William Griffith, PhD, Regents Professor and head of the Department of Neuroscience and Experimental Therapeutics at the College of Medicine, shares his research on the aging brain and how the developing field of optogenetics may help us better understand brain trauma.
Christina Sumners: Welcome to Science Sound Off. I’m Christina Sumners.
Tim Schnettler: And I’m her cohost, Tim Schnettler.
Christina Sumners: We are here today with Dr. Bill Griffith. He is the department head of the Department of Neuroscience and Experimental Therapeutics at the College of Medicine, and he’s a regents professor who studies neuroscience, in broadest terms. Neuroscience is obviously a big field. What, specifically, do you study, Dr. Griffith?
Bill Griffith: Well, I’ve been studying how cells talk to each other, communicate with each other. So, it’s synaptic transmission and how neurons, or the properties of neurons, what makes them fire, what makes them connect to each other and build circuits. So, we’ve been doing that for 30 plus years, and it’s one area of neuroscience that involves electrophysiology. That’s electrical recording of nerve activity. We do that in several different preparations, often ex vivo, and then record activity and test drugs. Specifically, my main interest has been studying age-related changes in neural activity for the last 25 years, because we all have relatives or friends that are sharp as a tack into their 90s, and then we also know individuals that are impaired much earlier than that. So, why do some individuals age well and some individuals age poorly? We just don’t know that, so we hypothesize that it had to do with neuronal properties and synaptic transmission and circuits.
Christina Sumners: So, the brain really is just basically a system of circuits? It’s neurons, it’s synapses, the spaces between them, and-
Bill Griffith: People that study neurons like to think that, but then there’s the individuals who study glia and all the support cells that, nowadays, are becoming increasingly important because of inflammation and all the control mechanisms that support neurons. That’s equally as important nowadays. But yes, historically, we thought the brain just contained neurons; that was the important part. But actually, it’s much more-
Christina Sumners: It’s the whole system, yeah.
Bill Griffith: It’s the whole system. I’m biased. I lean towards the neurons, but there are all the support cells as well.
Christina Sumners: So, as we age, different inflammation, you were saying, can happen, and different neurons can have different issues. What, specifically, are you looking at in the aging brain?
Bill Griffith: Okay, we’ve been looking at what makes neurons tick, essentially, how they function, some of the basic properties early on, and specifically, ion channels. So, these are channels in the membrane. You can have voltage-gated ion channels or chemically-gated, ligand-gated ion channels. So, we study both, and specifically, we were looking at age-related changes in ion channel function. We did that for many years, and then we focused on calcium changes, because back in the mid-80s there was a calcium hypothesis for aging, because it was thought that calcium homeostasis, intracellular calcium homeostasis, was disrupted. It’s pretty well-known that if you don’t have a proper concentration of calcium in cells that can be detrimental, and cells will degenerate and die.
So, we were interested in looking at do calcium currents change, and what we found was that, surprisingly, the current doesn’t change a great deal, but the cell’s ability to buffer the calcium once it goes into the cell… Age cells had an increased rapid buffering. You might say, “Well, who cares?” Or, “Why is that important?” It’s because we found… So, when we did behavior on these animal models, we could test cognitive impairment in several different… There’s Morris water maze test, and there’s a Barnes maze test, which studies spatial memories. So, what we found was that during aging, some animals become cognitively impaired, and some don’t. That’s just like when we talked earlier about some individual humans age well, and some do not. We were able to study calcium homeostasis in the two populations, and we found there was a correlation between increased calcium buffering and cognitive impairment.
Christina Sumners: Okay, so what does that-
Bill Griffith: Mean?
Christina Sumners: … mean? Yeah.
Bill Griffith: We didn’t know for… We’re still not 100% locked down on what its meaning… But intracellular calcium changing in the sense of rapid buffering increases, and that seems to be detrimental. So, we thought, how could we change that? Could we correct that?
Christina Sumners: Sure, with a drug or something, yeah.
