@misc{oai:repo.qst.go.jp:00078039,
 author = {小山, 佳 and 堀, 由紀子 and 永井, 裕司 and 平林, 敏行 and 宮川, 尚久 and 藤本, 敦 and 三村, 喬生 and 井上, 謙一 and Eldridge, Mark and Saunders, Richard and 須原, 哲也 and 高田, 昌彦 and 樋口, 真人 and Richmond, Barry and 南本, 敬史 and Oyama, Kei and Hori, Yukiko and Nagai, Yuji and Hirabayashi, Toshiyuki and Miyakawa, Naohisa and Mimura, Koki and Suhara, Tetsuya and Higuchi, Makoto and Minamimoto, Takafumi},
 month = {Jul},
 note = {To survive in a dynamic world, animals must rapidly adapt to novel environments and optimize their behavior to obtain rewards. The primate orbitofrontal cortex (OFC) is thought to contribute to reward-based adaptive decision-making. However, a causal relationship has not yet been established, mainly because the reversible inactivation of large and non-continuous areas of the brain, like the bilateral OFC, is technically challenging in non-human primates. In this study, we applied the chemogenetic technique, Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to reversibly inactivate OFC in macaque monkeys. Three monkeys underwent open surgery to receive multiple injections of an adeno-associated viral vectors expressing a silencing DREADD, hM4Di, into OFC bilaterally. Several weeks after the injections, we performed a positron emission tomography (PET) scan with a DREADD-selective ligand, [11C]deschloroclozapine (DCZ) and confirmed in vivo that hM4Di expression covered OFC bilaterally as intended. Reward-based adaptive decision-making was tested with a modified reversal learning task in which the monkeys were required to choose either of two visual stimuli presented on a computer screen. On each day, five new visual stimuli were paired with 1, 2, 3, 4, or 5 drops of juice. In each trial, two stimuli were randomly selected from the five. To maximize the rewards, the monkeys had to choose a better option by learning the session-specific stimulus-reward associations (learning phase). After the performance was stabilized (optimal choice >80%), the stimulus-reward associations were reversed (S1-R5, S2-R4…S5-R1). Now to maximize the reward, the monkeys had to select the previously inferior stimuli (reversal phase). After several months of training, the monkeys learned to choose a better option in both the learning and reversal phases within several tens of trials in each day’s session. Intramuscular injection of the novel DREADD agonist, DCZ, did not impair initial learning but was followed by impaired performance during the reversal in all three monkeys. This impairment is attributed to the OFC-DREADD inactivation, because the injection of DCZ alone did not affect the performance in a control monkey without DREADD expression. These results suggest that the primate OFC plays a critical role in reward-based adaptive decision-making when a situation requires overriding of the previously established associations. 

Support: MEXT/JSPS KAKENHI Grant Numbers JP15H05917, JP15K21742, JP18H04037 (to TM), 18K15353 (to KO), AMED Grant Numbers JP18dm0107146 (to TM), 第42回日本神経科学大会},
 title = {DREADD inactivation reveals critical role of orbitofrontal cortex in reward-based adaptive decision-making in monkeys},
 year = {2019}
}