Using lasers and designer drugs to prevent risky decisions
Mike recently discovered that by stimulating the central amygdala in the brain with lasers, using a technique called optogenetics, we are able to induce compulsive behavior in rats.
When asking the rat to choose between two identical rewards, a sugar pellet and an identical sugar pellet, Mike’s lab discovered that when one of the sugar pellet rewards is associated with laser light stimulation to the central amygdala, the animal becomes obsessed and compulsively chooses the reward with the stimulation up to 95–100% of the time.
In fact that sugar pellet becomes so much more valuable that the animals are willing to carry on lever pressing for one sugar pellet that’s paired with the laser light stimulation to the amygdala despite the alternative option of giving them ten sugar pellets for the same amount of effort.
I caught up with Mike to talk about optogenetics, drug receptors exclusively activated by designer drugs, and where this field is headed. You can read more about his current projects here.
Cindy Wu: Mike, tell us about who you are.
Mike Robinson: I was born in France, from British parents. I lived there for 18 years. And it is through international school there and education there that I got an interest for understanding the mind and psychology. That led me to go into the UK at the University of Sussex where I studied a Bachelor’s in neuroscience.
I realized I was still interested and was thirsty for more knowledge in studying how the brain worked. From a variety of surprising twists and turns, I found myself moving to Montreal, Canada to get a Master’s and Ph.D. in behavioral neuroscience from McGill University. I did my thesis on examining the impact of how we could modulate memory through a process called reconsolidation. I studied how we could affect old memories and weaken their impact on behavior to reduce the impact of associated with drug taking. We were interested in how we could reduce their ability to trigger relapse in addicts.
My interest in addiction developed over the years. After that I went to the University of Michigan where I did a postdoctoral fellowship with Kent Berridge who established one of the critical theories underlining our current understanding of reward and motivation, specifically the divide between what we call ‘wanting’ and ‘liking’. We can ‘like what we want’ and ‘want what we like’, but especially in the case of addiction, those two things become dissociated. We tend to want things more than we end up enjoying them. This explains a lot of the misery that’s associated with addiction.
After my postdoctoral fellowship, I started a position at Wesleyan University as an Assistant Professor in both Psychology and Neuroscience and Behavior in January of 2014. This is where I run my lab looking at the motivation and reward, which examines many of the undercurrents that unify different forms of addiction most notably drug addiction, gambling, but also diet-induced obesity.
When you were an undergraduate what was your first, what, what was your first research experience?
So surprisingly my first research experience had nothing to do with animals or addiction. Due to unfortunate events (two faculty in the department passed away when I needed to find a mentor) I found myself doing very fun and unlikely research using eye tracking devices to understand how we acquire targets in the shoot ‘em up video game called “Point Blank” that was quite the rage back in the day.
I essentially took a big leap of faith when I went off to McGill as I hadn’t worked with animals and hadn’t done any of the work that was there, but I deep down knew that it’s what I really wanted to do.
Did you go to McGill because you wanted to work with a particular faculty member or because of the program?
I went for a variety of things.
I went for the research topic, the idea of seeing if we could affect memory to change people’s impulses.
It was research that had re-emerged in the early 2000's and has given some good treatment opportunities, on both rewarding and aversive memories. This includes the drug addiction point of view, where it might be used to attenuate drug and cue-induced cravings, and also includes the negative side such as treatment for post traumatic stress disorder.
The other attraction was the ability to go to a place that was a new exciting experience. Going somewhere where I could speak both French and English was personally something important to me.
The last thing was the P.I. I was working for, Keith Franklin. He was a big name in the field and was one of the co-authors for the most commonly used brain atlas for mice. He was also an incredible mentor.
And when did you decide that being a professor is what you wanted to do?
It’s been a slow process. I wasn’t one of those people who in my late teens said I want to be a Professor. I am more driven by trying to live in the now and be excited by what I am doing at the moment and seeing where that would take me.
I was excited by my undergraduate experience. That gave me a big thirst for knowledge that French education had failed to instill in me. I came to the end of that and was still thirsty. My response was after finishing my final exams in undergrad was that I wanted more free time to sit in the library and just read books on the brain and addiction. That really told me I should be doing a Ph.D. So I set out to do that, not necessarily knowing where that was going to lead. Over the years I realized I that I’m still hungry, I’m still thirsty for knowledge, and I still want to solve problems.
That led me to doing the post-doctoral fellowship. That experience helped me enrich my research and perspective, and taught me new techniques, most notably learning how to do optogenetics. I had fabulous mentorship from both my Ph.D. and post-doctoral advisors, and I don’t think it I would be the researcher I am today if it hadn’t been for them.
Coming to the end of my training I also realized that I love teaching. Going to graduate school I got multiple opportunities to TA and really loved teaching. I got a rush from it. I loved inspiring students, seeing their eyes light up. I knew I wanted to do more of that. I knew I wanted to carry on answering questions.