Bill Griffith: Right, so today, one of the best anti-aging mechanisms, or I don’t want to say drug, would be caloric restriction.
Christina Sumners: Fasting, basically.
Bill Griffith: Fasting, so we do… We’ve done experiments where we took lifelong calorically-restricted animals, and they don’t show that increase in calcium buffering, or it reverses that. We’re currently doing intermittent fasting.
Christina Sumners: That’s the hot trend, yeah.
Bill Griffith: That’s the hot trend right now, and surprisingly, you can do it late in life, and it also seems to be beneficial and is correcting that change in calcium.
Christina Sumners: That’s fascinating.
Bill Griffith: So, how we translate that to humans, we’re not quite there yet, okay, but… Or pharmacologically, we haven’t gotten there, but there seems to be a relationship between increased calcium buffering, maybe detrimental. If you think back to what I said in the very beginning, people thought that there was a calcium hypothesis of aging, that too much calcium was detrimental. So, intuitively you would think that, well, if you increase intracellular buffering, it’d be a good thing, but it maybe is too good; it buffers too much. We’ve looked a long time for the caveats for intercellular organelles like mitochondria, ER, and that doesn’t seem to explain the rapid buffering.
Tim Schnettler: This is such a fascinating area of work. Can you tell us a little bit about how you got involved? Is there a family history that led you into this, or what was the reasoning behind getting into this area of research? Anything like that?
Bill Griffith: My father passed away from dementia, probably Alzheimer’s, but we didn’t do an autopsy. But even before that, I was interested in the nervous system and how cells talk to each other and communicate in the circuits. Then, back in the early 80s, I got interested in Alzheimer’s disease. The part of the brain in animal models that die off in humans, these are cholinergic cells. They have acetylcholine as a neurotransmitter. So, there are nuclei in the brain, the base of the forebrain, that these cells die off in humans. So, I thought nobody studied these, really, in detail, so maybe that would be interesting. That was in the mid-80s, and I’ve been studying that area ever since.
Then it transitioned, because Alzheimer’s, obviously, was more complicated than just cells dying off, all the plaques and tangles and inflammation, and all where we are today. I sort of transformed into looking at aging, because why do some people age well, and some individuals don’t? That’s always been a fascinating question for me, and so I think the calcium story was sort of an initial observation that we took for quite a while, but then we went from calcium buffering to looking at how calcium influences synaptic transmission and the circuits, and that’s probably… I believe nowadays, that disruption of synaptic circuits is probably the final common pathway for many neurological diseases, age-related Parkinson, Alzheimer’s, et cetera. So, that could occur by many different mechanisms, but the final common pathway is a disruption of synaptic transmission.
Tim Schnettler: You mentioned how some people age and they’re sharp as a tack, and some don’t. That’s always been something that’s been fascinating to me, how that can happen, and it can be in the same family. I mean, your dad-
Bill Griffith: Siblings can…
Tim Schnettler: Yeah, exactly. I mean, it’s such an amazing concept to me.
Bill Griffith: I’m sure there’s nurture and the environment and genetics, but you can look at a lot of the genetic profiles, and that’s another big area that I didn’t even touch on, that many people do look for genetic analysis of neurological diseases. That’s very important. That’s a big component, but there is some environmental factor also, but it has always been interesting, why do some people in the same family age well, and some don’t? I think it’s all synaptic transmission myself, so…
Christina Sumners: Synaptic transmission, that just means the neurons can’t talk to each other, and so everything else kind of doesn’t work for you?
Bill Griffith: Right, so we have a sort of simplistic way. We have excitatory and inhibitory neurons in the balance. A lot of people are interested in the E/I balance. They call it the excitatory to inhibitory ratio. So, if you get an imbalance in that ratio, then circuits will start to break down, and so it’s not a simple synapse, but a lot of research nowadays… It’s approaching looking at very complex circuits and how those are disrupted.
