matters in the brain—which cells, which activity, and which connections are

We used optogenetics in my lab to sort out how this happens, how the different features are obtained and wrapped up together. This was done using projection targeting. You can show that there’s a part of the extended amygdala called the bed nucleus of the stria terminalis (BNST) and that different projections coming out from the BNST, going to different parts of the brain, access these different features. There’s a projection that goes to the parabrachial nucleus, part of the brainstem that controls respiratory rate, the breathing changes associated with anxiety. But it doesn’t affect the behavioral decisions, or the positive or negative feeling-state, at all.

There’s another projection that goes from the BNST to the lateral hypothalamus, and that controls the behavioral decisions but doesn’t affect the breathing rate at all, or the subjective valence, the feeling-state.

And there’s a third that goes to the ventral tegmental area. This is the part of the brain where dopamine neurons live, that seems to set the negativity of anxiety and the positivity that comes from the release of anxiety. But it doesn’t affect respiratory rate or behavioral decisions. So, these different features can be cleanly broken apart, and they’re assembled by these projections.

Just how did you parse the anxiety response—how did you show projections from the BNST to different brain regions to be responsible for distinct facets of anxiety?

DEISSEROTH: We did this in mice, which have many of the same structures that we have and exhibit robust anxiety responses, using the projection targeting method that I described. We delivered excitatory or inhibitory channelrhodopsins to the BNST, and then we delivered fiberoptics to different downstream regions that we knew were connected to it but didn’t know how. And we explored what the causal impact was on which parts, which behaviors were elicited. We observed this clean deconstruction of the different features of anxiety, as a result of controlling these different projections from the anxiety control region of the BNST.

To take another example, Catherine Dulac at Harvard did the same kind of thing five years later for parenting. This is quintessential: There’s not much that’s more important to a mammal than parenting, right? As it turns out, as complex a state as it is, aspects of parenting can be broken down into component parts that map onto physical structures in the brain. What Catherine Dulac showed, using optogenetic projection targeting, was that there’s a connection that starts from one part of the brain and goes to another, that mediates the grooming of the young, the physical care that all mammals do. But it doesn’t affect the motivation to go out and retrieve the young that had strayed from the nest. That was controlled by a different connection, a different projection, which didn’t affect grooming at all. And there are many such examples.

You’re also a practicing psychiatrist. What kind of work do you do?

DEISSEROTH: Well, I really do three kinds of work. There are the extremely acute cases that come to the emergency room. They’ve been brought in by police, or by family, or they bring themselves in because they know they’re in danger. I’m the attending physician, and I work with the emergency room doctors and others, to sort out the right care.

I also run an outpatient clinic. I see those patients once a month, or some, if they’re quite ill, more often, even every week. I focus on very severe cases, hard-totreat illnesses, particularly two things: treatment-resistant depression and autism.

And finally—and this is more recent—we’re doing clinical trials, trying to understand the internal brain processes, the dynamics that underlie complex altered brain states like dissociation, which is a very important and mysterious brain state that shows up all across psychiatry.

How does your clinical work relate to your research? In your book, you suggest a kind of synergy between them.

DEISSEROTH: It’s so important to be able to go to my trainees in the lab, my students and postdoctoral fellows, and to tell them, “Look, this is what anxiety is really like. This is what depression is really like. This is what matters to someone with autism. It isn’t just one symptom from a list; it really disrupts their life, and this is how they feel about it.” That is so helpful to guide the research in the lab.

It works the other way, too. In the lab, we found this very interesting altered brain state that was associated with dissociation, and we were able to go and find that