Research interests

　

The limbic system has been the focus of researches aiming at understanding the neural substrates of learning, memory, emotion and motivation. Of the limbic structures, the amygdala plays an important role in emotion, and stimulus-affect association and the hippocampal formation is a critical structure for navigation, spatial learning and episodic memory. Mesolimbic dopamine systems, originates from the ventral tegmental area innervating limbic areas, have been emphasized on its control of physiological functions, including motivation, locomotion, addiction and reward processes, and also its involvement in several neural disorders, such as Parkinson's disease, Attention-Deficit Hyperactivity Disorder (ADHD), and schizophrenia, etc. These diseases affect millions people all over the world. Therefore, dopaminergic system has attracted attention of researches over past decades, and achievements from those researches benefited for understanding of the nature of several neural disorders and for sake of human being by contributing to treatment of those diseases. However, the specific role of dopamine receptors subtypes in the neural substrate for emotion, learning, motivation (the limbic structure) still remains to be specified.

　

In our recent studies, we found that lacking of a specific dopamine receptor (D1 or D2 receptor) altered prediction responses of neurons in the nucleus accumbens (NAc), a brain structure closely involves in motivation and goal-directed behavior, in a specific manner. Furthermore, lacking of dopamine receptors also compromised place-related activity of NAc neurons. These results provide evidence that dopamine receptor subtypes at the level of the NAc seems to be important for reward prediction and learning. The NAc, known as the limbic/motor interface, receives extensive inputs from the limbic (especially from the amygdala and hippocampal formation) and relays limbocortical processed information to output behaviors. Based on hierarchically anatomical connections of the NAc, we hypothesized that specific changes in predictive neural responses and place-related activity of the NAc might link with alterations in upward brain regions (such as the amygdala, prefrontal cortex, and hippocampus), and these alterations influence learning (Tran et al., 2002, 2005). Therefore we continue further studies to investigate systematically the role of monoamine receptors, particulary the dopamine receptor, in modulating neural activity of the limbic structures, and linking it to the neural mechanisms of learning, memory, and emotion, using knockout animals. We will also intend to investigate the interaction of dopaminergic system with other neurotransmitters at behavioral and neural network levels.

　

　

教育研究業績書 (表題・発表雑誌名（出版社名）・巻・)

　

・著　書

　

1) Tran, A.H., Tamura, R., Uwano, T., Kobayashi, T., Katsuki, M., Matsumot, G. and Ono, T. Dopamine D2 receptor-knockout changed accumbens neural response to prediction of reward associated with place in mice. In: Cognition and Emotion in the Brain. T. Ono, G. Matsumoto, R. Norgren, A. Berthoz, H. Nishijo, R. Tamura (Eds), Elservier Amsterdam pp. 493-508, 2003.

　

・原　著

　

1) Tran, A.H., Tamura, R., Uwano, T., Kobayashi, T., Katsuki, M., and Ono, T. Dopamine D1 receptors involved in locomotor activity and accumbens neural responses to prediction of reward associated with place. Proc. Natl. Acad. Sci. USA, 102: 2117-2122, 2005.

　

2) Tran, A.H., Tamura, R., Uwano, T., Kobayashi, T., Katsuki, M., Matsumoto, G., and Ono, T. Altered accumbens neural response to prediction of reward associated with place in dopamine D2 receptor knockout muce. Proc. Natl. Acad. Sci. USA, 99: 8986-8991, 2002.

　

3) Kobayashi, T., Tran, A.H., Nishijo, H., Ono, T., and Matsumoto, G. Contribution of hippocampal place cell activity to learning and formation of goal-directed navigation in rats. Neuroscience. 117: 1025-1035, 2003

　

4) Takamura, Y., Tamura, R., Tian Lu Zhou, Kobayashi, T., Tran, A.H., Eifuku, S., and Ono, T. Spatial firing properties of lateral septal neurons. Hippocampus. (in press), 2006.

　

　

Selected papers with abstracts

　

1) Tran, A. H., Tamura, R., Uwano, T., Kobayashi, T., Katsuki, M. and Ono, T. Dopamine D1 receptors involved in locomotor activity and accumbens neural responses to prediction of reward associated with place. Proc. Natl. Acad. Sci. USA, 102: 2117-2122, 2005.

http://www.pnas.org/cgi/content/full/102/6/2117

　

Predicting reward is essential in learning approach behaviors. Dopaminergic activity has been implicated in reward, movement, and cognitive processes, all essential elements in learning. The nucleus accumbens (NAc) receives converging inputs from corticolimbic information-processing areas and from mesolimbic dopamine neurons originating in the ventral tegmental area. Previously, we reported that in mice, a dopamine D2 receptor knockout (D2R-KO) eliminated the prereward inhibitory response, increased place-field size of NAc neurons, and reduced locomotor activity without marked change in intracranial self-stimulation (ICSS) behavior. The present study investigated the specific contribution of dopamine D1 receptor (D1R) in mediating reward, locomotor activity, and spatial associative processes and in regulating NAc neural responses. In contrast to D2R-KO animals, here we find D1R-KO in mice selectively eliminated the prereward excitatory response and decreased place-field size of NAc neurons. Furthermore, D1R-KO impaired ICSS behavior, seriously reduced locomotor activity, and retarded acquisition of a place learning task. Thus, the present results suggest that D1R may be an important determinant in brain stimulation reward (ICSS) and participates in coding for a type of reward prediction of NAc neurons and in spatial learning.

　

2) Tran, A. H., Tamura, R., Uwano, T., Kobayashi, T., Katsuki, M., Matsumoto, G., and Ono, T. Altered accumbens neural response to prediction of reward associated with place in dopamine D2 receptor knockout muce. Proc. Natl. Acad. Sci. USA, 99: 8986-8991, 2002.

http://www.pnas.org/cgi/content/full/99/13/8986

　

Midbrain dopaminergic activity seems to be important in forming the prediction of future events such as rewards. The nucleus accumbens (NAc) plays an important role in the integration of reward with motor function, and it receives dense dopamine innervation and extensive limbic and cortical afferents. Here, we examined the specific role of the dopamine D2 receptor (D2R) in mediating associative learning, locomotor activity, and regulating NAc neural responses by using D2R-knockout (KO) mice and their wild-type littermates. D2R-KO mice displayed reduced locomotor activity and slower acquisition of a place-learning task. D2R-KO eliminated the prereward inhibitory response of neurons in the NAc. In contrast, an increased number of neurons in D2R-KO mice displayed place-related activity. These results provide evidence that D2R in the NAc participates in coding for a specific type of neural response to incentive contingencies and partly in spatial learning.

　

前のページに戻る