Christina Sumners: Then that affects learning and memory and…
Bill Griffith: Right, so many of the behavioral tests that we can do study learning and memory and attention, and so we’re interested in the age-related effects that can occur.
Christina Sumners: So, you spent your career working on synaptic transmission. Are there any new techniques or technologies that are helping us better understand how that works?
Bill Griffith: There are new methods, and an exciting new method is called optogenetics, and… Step back for a second. Historically, when we would study synaptic transmission, we would record from a neuron, and stimulate electronically either a pair of fibers, or tried to stimulate selectively. But when you put an electrode in the brain, you non-specifically excite quite a few neurons. So, optogenetics was developed, and what that means is that it’s light-activated channels, so these are ion channels that are inserted into the membrane that allow cations, like sodium, calcium, and potassium to flow across the channel. That will excite a neuron, and it’s activated by specific wavelengths of light, so you can put many different kind of channels that are very specific, and they do that with a viral vector. Then you can target a certain kind of cell by putting a promoter before the viral vector.
We make a transgenic animal, and then prepare a preparation where we can have a brain slice record from a neuron, and then shine LED or a laser with a certain wavelength of light to excite, very specifically, a certain kind of neuron. Or, we could inhibit a certain kind of neuron with another opposite. So, these are natural light-sensitive channels that have been modified. There are some forms of blindness that are being treated in humans with optogenetics. They’ll insert the virus into the ganglion cells in the back of the retina, and natural light, in some cases, is enough to activate the channel rhodopsin, stimulate the ganglion cells, which form the optic nerve, and then we’ll… It’s not a perfect vision, but it’s a start, so that’s-
Christina Sumners: Yeah, can they see some light?
Bill Griffith: So, that’s in clinical trials right now.
Christina Sumners: Wow. So, it’s actually being translated into humans already. That’s incredible.
Bill Griffith: Our interest is the ideas that maybe someday we can have an implant that can be remotely activated to either excite or inhibit certain brain area to regulate activity. I mean, the easiest one you think about is for another age-related disease, Parkinsonism, and they have deep brain stimulation to help remove tremors. But with deep brain stimulation, you’re non-selectively stimulating many neurons.
Christina Sumners: Many different neurons, yeah.
Bill Griffith: Not just the neurons that you want.
Christina Sumners: That you want, so-
Bill Griffith: Hopefully, someone can design an implant that you could have a probe and stimulate with light only selectively what you want.
Christina Sumners: To have the same effects of stopping the tremors?
Bill Griffith: Yes. Right.
Christina Sumners: So, you were a co-lead on an X-Grant proposal that’s been recently funded. What is that? What will you be doing?
Bill Griffith: Well, this is an interesting grant, we think, because we’re trying to design a closed-loop system such that we not only can record brain activity, but when we reach some threshold, high or low, that we’ll turn on an optogenetic stimulation to correct that neuro activity. Simple example, and what’s been done before, is an epilepsy, okay, so you can monitor an animal with any number of ways, let’s say as simple as an EEG. Once the EEG reaches a certain threshold-
Christina Sumners: Threshold of spiking for epilepsy, yeah.
Bill Griffith: … activity… Right. That will be recorded, turn on a light, and then inhibit the activity. You can do that in a millisecond.
Christina Sumners: That’s so cool.
Bill Griffith: That’s been done in animal models a lot, and I think there are some therapies now being developed for humans, so ours is analogous to that in the sense that we were looking at… The main focus is not age-related, it’s PTSD and other-
Christina Sumners: Really? Okay.
Bill Griffith: … brain traumas, and we’ll have a closed-loop system. So, we’ll be able to record activity, which will then trigger the optogenetic pulse. So, our part will be to the engineer. Our colleagues have designed a remote, miniaturized… It’s about the size of your fingernail that can be implanted. What we’re going to do is study that in vitro, and then try to refine that activity.
Tim Schnettler: Let’s talk a little bit more about the X-Grant. You mentioned engineering, briefly. These X-Grants were designed to foster collaboration among departments within the university, so who are your collaborators on this project? Tell us a little bit more about the name of the project.
