多様な動物行動を規定する大脳基底核神経回路機構 Basal ganglia circuit mechanisms regulating a variety of animal behaviors
S3-3-3-1 報酬・忌避学習における大脳基底核神経回路の制御機構 Regulatory mechanism of basal ganglia circuit in reward and aversive learning ○疋田貴俊1 ○Takatoshi Hikida1 京都大学大学院医学研究科1 Kyoto University Graduate School of Medicine1 The basal ganglia-thalamocortical circuit plays a central role in selecting actions that achieve reward-seeking outcomes and avoid aversive ones. Inputs of the nucleus accumbens (NAc) in this circuit are transmitted through two parallel pathways, i.e., the striatonigral direct pathway and the striatopallidal indirect pathway. In the NAc, dopaminergic modulation of the direct and the indirect pathways is critical in reward-based and aversive learning and cocaine addiction. To explore how dopaminergic modulation regulates the associative learning behavior, we developed an asymmetric reversible neurotransmission blocking technique (aRNB) in which transmission of each pathway was unilaterally blocked by transmission-blocking tetanus toxin and the transmission on the intact side was pharmacologically manipulated by local infusion of a receptor-specific agonist or antagonist. This approach revealed that the activation of the direct pathway D1 receptors and the inactivation of the indirect pathway D2 receptors postsynaptically control reward learning/cocaine addiction and aversive learning, respectively. Furthermore, this study demonstrated that aversive learning is elicited by elaborate actions of NMDA receptors, adenosine A2a receptors, and endocannabinoid CB1 receptors, which serve as key neurotransmitter receptors in inducing long-term potentiation in corticostriatal glutamatergic transmission in the indirect-pathway neurons. Thus, reward and aversive learning is regulated by pathway-specific neural plasticity via selective transmitter receptors in the NAc circuit.	S3-3-3-2 Why coffee wakes us up? - The role of adenosine A2A receptors in the nucleus accumbens for sleep-wake regulation ○Michael Lazarus1, Yoshihiro Urade1, Zhi-Li Huang2 Osaka Bioscience Institute1, Fudan University Shanghai Medical College2 Adenosine promotes sleep through the activation of A2A receptors. A2A receptors are densely expressed on striatopallidal neurons of the basal ganglia, where dopamine D2 receptors are co-expressed with A2A receptors and involved in motor function, habit formation, and reward/addictive behaviors. The extent to which A2A receptors in the basal ganglia contribute to the regulation of sleep and wakefulness is not known. We investigated the role of A2A receptors in the basal ganglia for wakeful consciousness by using powerful tools for site-specific gene manipulations, including A2A receptor knockout mice based on the Cre/lox technology; focal A2A receptor knockdown in rats through the local infection with adeno-associated virus carrying short-hairpin RNA of A2A receptors; and modulation of neuronal activity through in-vivo stimulation with optogenetic technologies and receptor-channel systems. Our studies have revealed that the arousal effect of caffeine is mediated by A2A receptors on neurons in the shell of the nucleus accumbens (NAc) and that transient activation of NAc neurons promotes sleep. These observations strongly suggest that A2A receptors in the NAc are key structural elements for the control of sleep and wakefulness. These findings further suggest the intriguing possibility that the ventral striatum may be a key site through which sleep and wakefulness are regulated by behavioral processes and, by extension, that motivational state may be an important fundamental regulator of sleep and wake (Trends Neurosci, doi: 10.1016/j.tins.2012.07.001).
