At the Lab Season 1 Research Rewind: Neuroscience

Transcript

Sara Giarnieri: You’re now At the Lab with Cold Spring Harbor Laboratory. My name is Sara Giarnieri.

Nick Fiore: I’m Nick Fiore.

Luis Sandoval: I’m Luis Sandoval.

Caroline Cosgrove: I’m Caroline Cosgrove

Sam Diamond: My name is Sam Diamond.

Sue Weil-Kazzaz: I’m Sue Weil-Kazzaz.

Sara Giarnieri: And this week At the Lab we’re recapping all of our episodes from Season 1 that focus on CSHL’s innovative neuroscience research.

{Music}

SG: How does the brain control the body? How does it shape our behaviors and perceptions? We’ll explore each of these questions and more with the help of Cold Spring Harbor’s neuroscientists. For now, let’s start with a song.

Nick Fiore: Listen closely.

{A mouse ‘sings’ at a very high pitch.}

NF: Hear that? How about this?

{Another mouse responds at an even higher pitch.}

NF: These are the vocalizations of a special breed of mouse known as Alston’s singing mice. They got the name because they tend to communicate through a kind of call-and-response with differing tempos.

NF: While the sounds of their songs are unusual, it’s the tempo that fascinates Cold Spring Harbor Laboratory neuroscientist Arkarup Banerjee. Here’s Banerjee.

Arkarup Banerjee: There are many instances where as humans we have to do the same action but at different tempos. So, for example, I can suddenly slowww dowwwn the rate at which I’m talking to you. Or you can imagine a piano piece being played either faster or slower. So the question is, well, how does the brain do it?

NF: Our ability to naturally pick up the rhythm of conversations is central to our social interactions. Banerjee’s team studies Alston’s singing mice to answer the question of how our brain manages communication and other important activities.

NF: Figuring this out might provide us with a better grasp of neurological conditions like autism spectrum disorder and even strokes. It also might help explain how time is perceived and processed in the human brain.

AB: It’s this three-pound block of flesh that allows you to do everything from reading a book to allowing humans to send people on the Moon. It provides us with flexibility. We can change on the fly. We can adapt. We can learn. If everything was a stimulus-response, with no opportunity for learning, nothing that changes, no long-term goals, we wouldn’t need a brain.

{The mice ‘sing’ in concert with one another.}

NF: Banerjee’s research may bring us closer to understanding how this incredible block of flesh enables us to interact—both with each other and with our physical environment. What that might mean for science and society is as unlimited as our imagination.

{Music}

Luis Sandoval: Dating is complicated, even for fruit flies. The male fly tracks and woos potential partners by making “music” or vibrations with his wings. But how does he know the right song to sing? How does any animal? How do we?

LS: That’s one thing CSHL Assistant Professor Benjamin Cowley is trying to figure out. More precisely, he wants to know how visual stimuli drive the brain to execute rich and complicated behaviors. And fruit fly courtship is a great place to start.

Benjamin Cowley: Typically in nature, it happens really fast, like 5 seconds. In laboratory conditions, we can optimize it so that it’s not so quick and can last maybe 30 minutes, which is an insanely long time in the lifespan of a fly. This is like a 24-hour date at Starbucks. That gives us a lot of rich data to be able to see this courtship behavior unfold.

LS: Using this data, Cowley’s team built a special AI model of the fruit fly brain that can accurately predict how a real fruit fly will act in response to any sight of a female. In doing so, they found that the fruit fly brain depends on a collection of neurons to process visual information.

LS: Beyond fruit fly dating apps, Cowley’s AI could have curious real-world applications. For one, it could help prevent invasive insects from wrecking farmers’ fruit crops—a big problem out West.

BC: The trick is to release a bunch of sterile males to court with these females and then, when they produce their thousands of eggs, these eggs will not hatch. And that culls the population. So you can imagine if you can make more Don Juans, more of the ladies’ men, you’re going to be more effective at this.

LS: Cowley is hopeful his team’s new AI model will someday help us decode the computations underlying the human visual system. With any luck, it might also reveal the secret to the perfect date.

{Music}

Caroline Cosgrove: When it comes to sex hormones, most people associate men with testosterone and women with estrogen. And there is some truth to that. But, according to CSHL neuroscientist Jessica Tollkuhn, the whole truth isn’t so black and white. In fact, it’s not really pink or blue, either. Here’s Tollkuhn:

Jessica Tollkuhn: A lot of people, even neuroscientists, are not familiar with this idea that in rodents, estrogen is actually masculinizing for the brain. This is really counterintuitive. The testes make testosterone. The ovaries make estradiol, which is the principal estrogen. But you can treat females with estradiol on the first day of birth, and they will grow up and will be territorial like the males. They still have female physiology. They’re still cycling. They can still have babies. But their brain is permanently masculinized by seeing estrogen early.