Bill Griffith: The name of the project is Developing an Adaptive Closed-Loop Optogenetic Stimulator Cloud to Treat Neurological and Psychiatric Disease. There are three co-leads: Steve Maren in psychology, who does a lot of in vivo behavioral work and some optogenetics in vivo; Sung Il Park, who is in electrical engineering, designed the original remote miniaturized optogenetic stimulator, and then myself, in neuroscience. So, the idea is that we have a remotely-activated optogenetic stimulator that we could stimulate, but we don’t have the recording setup designed to record a signal that will then, in turn, automatically-
Christina Sumners: Automatically stimulate the… Okay.
Bill Griffith: … stimulate the LED. He has a system that has multiple LEDs, so we can excite or inhibit, depending on the signal.
Tim Schnettler: That’s Dr. Park in engineering that has that?
Bill Griffith: Yes.
Christina Sumners: It’s the electrical engineering that is…
Bill Griffith: It’s the Department of Electrical Engineering, then in Department of Psychology, and then Department of Neuroscience and Experimental Therapeutics.
Tim Schnettler: How was this collaboration born? I mean, how did you all get together and do this?
Bill Griffith: Well, that’s an interesting… In the first round… This happens to be the second round of the X-Grant. In the first round, we actually both put in, Steve Marin and myself, separate projects, okay, and we used the same engineer.
Christina Sumners: As your co-operator.
Bill Griffith: So, we felt that we were working against each other, and so in the end, we decided let’s unite and we’d make a better product. Sure enough, it was funded.
Christina Sumners: Yeah. Obviously, that approach worked.
Bill Griffith: Yeah, we were doing very similar things with the same third party, so it made sense to do it that way.
Tim Schnettler: Yes, sir.
Christina Sumners: Put them together. Yeah.
Bill Griffith: So, what I’m going to do is work with the engineers for the recording piece of the puzzle, and that’s easier to do in vitro than before we take it to the whole animal. So, that’s the big picture, and then use that for a psychiatric disease like PTSD. Also, fear conditioning. I don’t know if you know what that is.
Tim Schnettler: Can you explain that for those that don’t?
Bill Griffith: Fear conditioning is when you learn or you have a stimulus that predicts, or you’re inclined to have a fear response in response to some stimuli. So, for diseases like post-traumatic stress disorder, something will trigger a fear response.
Christina Sumners: Even innocuous things that…
Bill Griffith: Yes, will a trigger response, so there are parts of the brain that… The amygdala, which is involved in that. So, you can train a subject to any number of ways to anticipate a fear response, okay, so the idea is that clinically, it would be great if we could detect that response, and then turn it off before it gets out of control. That’s the big picture, again. So, we can do that in the animal model.
Christina Sumners: And hopefully, eventually, in humans with PTSD.
Bill Griffith: There’s a small component of human work in this also, and that is sort of at the end too with brain scans. I don’t think we will get to using optogenetics, but more of the fear conditioning, et cetera.
Christina Sumners: So, the engineering component of this is really interesting to me. How are you going to be collaborating with them, and how does neuroscience and electrical engineering… How do they fit together?
Bill Griffith: Engineering is a very important component of medicine nowadays in general, and particularly neuroscience, and that’s only increasing. So, two main collaborators in engineering will be Dr. Park, who is the hardware expert and has designed the hardware, and then Dr. Yoon is the software. He will use machine learning tools to develop software that will take in the signals that we record, massage those signals into a way that we can use them to excite or inhibit through the hardware. So, we have two components of engineering, hardware and software, in our X-Grant, and we hope to, like I said, do first the in vitro work with my lab, and then take it to the whole model.
Christina Sumners: Well, thank you so much, Dr. Griffith, for being with us today. It’s been great to talk to you.
Bill Griffith: Well, you’re welcome. I enjoyed it.
Christina Sumners: Thank you all so much for listening to Science Sound Off, and we will see you next time.