If you saw a mouse with a device attached to its head and a scientist using remote control to make it spin around in circles, what would you think? Don't be fooled by first impressions. DW spoke with those scientists.
In a paper published in the journal #link:http://www.cell.com/cell/abstract/S0092-8674(15)00828-4?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867415008284%3Fshowall%3Dtrue:Cell# last week, Washington University neurobiology researchers Michael Bruchas and Jordan McCall have demonstrated ability to manipulate the brains of mice. This alone shouldn't surprise the scientific community, nor even the general republic. Add a remote control device and extremely selective manipulation of neuronal activity, and the element of surprise - perhaps even shock - is there.
The experiments concerned the locus coeruleus, the population of cells responsible for secreting norepinephrine and controlling stress and anxiety. Using the techniques of optogenetics and chemogenetics, as well as a device designed to administer photo stimulation and chemicals inside the mouse brain, the scientists were able to inhibit anxiety (decrease firing in the locus coeruleus) in situations where the mice were stressed, but also to induce anxiety (increase firing in the locus coeruleus) in situations where no external grounds for stress were present.
DW: What do these experiments show?
Michael Bruchas: What we were able to do was to control those neurons, artificially, and show that when you control them using an optogenetic strategy, you're able to drive their behavior in the absence of stress in a similar way to the way stress does. What this shows us is that this brain structure, in particular these noradrenergic neurons, are sufficient to create this anxiety-like state.
The converse experiment was that we inhibited those neurons in stress and showed, using a selective technique called chemogenetics that allowed us to nail down that those particular neurons were involved, that they don't display this behavior in response to stress.
So you induced behavior with light stimulation, and inhibited behavior with chemicals?
Jordan McCall: Yes. The two of those together linked and allowed us to make the conclusion that these neurons [in the locus coeruleus] are necessary - and sufficient - to produce this stress-inducing anxiety-like state in an animal.
DW: Before we get bogged down in the mice, you have said that your ultimate aim with this research is to make advancement in human mental health. What fundamental advancements do you have in mind?
Michael Bruchas: We want to uncover the mysteries of how the brain functions to code behaviors, motivation in particular, and within that, we know that various stress states or environmental conditions or genetic attributes of individuals can shift the balance of good stress being motivating to stress that leads to things like panic attacks, PTSD, depression, anhedonia, relapse to addiction. What we're trying to do now is uncover how the brain is shifting the homeostasis. But before we proceed to the human brain, we need to know how this happens in a naïve animal, in particular how various environmental conditions or stressers impacting neuronal pathways.
DW: From making mice turn left and right to curing human depression - just how big of a jump is that?
Michael Bruchas: Yeah, this is an important point. Let me just say that the demonstrations we have done with mice are mostly functional demonstrations. We typically choose simple tasks, such as motor skills, in order to have the most likelihood of dynamic range to see an effect - to see that the technology works.
DW: Your research has met with reservations, in particular from neuroethicists, who ask whether you've considered the future moral redlines your work could be crossing - without knowing it now. How do you respond to people who say your work is something of a #link:http://www.thedailybeast.com/articles/2015/07/25/this-device-brings-brave-new-world-to-life.html:respirator for our world's mind control dystopias#?
Jordan McCall: I think mind control is a very strong term when used with regard to our work. What we've done here hasn't really pushed mind control any further than what groups have done for the last half century. We are delivering drugs into the brain, which is manipulating the activity of these neurons but not in a fashion that we really have complete control over. Our ultimate goal is to relieve symptoms of disease states better - and not to take actual control over the brain.
By adding a fluidic component to a medical device, we might be able to refine some of the treatments to make them more effective.
DW: So it's like an insulin pump therapy for a diabetic - now the injections are easier?
Michael Bruchas: That's an apt analogy. Building on what [Dr. McCall] was saying, which I think is really critical, in fact we're really actually trying to achieve almost the opposite of brain control or mind control. In present reality, a lot of people take a drug, they swallow the pill, the pill is metabolized and it goes to a variety of places in the body - essentially wherever that particular compound has an affinity for a target. This results in side-effects throughout the brain - in different regions than were maybe the intent.
We are hoping that by better understanding the brain circuits and coupling this with parallel development of better technologies, that eventually we will be able to more discretely target subpopulations, so that you don't have these other effects that could be deleterious - for instance when you take morphine, or antidepressants, or alcohol. Ultimately we are looking for way to more selectively target, and this would have less global impact on the brain - we hope.
DW: Returning to ethics, though, what role does it play in your work? Do you think about ways your discoveries could be used - or abused - in the future?
Michael Bruchas: I think the ethics questions are super important. I don't ignore them. Our laboratory group has regular active discussions, and we have all gone through formal training. Both students and postdocs are required to attend and participate in ethics discussions, both through case studies and formal didactic training [… ] You don't want to not be thinking about these things before it's too late, and we certainly take this seriously.
Jordan McCall: You have to have concerns every time you develop new technology, whether it's for biomedical applications or otherwise. The best, I think, we can do is to help develop technology that we believe will be helpful and beneficial for mankind, and do our part to keep it out of the wrong hands. But ultimately, technology of any kind can be used and abused, so we, both as scientists and members of society, have to keep an active eye on that going forward.