CC: This has been known for decades. What scientists didn’t understand is how a temporary hormone surge can have lifelong effects. Today’s advanced technologies have made it possible to see what’s going on at the cellular level. Tollkuhn’s team zeroed in on a particular part of the mouse brain and then went even deeper.

JT: So, there’s kind of two questions. Where are the hormone receptors binding? And then how does this relate to sex differences in the brain?

CC: Tollkun’s team was able to identify the specific genes under estrogen’s control, including many involved in brain development.

CC: Now she’s exploring the roles these genes play later in life. Her work may one day lead to new hormone replacement therapies or treatments for neurodegenerative diseases like Alzheimer’s. But it’s also eye-opening in another way. It suggests that brain sex is the product of fluctuating hormones rather than unchanging sex chromosomes.

JT: If you consider that there’s variation in hormone receptors and hormone levels and the target genes of hormones just across individuals, then you can imagine there’s this whole rainbow of different ways that the brain can be differentiated. There’s always a question of what can we learn about ourselves? Where does personality come from? So yeah, I’m excited to keep working on hormones and how they affect different aspects of the brain.

CC: And we’re excited to see what she comes up with next, At the Lab.

{Music}

Sam Diamond: It’s one of humanity’s oldest arguments. Are we solely the product of our genetics? Or is it our upbringing and surroundings that determine who we are? Today, we understand that the answer is a bit of both.

SD: What we don’t know is precisely how this works. How do nature, in the form of our individual biological makeup, and nurture, in the form of environmental and experiential factors, interact during our brain’s development?

SD: That question is central to the work of CSHL Assistant Professor Gabrielle Pouchelon. To answer it, she starts with our earliest neural connections.

Gabrielle Pouchelon: In mice, they happen during the first week after birth. So, right after birth, they’re highly connected to their sensory system. And that is also very important because we’re not yet able to create sensorimotor action to integrate the world. But we’re definitely receiving all those sensory inputs.

SD: Pouchelon’s team identified a specific protein that helps regulate the timing of the mouse brain’s early neural connections. Importantly, these connections are temporary and highly dynamic.

SD: That’s critical because it means the brain can adapt to minor mishaps in development without a significant impact. In fact, that’s exactly what Pouchelon’s team observed. When the timing of these connections was altered in mice, the resulting changes were so minute they were hardly detectable.

GP: Indeed, there is no huge defect. They run fine. They explore the same way. And it’s only when we take all of those little behavior sequences and look at them together that we see a difference. So, what we see is nothing that we can interpret as dysfunctional. We can just say that they use their system differently.

SD: Sound familiar? While Pouchelon’s research does not directly connect this atypical behavior with autism, she is willing to speculate that disruptions in the timing of early neural connections could impact how we think and act later in life.

SD: And this speaks to an overarching theme of Pouchelon’s work. Long before we utter our first words, our genetic programming and environmental cues are in regular conversation—nature and nurture talking it out and always listening.

{Music}

{Mighty Mouse theme}

Sue Weil-Kazzaz: It’s a bird! It’s a plane! It’s … your mother!

SWK: Mother’s Day is around the corner. So, right about now, you’re probably A) realizing you forgot to buy a gift and B) recalling memories of childhood, like a time your mom picked you up after a bad day at school or a devastating dance recital or—well, you get the idea.

SWK: No matter what else she has going on, supermom is always ready to come to the rescue. This behavior isn’t unique to us. CSHL Professor Stephen Shea investigates maternal pup retrieval in mice as a way to better understand how mammals’ brains navigate all kinds of social situations. Here’s Professor Shea.

Stephen Shea: We all know that as human beings, it’s rewarding to touch another person, but we don’t know a lot about the mechanisms of that. We know a lot about how we find drugs and cake and fun rewarding. But we know far less about how we perceive social contact as rewarding. We’re interested in not only how we perceive that, but how we use that to modify future behavior.

SWK: In other words, how do supermoms know to come get the kids and why do they like it so much? Shea’s team found their answers in a part of the brain called the VTA. Here, they identified a group of neurons that release dopamine whenever a mother mouse picks up a crying pup.