I love the idea that my life as a professor and researcher is never repetitive. You are always finding a new question, even if you use the same techniques. You can go into work everyday knowing that it’s a new day and there’s something new. It is constantly moving forward and exciting.
That’s a great answer. Tell me more about this current project that you have on experiment.
We now understand that the brain works more like a pathway rather than just a set of neurotransmitters inside of a particular brain area. There seems to be a pathway that’s involved in making our behavior’s compulsive. In a normal situation, our life is surrounded by a variety of rewards some that are immediate rewards, some that are long-distance rewards. Whether it’s grabbing a donut or going to study for a degree and get fulfillment, all of those are a variety of rewards we get to choose from on a regular basis. We get to make the decision. Should I go out with my friends or should I study? Should I stay in and work out or should I go out for dinner and spend time with my family? Whatever it may be, we are constantly making choices.
Those choices are generally evenly spread. Whenever we make a decision in one direction, we tend to even things out over time and choose something else next time a similar choice comes up. That way the rewards we go after tend to balance themselves out. However, we see a problem when the decisions we make become exclusive and compulsive. Once we start choosing one reward over and over again at the detriment of others, that’s when we start seeing problems emerge.
This is not necessarily just about drug addiction because we see this same behavior in craving and wanting for a variety of rewards. Whether it’s gambling, food addiction, compulsive over-exercising, or internet gaming, it’s when the reward and fulfillment that we choose in our life is consistently the same that we start seeing problems in our behavior. The behavior starts impacting other areas of our life and we start developing a sort of personal misery and unpleasantness. It is this dissatisfaction with everything else where people start running onto problems with the law, losing their jobs, losing the connections with their friends and family.
What I do is try to see a way to understand what makes those decisions impulsive. We’ve found an area of the brain that seems to trigger that. This area seems to impose compulsive choice of otherwise equivalent rewards.
In our case we use optogenetics, or laser light stimulation, to activate a certain area of the brain in animals which is the central amygdala. This area makes the animal compulsively choose between two identical rewards. In our experiments, the rewards are acquired by pressing a lever to get a sugar pellet or pressing another lever to get an identical sugar pellet.
Yet somehow, the same sugar pellet becomes different. When the lever pressing and sugar pellet reward is associated with laser light stimulation to the central amygdala, the animal becomes obsessed and compulsively chooses the reward paired with the stimulation up to 95–100% of the time. This is despite the fact that the outcome is the same.
That compulsive behavior seems troublesome and seems to share a lot of the same qualities that we see in drug addiction. We’ve recently shown that that animal will chose that pellet outcome paired with laser light stimulation to the central amygdala, even if it’s associated with increasing adverse consequences such as a foot shock, having to work harder to get it, or having to wait longer and longer to get that reward.
Somehow with the laser light stimulation, that reward has increased in value where it is better than the same exact sugar pellet that would be acquired from the other side. In fact that sugar pellet becomes so much more valuable that the animals are willing to carry on lever pressing for that laser-paired sugar pellet at very high rates despite the alternative lever option giving them ten sugar pellets for the same amount of effort.
This reward somehow becomes at least ten times better and that gives us the idea that it can beat out any other kind of rewarding opportunity in life, as does drug taking or gambling. What we want to try and achieve through our studies to see if we can find the areas of the brain that temper this behavior, that reduce this compulsive urge, so that we can increase their activity and attenuate addition-like behavior. What we want to know is: Can we turn these urges down? Can we modulate them? Can we turn them off?
We’re looking at activating parts of the prefrontal cortex, the reasoning and decision making areas to sort of say, “no that’s not a good choice, turn back and reassess”. We think that through that we can create new treatment strategies that will help cure various forms of addictions or at least help addicts deal with the cravings they have and make abstinence a more likely outcome.
Can you explain optogenetics in more detail?
Optogenetics is a very cool technique, which is driven by the idea that at the back of our eye, in our retina, we have these photoreceptors that have this fabulous property of transforming light energy of different wavelengths into neuronal activity, or electrical activity that neurons use to communicate.
What has been done by some amazing bioengineers at Stanford and MIT was to take this ability of photoreceptors and harness it.
Essentially take the genetic code (DNA) for that photoreceptor and put it into a viral construct, which allows us to deliver it to certain cells in the brain or anywhere else for that matter. We can then put this DNA into neurons in some part of the brain, the neurons will then act like this DNA is their own and start expressing photoreceptors on their cell surface.
Now, the brain does not normally have light in it, so we can deliver light using LEDs or lasers. Simply just by flashing pulses of light we can control those neurons and turn them on and off at a specific time and at a certain rate and intensity. That allows us to control parts of the brain. We’re able to understand exactly what happens when we turn on or turn off that part of the brain during a certain behavior. That allows us to really get at mechanistic principles and pathways involved in these complex behaviors.
So in order to shine that light on the brain do you have to add an implant to the animal?