S3-3-3-3 線条体コリン作動性介在ニューロンへのドーパミンニューロン入力の部位特異的多様性 Regional heterogeneity in dopamine neuron input to cholinergic interneurons in the striatum ○中馬奈保1,2 ○Nao Chuhma1,2, Susana Mingote1,2, Holly Moore1,3, Stephen Rayport1,2 コロンビア大学1 Columbia University1, Dept Mol Therap, NY State Psych Inst, New York, USA2, Dept Integr Neurosci, NY State Psych Inst, New York, USA3 The striatum is comprised of about 95% medium spiny projection neurons (SPNs) and 5% interneurons. SPNs have been regarded as playing the key role in striatal circuit function. However, cholinergic interneurons (ChIs), which comprise only about 1% of striatal neurons, have been increasingly recognized as playing a crucial role in reward processing, motor control and associative learning. These different functions are regionally segregated in the striatum. Dopamine (DA) neurons in the ventral midbrain project to all striatal domains and likely contribute to the regional differences. While cholinergic and DAergic interactions are likely to be of particular importance, most studies of DA input to the striatum have focused on the SPNs, and not on direct DA neuron input to ChIs. We used an optogenetic strategy to activate DA neuron synapses and recorded from ChIs in three representative regions: the dorsal striatum, nucleus accumbens core and medial shell. Train stimulation mimicking DA neuron burst firing elicited different responses in ChIs in the three striatal domains; we observed a pause in firing and hyperpolarization in the dorsal striatum, a slight reduction in firing in the accumbens core, and burst firing and depolarization in the accumbens medial shell. The pause was mediated by the sub-second action of DA acting through D2 receptors, while ChI bursting was mediated by DA neuron glutamate co-transmission, which determined the regional heterogeneity. Following amphetamine administration, DA neuron input to ChIs showed dose-dependent and regionally heterogeneous changes, suggesting the importance of DA neuron connections to ChIs in the early phase of psychostimulant addiction.	S3-3-3-4 運動制御における線条体投射ニューロンの生理学的役割 Physiological roles of striatal projection neurons in voluntary movements ○佐野裕美1, 知見聡美1, 小林和人2, 田中謙二3, 南部篤1 ○Hiromi Sano1, Satomi Chiken1, Kazuto Kobayashi2, Tanaka Kenji F3, Atsushi Nambu1 生理学研究所1, 福島医大・医・生体機能2, 慶應大・医・精神神経科3 National Institute for Physiological Sciences1, Dept. of Mol. Genetics, Fukushima Med. Univ., Fukushima, Japan2, Dept. of Neuropsychiatry, Keio Univ. School of Med., Tokyo, Japan3 The basal ganglia are considered to regulate voluntary movements. The striatum, one of the input nuclei of the basal ganglia, is composed of two groups of projection neurons based on their target sites: striato-pallidal neurons projecting to the the globus pallidus (GP) and striato-nigral neurons projecting to the substantia nigra pars reticulata (SNr). In the standard model of the basal ganglia, striato-nigral neurons are considered to suppress the activity of the output nucleus of the basal ganglia, i.e., the SNr, and increase motor activity. On the other hand, striato-pallidal neurons are considered to increase the activity of the SNr through the GP-subthalamo-SNr pathway and suppress motor activity. To understand the relation between neural activity of the basal ganglia and motor activity, we combined genetic manipulation and electrophysiological recordings under awake state. 1)We selectively ablated striato-pallidal neurons by applying immunotoxin-mediated cell targeting method to transgenic mice. These mice showed increased motor activity. Spontaneous activities in the GP and SNr have shown little effects. However, their phasic response patterns to motor cortical stimulation have largely changed. 2) We generated transgenic mice that expressed channelrhodopsin-2 in the striatal projection neurons. Photostimulation of the striatum has induced phasic responses in the GP and SNr and significantly altered behaviors under freely moving state. These results suggest that striato-pallidal/nigral neurons control motor behaviors through phasic activity changes in the GP and SNr.
S3-3-3-5 中脳ドーパミンニューロンによる部位特異的な情報表現 Midbrain dopamine neurons are divided into anatomical groups encoding distinct signals ○松本正幸1,2,3 ○Masayuki Matsumoto1,2,3 筑波大院・人間総合・感性認知脳科学1, 筑波大・医学医療系・生命医科学域2, 京都大・霊長研・統合脳システム3 Graduate School of Comprehensive Human Science, Univ of Tsukuba1, Division of Biomedical Science, Faculty of Medicine, Univ of Tsukuba, Tsukuba, Japan2, Systems Neuroscience Section, Primate Research Institute, Kyoto Univ, Inuyama, Japan3 Dopamine neurons in the substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA) have been shown to encode a reward value signal and to play important roles in reinforcement and motivation. Our recent study reported, however, that not all dopamine neurons encode the value-related signal uniformly. Using a classical conditioning with appetitive and aversive outcomes (liquid rewards and aversive airpuffs) in monkeys, we found that some dopamine neurons were excited by reward-predicting stimuli and inhibited by airpuff-predicting stimuli, as the value-coding theory predicts. However, a greater number of dopamine neurons were excited by both of these stimuli, inconsistent with the theory. These data led a hypothesis that dopamine neurons are divided into multiple populations encoding distinct signals. Consistent with this idea, the dopamine system has been reported to be involved in a number of functions, not only in motivational functions but also in some cognitive ones. However, despite abundant studies demonstrating dopamine neuron activity related to reward, little is known about what signals dopamine neurons convey to promote cognitive processing. Therefore, we next examined dopamine neuron activity in monkeys performing a delayed matching-to-sample task that required working memory and visual search. We found that dopamine neurons responded to task events associated with cognitive operations. A subset of dopamine neurons were excited by visual stimuli if the monkey had to store the stimuli in working memory. These neurons were located dorsolaterally in the SNc, whereas ventromedially located dopamine neurons, some in the VTA, represented a reward value signal. Furthermore, dopamine neurons monitored visual search performance, becoming active when the monkey made an internal judgment that the search was successfully completed. Our findings suggest that dopamine neurons are divided into anatomical groups suitable for distinct functions.

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