SS: It’s a very ancient mechanism in the brain that mice and humans and many other animals share. Dopamine is important for motion and reward and motivation, but in this case, dopamine is actually instructing the behavior and reinforcing it.

SWK: The mother’s social contact with the pup feels, well, rewarding! This instructs her to continue picking up the pup whenever there’s a sign of distress.

SWK: Shea is now investigating how VTA neurons influence other social interactions. This might someday provide new insight into neurodevelopmental disorders and a better understanding of how our brains work.

{Cartoon narrator: Mighty Mouse!}

SWK: Oh, and remember to thank your supermom this Mother’s Day!

{Music}

Nick Fiore: In some ways, your brain is like the puppet master of your entire body. It pulls all the strings. But this week we’re looking at a specific part of the brain called the NMDA receptor.

NF: The NMDA receptor is a protein that plays a key role in learning and memory. It has two parts. There’s a globe-like head that binds natural chemicals or drugs. And there’s a channel that allows charged particles, called ions, to pass through.

NF: Now, here’s where the molecular puppetry really comes into play. It turns out that the head part opens or closes the channel much like a puppeteer controls a marionette.

Hiro Furukawa: We’re basically trying to figure out how proteins move. So what is the pattern of movement, which elicits opening and closing of the ion channel?

NF: That’s Cold Spring Harbor Laboratory Professor Hiro Furukawa. His lab figured out each step in the puppet master routine using a technique called cryo-EM.

HF: Cryo-EM stands for cryo-electron microscopy.

NF: Yes, that’s cryo as in cryogenic. Furukawa’s team flash-froze molecules in place at various points in the opening and closing cycle. Using many still images, they were able to construct a video showing just how the NMDA receptor opens and closes.

HF: Because we have such a state-of-the-art facility for cryo-electron microscopy that we established here at Cold Spring Harbor, we can image things at high resolution. The better the microscope, the better the sample, the more you see.

NF: But that’s not all. Furukawa’s lab imaged the NMDA receptor in the presence of various drug molecules that slowed or stopped the action.

HF: We’re basically just figuring out how the NMDA receptor dances around to open and close the ion channel. They literally dance around.

NF: The idea is that if researchers can figure out these dance steps, they can design drugs to control NMDA receptor activity. And that could someday help treat conditions like Alzheimer’s disease, depression, schizophrenia, strokes, and epilepsy—with no strings attached.

{Music}

{Intercom effect}

SG: Cleanup on IL-6.

SG: That’s IL as in interleukin. We’ll get to that in a minute. But first, another common expression.

SG: Say what you will about the phrase “mind over matter.” New research from CSHL Professor Bo Li suggests that the connections between the brain and body may in fact be tighter than expected. And that could have big implications for cancer medicine.

SG: Li’s study focused on a lethal disease called cachexia, most often seen in late-stage cancer patients. It’s one of those medical conditions you might already know about without knowing its name. Li explains:

Bo Li: It occurs in a lot of cancer patients. In fact, most people with cancer die of cachexia instead of the tumor itself. And if we can somehow prevent or treat this syndrome, it will allow the patient to survive longer. The patient can undergo other therapies to treat the tumor. So, I think it’s going to have a big impact for many people.

SG: The idea is that many patients who develop cachexia can’t stand up to chemotherapy, radiation, or even surgery. So, treating or preventing cachexia could help ensure that they can get treatment.

SG: But where does IL-6 come in?

BL: Yeah, it’s a great question. Cancer cachexia has been studied for a long time. It has been known that interleukin-6 is important, but people don’t know why. We set out to study whether it is important for engaging the brain during cancer.

SG: Li and his colleagues identified the specific neural receptors in the brain that IL-6 overstimulates.

BL: And this is critical for the development of cachexia.

SG: So, figure out how to target the IL-6 receptors and you may someday be able to stop cachexia. As amazing as that sounds, this could be the start of something even more remarkable.

BL: It gives us an example of how disease is influenced by the brain. Simply changing a small number of neurons in the brain has a profound effect on whole-body physiology. So, theoretically, it’ll give us some understanding of how the brain really interacts with the body.

SG: That understanding could change how we think about the whole human experience. Thanks, IL-6!

{Music}

SG: And thank you for joining us At the Lab. If you like what you heard, please remember to subscribe wherever you get your podcasts and tune in next week as we rewind this season’s genetics stories. You can also find us online at CSHL.edu. For Cold Spring Harbor Laboratory, I’m Sara Giarnieri, and I’ll see you next time At the Lab.