiken（知見 聡美）1,2，Atsushi Nambu（南部 篤）1,2
1生理学研究所・生体システム
2総研大院生命科学生理
Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor and non-motor symptoms, such as bradykinesia, rigidity, tremor, depression, and autonomic dysfunctions. Progressive loss of nigrostriatal dopaminergic neurons has been proposed to cause abnormal neuronal activities in the basal ganglia, such as spontaneous firing rate and pattern changes, and result in PD symptoms. However, controversy still remains over whether these models can fully explain the pathophysiology of PD. To elucidate pathophysiological mechanism underlying PD symptoms, we have analyzed neuronal activities in primate and rodent models of PD. In PD monkeys generated by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; dopaminergic neurotoxin) treatment exhibited obvious motor symptoms such as akinesia and rigidity. In normal monkeys, motor cortical stimulation, which mimics cortical excitation initiating voluntary movements, induces a triphasic response composed of early excitation, inhibition, and late excitation in the internal segment of the globus pallidus (GPi), the output station of the basal ganglia. On the other hand, in PD monkeys, cortically evoked inhibition, which is mediated by the cortico-striato-GPi direct pathway, was strongly diminished without apparent changes in spontaneous firing rate and patterns in the GPi. These results suggest that interruption of information flow through the cortico-striato-GPi direct pathway, which initiates movements, is responsible for PD symptoms and that spontaneous activity changes are an epiphenomenon. Similar activity changes were also observed in PD rodents. In this talk, we will discuss pathophysiological mechanisms underlying PD symptoms based on abnormal information processing through the cortico-basal ganglia pathways. | | 7月27日（土）17:18～17:42 第2会場（朱鷺メッセ 2F メインホールA）
3S02e-3
Chemogenetic and pharmacological deconstruction of hypokinesia and dyskinesia in Parkinson models
M. Angela Cenci Nilsson（Cenci Nilsson M. Angela）
Dept. Experimental Medical Science, Lund University, Lund, Sweden
Movement control relies on the interplay of two pathways linking the striatum with the basal ganglia output nuclei. These are the `direct pathway' and the `indirect pathway' originating from striatal projection neurons (SPNs) that express D1 or D2 dopamine receptors, respectively. The loss of dopamine (DA) in Parkinson disease causes hyperactivity of indirect pathway (iSPNs) relative to direct pathway neurons (dSPNs), while an activity imbalance of opposite sign emerges after chronic treatment with L-DOPA inducing dyskinesia (abnormal involuntary movements). In our group, we are combining chemogenetic and pharmacological tools in order to explore the causal contribution of changes in DA receptor stimulation and dSPN/iSPN activity to the hypokinetic and dyskinetic features of Parkinson disease. To this end, we use unilateral 6-OHDA lesions of nigrostriatal DA neurons to produce Parkinson models in rats and mice. In these animal models, we modulate the activity of dSPNs or iSPNs using both excitatory and inhibitory DREADDs, combined with the administration of L-DOPA or specific DA receptor agonists/antagonists. The effects of these interventions are examined using several behavioural and molecular endpoints. The behavioural endpoints include ratings of rodent dyskinesia and dystonia with scales that we have developed and validated. The lecture will present both published and unpublished data elucidating the causal effects of D1/D2 receptor stimulation, and changes in dSPN/iSPN activity, on specific motor features of Parkinson disease and L-DOPA-induced dyskinesia. Our data have significant translational implications that will be discussed at the end of the lecture. | | 7月27日（土）17:42～18:06 第2会場（朱鷺メッセ 2F メインホールA）
3S02e-4
L-ドパ誘発ジスキネジアの形態学的異常
Masahiko Tomiyama（冨山 誠彦）
弘前大学脳神経内科
Parkinson's disease (PD) is a neurodegenerative disorder associated with the progressive loss of nigrostriatal dopaminergic neurons. Levodopa is the most effective therapeutic option for the motor symptoms in PD. However, chronic levodopa treatment often leads to problematic dyskinesia due to nonphysiological pulsatile dopaminergic stimulation in the brain. Examinations of autopsy cases with PD have revealed a decreased number of dendritic spines of striatal neurons. Animal models of PD have revealed altered density and morphology of dendritic spines of neurons in various brain regions after dopaminergic denervation or dopaminergic denervation plus levodopa treatment, indicating altered synaptic transmission. Recent studies using rodent models have reported enlargement of dendritic spine head in the caudate-putamen, nucleus accumbens, primary motor cortex, and prefrontal cortex in cases where chronic levodopa treatment following dopaminergic denervation induced dyskinesia-like abnormal involuntary movements. Hypertrophy of spines results from insertion of alpha-amino-2,3-dihydro-5-methyl-3-oxo-4-isoxazolepropanoic acid receptors into the postsynaptic membrane. Such spine enlargement indicates hypersensitivity of the synapse to excitatory inputs and is compatible with a lack of depotentiation, which is an electrophysiological hallmark of levodopa-induced dyskinesia found in the corticostriatal synapses of dyskinetic animals and the motor cortex of dyskinetic PD patients. This synaptic plasticity may be one of the mechanisms underlying the priming of levodopa-induced complications such as levodopa-induced dyskinesia and dopamine dysregulation syndrome. Drugs that could potentially prevent spine enlargement, such as calcium channel blockers, N-methyl-D-aspartate receptor antagonists, alpha-amino-2,3-dihydro-5-methyl-3-oxo-4-isoxazolepropanoic acid receptor antagonists, and metabotropic glutamate receptor antagonists, are candidates for treatment of levodopa-induced complications in PD. | | 7月27日（土）18:06～18:30 第2会場（朱鷺メッセ 2F メインホールA）
3S02e-5
Mutations in CalDAG-GEFI lead to motor and psychomotor symptoms in multiple species including human.
Ann M. Graybiel（Graybiel Ann M.）
McGovern Institute for Brain Research, Massachusetts Institute of Technology (MIT)
Ann M. Graybiel and Jill R. Crittenden
Fast platelet aggregation to stop bleeding occurs by evolutionarily conserved signaling pathways that converge on CalDAG-GEFI, a calcium-responsive activator of Rap GTPases and integrin-adhesion. We show here that CalDAG-GEFI is a key component of forebrain function. Mutations that disrupt CalDAG-GEFI’s enzymatic domain are associated with psychomotor phenotypes in humans, dogs and mice with global and striatum-specific CalDAG-GEFI mutations. Knockout mice have deficits in striatal long-term potentiation and dopamine, acetylcholine and glutamate signaling linked to their behavioral abnormalities. Thus, loss of CalDAG-GEFI signaling, including in humans, produces a syndromic disorder characterized by bleeding and psychomotor dysfunction. | | | |
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