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(l to r) Sachie K. Ogawa, Mitsuko Watabe-Uchida, and Nao Uchida

When I told my niece in medical school that I am studying dopamine, she looked surprised, asking, “Isn’t the function of dopamine already known?” My daughter in high school also “knew” the function of dopamine, and serotonin as well: dopamine is for pleasure, she told me, and serotonin for happiness. In fact, as many high schoolers know, psychostimulants act primarily through these two pathways. Amphetamine, for example, acts on dopamine to cause delusions, while ecstasy acts on serotonin to cause euphoria.
This idea, of course, is a vast oversimplification of what dopamine and serotonin are doing in the brain. Dopamine neurons encode not pleasure itself, but “reward prediction error”, which can be used to promote learning about reward. Serotonin, on the other hand, is more mysterious but is also thought to be involved in processing reward and/or punishment. It has even been proposed that the functions of dopamine and serotonin oppose each other.
Despite public awareness and decades of scientific research, we are still at an early stage in understanding how dopamine and serotonin neurons work, and in particular, how they are regulated and interact with each other. We do not even know how these neurons are connected to the rest of the brain. One of the reasons is the anatomical complexity of the brain. Both dopamine and serotonin neurons are surrounded by other types of neurons, such as GABA and glutamate neurons. We needed new tools to examine the connectivity of dopamine and serotonin neurons without contaminating our findings with these other neuron types. Two years ago, we established such a system and presented the inputome (whole brain map of monosynaptic inputs) of dopamine neurons by using modified rabies virus. The results gave us a crucial base of knowledge with which to devise new experiments on dopamine function.  In the current paper, we had two purposes: The first was to analyze the inputome of serotonin neurons using the above method and the second was to examine the interaction of dopamine and serotonin neurons
Our system allows a modified rabies virus to infect a specific cell type and retrogradely hop once. Because the rabies virus carries the fluorescence marker GFP, we could visualize all the monosynaptic inputs to serotonin neurons. The first author, Sachie K. Ogawa, counted all the GFP-positive neurons manually. The resulting inputome of serotonin neurons led to many interesting findings. For example, although the main information flow from the forebrain to all serotonin neurons had always been believed to be through the habenula (“dorsal pathway”), we found that the monosynaptic inputs from habenula to serotonin neurons are limited to serotonin neurons in the median raphe (MR), rather than the dorsal raphe (DR). Thus, direct inputs to DR and MR serotonin neurons are different, suggesting different functions.
We then compared the inputs to dopamine and serotonin neurons. Surprisingly, we found that dopamine neurons in the ventral tegmental area (VTA) and serotonin neurons in DR receive similar inputs. A more detailed examination showed that spatially, three input streams control dopamine and serotonin neurons: one medial stream from the cingulate cortex to MR serotonin neurons, one stream from the lateral orbital cortex to DR serotonin and VTA dopamine neurons, and one latero-dorsal stream from the motor and sensory cortex to the substantia nigra compacta (SNc) dopamine neurons. In short, VTA dopamine and DR serotonin might have similar functions, in contrast to MR serotonin and SNc dopamine. Further, we observed a largely one-directional direct interaction from serotonin neurons to dopamine neurons, suggesting hierarchical control of serotonin over dopamine.
Our results help reveal the global organization of dopamine and serotonin connectivity in the brain. Although this is only the starting point, I hope I can convince my niece that we’re making progress towards our goal of understanding the function of these fascinating neuromodulators.
Read more in Cell Reports or download PDF.


View Nao Uchida’s Faculty Profile