Carney Institute (CI): Tell us a bit about yourself.
Robyn St. Laurent (RS): I grew up in Newmarket, New Hampshire, which is in southern New Hampshire and went to Colby College where I majored in psychology with concentration in neuroscience.
For my very first research project, I'd noticed that when people run, they tend to run in sync. I wondered if the auditory feedback of hearing other people's footsteps was causing people to link up the speed of their stride.
I ended up testing people with just a set of headphones that was playing footsteps that were either slightly faster or slightly slower than their normal speed to see if they would sync up with the auditory feedback, and then had this remote-controlled backpack where you could record their actual gate mechanics so that you could see if they were syncing up or not. That was my very first foray into research. From that I learned that research was fun, but I wanted to be able to understand how the brain works and I knew that neuroscience was the way to go.
After Colby, I worked as a postbac at the National Institute on Drug Abuse (NIDA) for two years. We were investigating how the context of the environment can cause reinstatement of drug seeking behavior. This experience really spurred my interest in drugs of abuse. They have such a potent effect on the brain and on certain brain cell types and certain brain regions and connections. It's just an interesting way of perturbing the system that normally works and then seeing how those results in different behaviors and different circuit adaptations in the brain.
When I came to Brown, I first worked with professor Karla Kaun researching alcohol addiction in Drosophila. I then rotated into another lab that was looking at how stress affected long-term potentiation in the ventral tegmental area (VTA). That's where a lot of the dopamine cells in the brain live and where a lot of drugs of abuse have their action. This lab was looking at how stress could block forms of synaptic plasticity in that brain region.
I started with a bunch of exploratory research, and what I ended up finding was a form of plasticity onto dopamine neurons that hadn't been documented before. This form of plasticity was sort of unique in that potentiation, or strengthening of the synapse, was generated by low frequency stimulation. Normally, if you give a low frequency stimulus, you decrease the activity at that synapse, but what I was seeing was opposite, which was surprising and something that I couldn't find anywhere else in the literature. And so that was the jumping off point for that whole project exploring what that plasticity was, how it was happening, and where it’s coming from.
From there, I was able to determine that this plasticity was occurring at a specific input from the periaqueductal gray inhibitory cells onto the VTA dopamine cells. This was in direct contrast to another major input called the rostral medial tegmental area, which those inhibitory cells with the exact same stimulus do depress like a normal synapse would. So, I found this bidirectional modulation of plasticity based on different input regions to the VTA dopamine cells.
Looking more deeply, I found that the periaqueductal input to the dopamine cells was regulating immobility behavior, whereas the rostral medial tegmental input was regulating aversive responses.
Bringing it all together with my interest in drugs of abuse, I looked to see if opioids affected the plasticity, and found that opioids blocked potentiation. I was able to show that if you give opioids prior to doing the stimulus, the low frequency stimulus, you can completely block the induction of the plasticity of the periaqueductal gray synapse on VTA cells.
CI: Can you talk about how you're defining plasticity?
RS: Here, I’m defining plasticity at the more granular, molecular level than when you hear about plasticity in the media. Synaptic plasticity is the temporary weakening or strengthening of the communication between two cells. For example, if you're increasing the strength of the input between the periaqueductal gray and the VTA, and if that pathway controls immobility behavior, then that behavior might be upregulated. So, you might have a stronger generation of that behavior the next time that it occurs.
CI: What’s been your path since you left grad school?
RS: Since then, I've been working on obsessive compulsive disorder (OCD), first at the Gladstone Institutes and now at Stanford. Psychiatric disorders are particularly interesting to me for the same reason that drugs of abuse are, in that there are some changes in the brain that are disrupting these systems that normally work so well, and we don't fully understand what the changes are.
I had narrowed down on this one part of the amygdala called the intercalated nuclei of the amygdala (ITC) which is a set of inhibitory cells that hadn't been looked at through the lens of OCD as far as I can tell. It's a bunch of separate clusters that surround the rest of the amygdala subregions. They have a very dense expression of the mu opioid receptor and there’s the possibility of opioids being able to enact changes there strongly because of the dense expression.
We also know that this area regulates fear learning, extinction and — of particular interest with respect to OCD — negative reinforcement learning.
CI: Like washing your hands repetitively or turning a doorknob to keep bad things at bay?
RS: Exactly. It's adaptive to wash your hands to get rid of germs. You have germs on your hands, you go to the sink, you wash them, germs are gone; you extinguish the response to the negative stimuli. In people with OCD, there's a deficit in stopping the behavior even though the actual threat is now gone. So, you're unable to extinguish the behavior of the negative stimulus.
We don't think that one brain region is solely responsible for OCD; we think many different brain regions have changes that are leading to the disruptions that we characterize as OCD. My idea was that perhaps in this ITC region, something is being disrupted and is leading to some of the deficits that we see in negative reinforcement extinction.
To investigate this, we explored two questions. First, if you take a mouse that's genetically altered to have an OCD-like phenotype, is there a deficit in negative reinforcement extinction? Second, in those same mice, can we shift their behavior by altering the activity of the ITC cells?
We used two groups of mice: a healthy group and another group whose Sapap3 protein has been genetically deleted. There's some link between the Sapap3 protein and OCD; mice with this mutation exhibit repetitive grooming and anxiety. I implant light fibers into their ITC, and I put optogenetic proteins into their cells that I can either silence or activate the ITC cells. Using a series of stimuli — including warning tones, sugar water, a shock plate, a refuge area — I found that the OCD mice were generally more avoidant, staying on the refuge platform even in absence of the negative stimuli. But if I block the activity of the ITC cells, this manipulation brings them back down to the level of the healthy mouse, which means that you're essentially treating them. You're able to overcome this disruption they have in their brain circuit and get them to perform like a normal mouse in the task.
On the other hand, if I activate the ITC cells in a healthy mouse, they become more avoidant and spend more time on the refuge area, like the Sapap3 knockout mice. This tells us that ITC activity is important for the ability to discriminate between safe and threat situations, and adjust our behavior accordingly. Hopefully, this work can be informative in future therapies where we are trying to target specific parts of the brain for patients who happen to have deficits in extinction of responses to negative stimuli.
CI: You just competed in the Boston Marathon. How does running figure into your work?
RS: Aside from being the inspiration for my very first research project? Who knows, perhaps running is making my brain more plastic. I feel like running allows me to work through problems and experience my emotions – the good and the bad. Also, a lot of my best science ideas have come to me on runs. So, I think it helps me clear my mind and focus.