From Memory to Mood

Following the tremendous news that I have received a Pivot Fellowship from the Simons Foundation to redirect my research program "From Memory to Mood," I want to elaborate on the "Why?" and "How?" behind it.

In broad strokes, my future research program will focus on understanding how our brains drive our moods, including answers to questions like "How happy are you right now?" I will also focus on how our brains integrate information of many types (external and internal) to shape our moods. As I describe below, the reason we know so little about mood is because it turns out to be a tricky thing to study.

Let me begin with a short introduction to set the stage for the "Why?" behind this pivot. I'm a foundational researcher focused on understanding how the healthy brain and mind work. The rationale behind the type of work I do is that a nuts-and-bolts understanding is a bottleneck to a number of benefits to society, including treating brain and mental disorders. While I am motivated by the end goal of treatments, I don't believe that focusing squarely on that end goal alone will get us there. At least some of us need to begin at the beginning, and that's why I focus on foundational research.

A handful of years ago, I began to hear murmurings about disconnections between the foundational and translational arms of brain and mind research. I realized that I could not spell out my own optimistic throughlines for how we'll traverse from where we are now to treatment end-goals and that bothered me. I also couldn't find satisfying answers written down anywhere. And so I decided to sit down and figure it out for myself. That project ultimately became a book, Elusive Cures.

Writing that book was a privilege. It happened at a time when my research lab was full of terrific scientists and well-defined projects, and those projects were fully funded through research grants. I was thus able to keep that science going while also working on the book. When I began writing, I stopped committing to future projects, not knowing where the book would take me. On the other side, I had the good fortune to ask myself: What do I want to work on next? More of the same (memory)? Or something different? Armed with new insights, I was ready for a change.

Of all the topics I encountered while writing, the one that fascinated me the most was mood. It's among the biggest unsolved mysteries of the brain and mind — right up there with consciousness (and mood is in fact one type). Unlike brain functions whose purpose is more obvious (like seeing or remembering), it's unclear what mood is and why it exists. One might even wonder: Is mood beneficial? Or is it some type of vestigial function that was once useful in our evolutionary history but no longer serves us? It turns out that there are good reasons to think that our moods are beneficial but also fragile (leading to mood disorders like depression).

So, what is mood? Mood is one of those things that everyone knows but no one can define precisely. We all experience it as an ever-present, continuous feeling, characterized by states like happiness, sadness, anxiousness, and calmness. In comparison to emotions (which are targeted at something specific), moods are often diffuse. We are afraid of tigers and disgusted by rotting garbage, but we cannot always explain why we feel happy or calm. This is because our moods do not follow from a single experience, but an integration across many (as well as our internal states like hunger and hormone levels).

There's certainly a lot that we don't know about mood, especially when it comes to the brain — including what in the brain drives our answers to the question, "How happy are you right now?" Over decades, I've contributed to figuring out how the brain drives answers to analogous questions for vision and memory such as, "Have you seen this thing before?". One of the central goals of my future research program is to understand what in the brain drives mood. Simply put, there's a lot we don't understand from the perspective of "systems neuroscience" about what mood is and how it's determined in the brain. That's not because we haven't had many terrific researchers working to figure it out. Nor is it because they haven't gotten anywhere with it — we know a tremendous amount about what's happening at the level of synapses and in large brain networks of the type that can be studied with fMRI. However, it turns out that filling in the middle has been really (really!) challenging.

Why is mood so difficult to understand? Mood (like other emotions) is a subjective experience. It's unlike memory, where there's an objective ground truth about whether you've seen something before or not. In comparison, only you know how happy you are. That means we have to approach mood differently, in ways that rely (at least in part) on asking individuals how they feel. Despite its challenges, we cannot shy away from tackling mood — a remarkable 21% of adults will experience a mood disorder at some point in their lives, and for a third of those, existing treatments will not help. Until we understand mood better, improving treatments for these individuals will be difficult.

Likewise, mood is shaped by a reciprocal interaction between our brains and the things we experience — our moods impact our percepts of the things that happen, and those percepts in turn shape our moods. Mood is thus a form of continuous learning that requires our brains to continually rebalance and adjust. How the brain manages to continuously learn while not messing itself up is one of the big frontiers of modern neuroscience. In the famous distinction between static "things" and ever-changing "processes," mood is much more a process than a thing, and it's process-like brain functions that we understand the least.

In terms of the throughline from where we are now to treatments for mood disorders, I've thought a lot about whether we should focus on mood in the brain, the mind, the environment or all three. Needless to say, my own take is that until we understand more about mood in the brain, we won't understand mood in the mind and environment, and this is why I'm focusing on research that spans them all. Of note is that while the end-goal of understanding mood in the brain might be brain-based interventions, it might also contribute to improving behavioral therapies — as Ken Kendler so poignantly describes, understanding the brain can help us "expand the domain of the understandable" about the mind.

In any era, brain researchers are faced with finding some compromise between what we really want to know and what we can accomplish. Breakthroughs in biotechnology and Artificial Intelligence have opened the floodgates of opportunity, and we now each get to ask ourselves: What will we do with it? For me, the answer is: tackle mood.

I am tremendously grateful to the Simons Foundation for awarding me this Fellowship and to my Fellowship mentor, Yael Niv, whose group has developed what I regard as the most compelling theory to date about what mood is and why it exists (you can read about those ideas here and here). As part of the Fellowship, I get to embed in Yael's lab at Princeton for a year. This is one of those times in my life in which I find it hard to believe that I get paid to do something so fascinating and so fun. I'm absolutely thrilled to take these next steps. But before I do, I will be excited to report the emerging insights about memory that the terrific members of my current team are currently wrapping up.

Nicole Rust

November 2024