Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 1, Pages 342-347Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1220358110
Keywords
avoidance; decision-making; drug addiction; reward-based learning; synaptic plasticity
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Funding
- Ministry of Education, Culture, Sports, Science and Technology of Japan [2222005, 23120011, 23680034]
- Japan Science and Technology Agency
- TK Project of Medical Innovation Center of Kyoto University
- Ministry of Health, Labor and Welfare of Japan
- Takeda Science Foundation
- Naito Foundation
- Uehara Memorial Foundation
- Senri Life Science Foundation
- Grants-in-Aid for Scientific Research [23680034, 22220005, 22500343] Funding Source: KAKEN
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The basal ganglia-thalamocortical circuitry plays a central role in selecting actions that achieve reward-seeking outcomes and avoid aversive ones. Inputs of the nucleus accumbens (NAc) in this circuitry are transmitted through two parallel pathways: the striatonigral direct pathway and the striatopallidal indirect pathway. In the NAc, dopaminergic (DA) modulation of the direct and the indirect pathways is critical in reward-based and aversive learning and cocaine addiction. To explore how DA modulation regulates the associative learning behavior, we developed an asymmetric reversible neurotransmission-blocking technique 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 D1 receptors and the inactivation of D2 receptors postsynaptically control reward learning/cocaine addiction and aversive learning in a direct pathway-specific and indirect pathway-specific manner, 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 the indirect pathway. Thus, reward and aversive learning is regulated by pathway-specific neural plasticity via selective transmitter receptors in the NAc circuit.
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