This paper changed my life: Talia Lerner reflects on dopamine neuron diversity and the value of simple experiments

Answers have been edited for length and clarity.

What paper changed your life?

Projection-specific modulation of dopamine neuron synapses by aversive and rewarding stimuli. Lammel S., Ion D.I., Roeper J., Malenka R.C. Neuron (2011)

This paper was one of the first to highlight the heterogeneity of dopamine neurons. The researchers used retrograde labeling and slice electrophysiology in mice to show that dopamine neurons that project to different areas of the brain have different physiological properties and undergo plasticity in response to different types of stimuli.

By today’s standards, the paper seems very simple. The authors found that a single rewarding experience (a dose of cocaine) specifically strengthened certain dopamine neurons in the mesolimbic pathway. A single aversive experience (hind-paw formalin injection) potentiated other dopamine neurons in the mesolimbic and mesocortical pathways. 

The general insight to me was profound: Although all dopamine neurons may play a role in learning, there are diverse rules for plasticity that can support learning about different types of stimuli.

When did you first encounter this paper?

When this paper was published, I was just finishing graduate school at the University of California, San Francisco, in Anatol Kreitzer’s lab. I was using slice electrophysiology to study dopamine-dependent plasticity in the dorsolateral striatum. It was interesting to me that to get plasticity at excitatory synapses onto striatal neurons, you not only needed simultaneous pre- and postsynaptic activity, but you also needed the mix of neuromodulators to be right. By studying how dopamine was important for controlling available windows for synaptic plasticity, I began to understand how it could operate to change future behavior.

Why is this paper meaningful to you?

As I neared the end of graduate school, I was thinking a lot about why the plasticity mechanisms I was studying might matter for behavior. In my graduate school paper, I explored how aberrant dopamine-dependent plasticity might contribute to Parkinsonian symptoms. But as I read more and more of the literature, I became increasingly curious about how habits form. There was a beautiful review article published in 2006, right as I started graduate school, by Barbara Knowlton and Henry Yin on habit formation, which outlined how the dorsomedial striatum (DMS) and dorsolateral striatum (DLS) were responsible for different types of motivated behavior. The review introduced me to the idea that these two circuits might control the transfer of information in the basal ganglia by acting on subsets of dopamine neurons.

Then, when I saw the Lammel paper at the end of graduate school, I was inspired by their approach and thought about what it meant for my interest in habits and the functions of the DMS and DLS. I saw that they did not make any distinction between dopamine neurons projecting to the DMS and DLS, lumping everything as nigrostriatal. And they didn’t see any plasticity when they administered a single rewarding or aversive experience! 

Was there something else that would cause plasticity of inputs to nigrostriatal dopamine neurons? Are DMS- and DLS-projecting dopamine neurons different? Do they have specialized inputs or mechanisms of plasticity? I thought, “I can add to this!” These became the driving questions in my postdoctoral fellowship and my independent laboratory.

How did this research change how you think about neuroscience and influence your scientific trajectory?

At the time, it was gospel in the field that dopamine neurons should have H currents, that they should have D2 autoreceptors and wide action potentials. This and other papers showed that there are dopamine neurons that don’t meet these criteria. In our rush to find useful proxies for cell type identification, especially when working in vivo, we blinded ourselves. Reading and admiring this paper helped me think about how to go about challenging assumptions. I saw how, as a researcher, you can make your case clearly without feeling like you’re personally attacking someone’s work. And this work shows that when you’re willing to challenge assumptions, you can help move a whole field beyond a common roadblock.

It also helped reinforce that even when I thought I knew something, I needed to look back at primary data. Review articles are useful, but they can oversimplify the current consensus and leave out nuance. 

This paper set me on my research path. In 2012, I moved to Stanford University to start my postdoctoral work with Karl Deisseroth. I was eager to learn systems and circuit neuroscience and apply it to study dopamine heterogeneity in the dorsal striatum. I knew that Stephan Lammel, the first author on the paper, was there, still working in Rob Malenka’s lab nearby. So one of the first things I did on arriving at Stanford was email him. I was such a fan! Stephan was incredibly generous with his time. He gave me all his best tips for patching dopamine neurons. I was lucky to find a friend who cared about dopamine as much as I did.

Is there an underappreciated aspect of this paper you think other neuroscientists should know about?

I’m not sure if it’s underappreciated, but this paper shows that simple is good. A simple, straightforward experiment, when well conceived and well executed, can change everything. It is preferable to a complicated paper that no one can understand. It is better to publish an intriguing piece of a story than imagine you can solve everything at once. I have used this paper in my teaching in part because I want to demonstrate these principles to trainees. This is a simple paper that led to so much new thinking. The authors didn’t have to do everything in one paper to make their point. Technical proficiency is necessary, but thinking clearly is what creates impact. 

What new progress has been made since this paper was published?

Dopamine heterogeneity studies have flourished over the past 15 years. We now have a handle on gene expression patterns of dopamine neuron subtypes and understand that they have unique inputs and computational functions. Dopamine subtypes present different susceptibility to neurodegeneration and have different patterns of activity in response to drugs of abuse. 

I think we’re poised now for a big leap forward if we can figure out how to harness everything we’ve learned into translational opportunities. You can’t treat addiction, for example, by simply blocking dopamine receptors or shutting down the dopamine system, because the side effects are too severe. But what studies of heterogeneity tell us is that the situation is not hopeless: Severe side effects arise because we don’t have the tools to manipulate subcircuits within the dopamine system more delicately. It is an area where we can innovate. I think we will get there, and we will learn a lot more about the dopamine system as we do so. I’m very optimistic about the field going forward.