Mitsuko Watabe-Uchida

Selected Publications

Dopamine in the tail of the striatum

Although it is widely accepted that dopamine is important for reward value-related behaviors, accumulating evidence suggests that dopamine neurons are more diverse than previously thought. To study the diversity of dopamine neurons, we first examined the monosynaptic inputs of subpopulations of dopamine neurons with different projection targets. In this anatomical study, we found that dopamine neurons projecting to the tail of the striatum (TS) are anatomically unique. In a follow-up study, we systematically examined the activity of dopamine axons in the striatum, and found that dopamine axons in TS monotonically signal stimulus salience, unlike dopamine axons in other striatal regions. Further, we found that TS-projecting dopamine neurons are important for threat avoidance. Our results suggest that not only the absolute amount of dopamine, but balance between different dopamine systems, is important for normal behaviors.

1. Tsutsui-Kimura, I, Tian, ZM, Amo, R, Zhuo Y, Li Y, Campbell MG, Uchida N, Watabe-Uchida, M. (2025) Dopamine in the tail of the striatum facilitates avoidance in threat-reward conflicts. Nature Neurosci. 28: 795-810. PMCID: PMC11976289

2. Kamath T, Lodder B, Bilsel D, Green I, Dalangin R, Capelli P, Raghubardayal M, Wang W, Capelli P, Legister J, Timmins J, Hulshof L, Wallace JB, Tian L, Uchida N, Watabe-Uchida M, Sabatini BL. (2025) Hunger modulates exploration through suppression of dopamine signaling in the tail of the striatum. Neuron 113: 4055-4068.

3. Akiti, K., Tsutsui-Kimura, I., Xie, Y., Mathis, A., Markowitz, J., Anyoha, R., Datta, S.R., Weygandt Mathis, M., Uchida, N., Watabe-Uchida, M. (2022) Striatal dopamine explains novelty-induced behavioral dynamics and individual variability in threat prediction. Neuron 110 (22), 3789-3804, e9

4. Menegas, W., Akiti, K., Amo, R., Uchida, N., Watabe-Uchida, M. (2018) Dopamine neurons projecting tothe posterior striatum reinforce avoidance of threatening stimuli. Nature Neuroscience 21 (10), 1421. PMCID: PMC6160326

5. Menegas, W., Babayan, B.M., Uchida, N., Watabe-Uchida, M. (2017) Opposite initialization to novel cues in dopamine signaling in ventral and posterior striatum in mice. eLife, 6, e21886. PMCID:PMC5271609

6. Menegas, W., Bergan, J.F., Ogawa, S.K., Isogai, Y., Umadevi Venkataraju, K., Osten P., Uchida, N., Watabe-Uchida, M. (2015) Dopamine neurons projecting to the posterior striatum form an anatomically distinct subclass. eLife, 4, e10032. PMCID: PMC4598831

Computation of dopamine signals

Dopamine is important for various behaviors such as decision-making, learning and movement. Abnormal regulation of dopamine is related to many psychiatric conditions. To understand the neural circuits that regulate dopamine neurons, we systematically mapped monosynaptic inputs to dopamine neurons in the entire brain. We then combined the tracing method with optogenetic cell type identification in behaving mice, and mapped the activity of monosynaptic inputs to midbrain dopamine neurons. This study of input activity showed that information is mixed and distributed across regions in monosynaptic inputs to dopamine neurons and thus challenged the classical view that dopamine signals are simply computed at one synaptic level. Finding distributed inputs to dopamine neurons, we turned to population inputs to dopamine neurons. Because most inputs to dopamine neurons are activated by reward and reward-predicting cues, we focused on glutamate inputs to dopamine neurons and found that population activity of glutamate inputs contain information for prediction error of reward including reward omission, but not for negative value of aversive events. Together, these studies revised models about the regulation of dopamine neurons.