The way we do it is we use a painless technique which is to basically take a very thin optic fibers, measuring only a few micrometers in diameter, that we introduce into the brain of the animal when the animal is under deep anesthesia during the surgical procedure. That allows us to basically deliver that light to a very specific place. Now the light is absolutely painless. You can harmlessly shine that laser light on the palm of your hand. It is not the type of lasers we use to cut materials, it’s just intense and focused light of a particular wave length.
Do you have to open up the head of the animal?
“Open up” makes it sound more traumatic than it actually is. We drill a tiny little hole, a microscopic hole, in part of the skull and insert the optic fiber into the brain. It’s no different than some of surgeries that we do in humans. Specifically, deep brain stimulation is currently used in humans and is a very similar technique to what we’re doing. Deep brain stimulation is used as a treatment to stimulate areas of the brain that are problematic in some diseases such as depression, Parkinson’s disease, or obsessive compulsive disorder.
I see. Let’s talk more about this new research project. You’re raising four thousand dollars. What will you and your students be able to complete with this budget?
We need to get the hardware, including some lasers to use the optogenetics technique in a manner that will allow us to get enough results to publish and present our results to the world. We also want to see if we can use another technique which we call DREADDs for influencing activity in the brain, to see if we can pinpoint the area of the brain that might be capable of turning down those compulsive choices and almost possibly turning off those compulsive choices entirely.
DREADDs stands for Designer Receptors Exclusively Activated by Designer Drugs. Tell us more about how DREADDs work.
We now understand that the brain is made up of pathways of neurons that communicate by using a variety of neurotransmitters systems. These are the neurotransmitter systems that most pharmaceutical drugs target when trying to restore some kind of balance. But these neurotransmitters systems appear in multiple places in the brain and have many different functions, which explains why most drugs are accompanied by unwanted side effects. But what if we just want to use a certain part of a system and investigate exactly what that particular system is doing? Can we create our own neurotransmitter system and install it in the brain?
To address this, scientists recently designed a receptor that is not one that exists naturally in our body. This engineered receptor, or designer receptor as the name of the technique indicates, can be inserted into the part of the brain we want to modulate, the area we want to activate or inhibit. And then, we can use a designer drug unique to this receptor to modulate that specific part of the brain.
So we can then inject or ingest a drug into the body as a whole, which makes it a lot less invasive, and that drug will course around the body but only ever interact with the specific engineered receptors we placed on particular cells in the brain. The drug otherwise inert, it does nothing anywhere else in the brain and body, and only targets that specific designer receptor. It allows us to create a micro system within the brain to help us uncover some of the deep dark secrets that the brain holds.
What is the drug that is used?
It’s one specific drug. The drug is called CNO or clozapine-N-oxide. If you were to take a pill of CNO, it would do nothing to your system. It would just travel through your body and be flushed out. However, we’ve been able to engineer different types of designer receptors that either activate or inhibit certain cells briefly or for longer periods of time, all of which are responsive to this drug CNO.
What this DREADDs technique enables us to do, is to implant this designer receptor system within an already existing neurotransmitter system in our brain. We can for example target the dopamine system and hijack or co-opt this system in order to understand how those cells affect motivation and reward.
How does the DREADDs system affect the host?
You can think of your neurotransmitter systems as being a lock and key mechanism. Whereby receptors are the lock and your neurotransmitters are the key. Using DREADDs, you would essentially be installing a second set of locks on all these doors. So it’s like thinking of the brain as a hallway with a large number of locked doors, where you can decide to put a new lock on a given door, for which only you have the key. The original lock is still there and it will still be accessible through the original key, but you now have your own master key for that door, so that you can open up this system to understand its workings.
So in your case, you end up adding locks to the pathways involved with motivation and reward, and are able to turn on and off these pathways using the drug clozapine-N-oxide? And without adding any locks the drug has no effect on the host?
That is amazing. I have so many more questions, but we need to wrap up this interview. Last two questions. If you could give a piece of advice to a younger version of yourself, what would it be?
I honestly feel like I’ve been particularly blessed throughout. Getting to where I am, it’s been a lot of work and it’s been a struggle at times, but I don’t think it could have turned out any better than it did.
If I was looking at a younger version of myself, I would say don’t hesitate to have fun in between. Remember how breaking up hard work with fun can help you be just as productive in the long run.
When you were a kid what did you want to be when you grew up?
When I was a kid?
As a kid the thing I wanted to be more than anything was I wanted to be a parent. I think in some ways that meant I wanted to foster and support other people. And, I think that speaks to my interest in teaching, educating, and mentoring the students in my lab, to bring out the best in people in some way, to excite them, to help them make their dreams come true.
Are you a parent now?
Yes, I’m currently a parent of two lovely young daughters of three and one years.
If you want to ask Mike additional questions about optogenetics and DREADDs, you can do so on his Experiment. Mike is raising $4,000 to complete his experiments confirming his results for publication and putting together a set up for the DREADDs system. You have a few days left to support his work here.