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Dopamine D2 receptors detect transient decreases in dopamine concentration to correct inaccurate emotional memory
Yusuke Iino, Takeshi Sawada, Kenji Yamaguchi, (Haruo Kasai, Sho Yagishita)

Dopamine D2 receptor (D2R) is the main target of antipsychotic drugs. However, the role of D2R in the regulations of synaptic plasticity and behavior remains unclear. It is thought that D2R can detect transient decreases in dopamine concentration (DA dip). By observing and manipulating DA dips, we investigated the function of D2R in mice via behavioral and slice physiological experiments. We found that emotional memory was broadly formed by generalizations mediated by D1 receptors in reward-based conditioned learning. When this generalized memory was inaccurate, DA dip occurred in the nucleus accumbens and causally corrected the memory (discrimination). In brain slices, D2R detected a narrow DA dip as short as 0.4‐2 s to disinhibit spine enlargement. This sensitive mechanism for DA dip detection and correction of overgeneralized memories was disrupted by excess dopamine caused by psychostimulants and was recovered by a D2R antagonist (antipsychotics). This research reveals a new learning principle in the brain and leads to a new synaptic hypothesis to explain psychotic symptoms in neuropsychiatric diseases such as schizophrenia.

Yusuke Iino*, Takeshi Sawada*, Kenji Yamaguchi*, Mio Tajiri, Shin Ishii, Haruo Kasai† and Sho Yagishita†. Dopamine D2 receptors in discrimination learning and spine enlargement
Nature 579, 555–560 (2020)  (*equal contribution、†corresponding authors)

<Figure Legends>
Figure. Model for generalization and discrimination learning and novel hypothesis for psychotic symptoms.

A. Generalization and discrimination of associative memory in mice. B. Optogenetically-mimicked tonic dopamine inhibited spine enlargement in D2R-expressing neurons (D2R-neurons) via D2R. By contrast, transient reductions in dopamine concentration (DA dip) deactivated D2R and disinhibited spine enlargement. C. Reward-evoked phasic elevation of dopamine induced spine enlargement in D1 receptor-expressing neurons to produce generalized emotional memory. However, if the expected reward was omitted, DA dip was observed. DA dip disinhibited spine enlargement in D2R-neurons to discriminate inaccurate emotional memories. D. As negative emotions as well as positive emotions are known to elevate dopamine concentration in some regions of the nucleus accumbens, it is possible that similar generalization and discrimination learning exists. Associative learning by aversive stimuli is generalized to unrelated people. This generalized memory is discriminated by D2R-neurons in healthy conditions. However, dopamine overload impairs the discrimination and this study suggests that impaired discrimination learning may cause delusions of persecution.

Laboratory of Structural Physiology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo/International Research Center for Neurointelligence The University of Tokyo