1. Amo, R., Uchida, N., Watabe-Uchida, M. (2024) Glutamate inputs send prediction error of reward but not negative value of aversive stimuli to dopamine neurons. Neuron 112, 1001-1019

2. Amo, R., Matias, S., Yamanaka, A., Tanaka, K.F., Uchida, N., Watabe-Uchida, M. (2022) A gradual temporal shift of dopamine responses mirrors the progression of temporal difference error in machine learning. Nature Neuroscience 25, 1082-1092

3. Tsutsui-Kimura, I., Matsumoto, H., Akiti, K., Yamada, M.M., Uchida, N., Watabe-Uchida, M. (2020) Distinct temporal difference error signals in dopamine axons in three regions of the striatum in a decision-making task. eLife 9, e62390. PMCID: PMC7771962

4. Matsumoto, H., Tian, J., Uchida, N., Watabe-Uchida, M., (2016) Midbrain dopamine neurons signal aversion in a reward-context-dependent manner, eLife, 6 e17328

5. Tian J., Huang R., Cohen J.Y., Osakada F., Kobak D., Machens C.K., Callaway E.M., Uchida N., Watabe-Uchida M. (2015) Distributed and mixed information in the monosynaptic inputs to dopamine neurons. Neuron, 91: 1-16. PMCID: PMC5033723

6. Ogawa, S.K., Cohen, J.Y., Hwang, D., Uchida, N., Watabe-Uchida, M. (2014) Organization of monosynaptic inputs to the serotonin and dopamine neuromodulatory systems. Cell Reports, 8: 1-14. PMCID: PMC4142108

7. Watabe-Uchida, M., Zhu, L., Ogawa, S. K., Vamanrao, A., Uchida, N. (2012) Whole-brain mapping of direct inputs to midbrain dopamine neurons. Neuron, 74: 858-873.

Cell-cell adhesion and signaling molecules (previous works) 

Cadherins are a family of cell-cell adhesion molecules that are important for selective tight adhesion between cells. Catenins are molecules that bind to the cytoplasmic domain of cadherin. We found that the cadherin-catenin adhesion system is important not only for adhesion but also for epithelial polarity formation and regulation of cell growth, and that some type of cancer cells lose cell adhesion merely because of loss of the α-catenin gene. We further identified the domain of α-catenin important for the epithelial organization and found that this domain binds to vinculin, through which cadherin can bind to cytoskeleton actin. These series of studies revealed how cadherin interacts with the cytoskeleton and what is the role of this interaction beyond cell-cell adhesion. In addition to epithelial polarity, I also examined neuronal polarity formation. We found a signal cascade involving DOCK7, Rac activator, which is important for axon formation and regulation of a microtubule binding protein, stathmin. From the results, we proposed a possible link between signaling in the cytoplasm and regulation of cytoskeleton mictotubules during neuronal polarity formation.

1. Watabe-Uchida, M., John, K. A., Janas, J. A., Newey, S. E. and Van Aelst, L. (2006). The Rac activator DOCK7 regulates neuronal polarity through local phosphorylation of stathmin/Op18. Neuron. 51:727- 739.

2. Watabe-Uchida, M., Govek, E.E., Van Aelst, L. (2006). Regulators of Rho GTPases in neuronal development. J. Neurosci. 26:10633-10635.

3. Watabe-Uchida, M., Uchida, N., Imamura, U., Nagafuchi, A., Fujimoto, K., Uemura, T., Vermeulen, S., van Roy, F., Adamson, E.D., and Takeichi, M. (1998). α-Catenin-vinculin interaction functions to organize theapical junctional complex in epithelial cells. J. of Cell. Biol. 142:847-858. PMCID2148175.

4. Watabe, M. Nagafuchi, A., Tsukita, S., and Takeichi, M. (1994). Induction of polarized cell-cell association and retardation of growth by activation of the E-cadherin-catenin adhesion system in a dispersed carcinoma line. J. of Cell. Biol. 127:247-256.