Mitsuko Watabe-Uchida

Published Projects

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 intensity of external stimuli, unlike dopamine axons in other striatal regions. Further, we found that TS-projecting dopamine neurons are important for threat avoidance in binary choice task and naturalistic novelty exploration. These studies contributed to the broad fields in three points. First, we provided important resources for the community, such as a list of the inputs and activity patterns of dopamine subpopulations with different projection targets. Second, we indicated that there could be a clear distinction between dopamine functions in different regions of the striatum – especially in TS. Third, the results changed the way we connect the role of dopamine with normal and abnormal conditions; our results suggest that not only the absolute amount of dopamine, but balance between different dopamine systems is important for normal behaviors.

1. 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

2. 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

3. 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

4. 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

5. Tsutsui-Kimura, Uchida, N., Watabe-Uchida, M. (2022) Dynamical management of potential threats regulated by dopamine and direct- and indirect- pathway neurons in the tail of the striatum. bioRxiv 2022.02, 05.479267

Presynaptic inputs to dopamine neurons

Dopamine is important for normal behaviors, and the abnormal regulation of dopamine is related to many psychiatric conditions. To understand the neural circuits that regulate dopamine neurons, we established a systematic method for labelling brain-wide monosynaptic inputs to genetically-specified populations of neurons using a modified rabies virus. With this tool, we mapped and quantified all monosynaptic inputs to dopamine neurons residing in either the ventral tegmental area (VTA) or the substantia nigra compacta (SNc). This study has become foundational for the study of dopamine across many fields because it provides a solid anatomical basis to understand regulation of dopamine. We then combined the aforementioned tracing method using rabies 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 reward prediction error is computed by simple subtraction at one synaptic level. Together, these studies revised models about the regulation of dopamine neurons.

1. 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.

2. 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

3. 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

4. Ogawa, S.K., Watabe-Uchida, M. (2018) Organization of dopamine and serotonin system: Anatomical and functional mapping of monosynaptic inputs using rabies virus. Pharmacology, Biochemistry and Behavior, 174, 9-22

5. 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

Temporal difference learning and the biological brain

To fully understand biological meaning of diverse and complex roles of dopamine, the understanding of the complexity at the algorithmic level is important. Combined with computational modeling and recording of dopamine activity, we found that reward prediction error (RPE) signals in dopamine signals in the striatum are positively or negatively biased across different subareas in the striatum. We proposed that positively biased dopamine signals in the dorsolateral striatum, a critical brain area for habit formation, play a role in reinforcing habitual action. In the canonical dopamine system, we found that activity dynamics of dopamine signals resemble dynamics of reinforcement signals in the temporal difference (TD) learning, a frequently used algorithm in machine learning. We also found that the canonical dopamine systems integrate appetitive and aversive information.

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

2. 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

3. 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

Cell-cell adhesion and signaling molecules

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 a-catenin gene. We further identified the domain of a-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 clarified 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 andregulation 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, 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.

2. 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.

3. 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.

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