In the early 1990s, more than 100,000 children in Romania were living in overcrowded, under-funded orphanages. They suffered from severe neglect, having little interaction with caretakers.

This lack of nurturing altered the structure and function of their brains. These children developed a host of behavioral and emotional problems that many of them are still coping with today.

Now, neuroscientists at Northeastern are using rats to understand some of the physical changes in the brain caused by such severe neglect.

In a recent paper, the researchers found that female rats, in particular, developed abnormal connections between two areas of the brain in response to neglect. These are the same areas that show abnormal activity in brain scans of children raised in orphanages, as well as those who have suffered from child abuse or other forms of severe maltreatment. Children with this abnormal activity are more likely to develop anxiety later on in childhood or adolescence.

[Top Right] Heather Brenhouse, associate professor of psychology, right, watches as doctoral student Kelsea Gildawie cleans slices of rat brains.[Bottom Right] Doctoral student Lauren Granata studies a rat brain in Heather Brenhouse’s lab. Photos by Ruby Wallau/Northeastern University

“The early work looking at biological underpinnings of this specific circuitry has been largely in male animals,” says Jennifer Honeycutt, a postdoctoral researcher at Northeastern and the lead author on the paper. “We were able to not only expand what we know about generally how the circuitry is developing in both sexes, but now we can pinpoint a possible locus of unique vulnerability for females.”

Honeycutt and her colleagues were examining the connections between the basolateral amygdala, part of an almond-shaped structure tucked in near your temple, and the prefrontal cortex, which is right behind your forehead.

When you see something that might be a threat (say, a tiger), your amygdala fires off signals to several areas of the brain, including the prefrontal cortex, indicating that you should be frightened. The prefrontal cortex responds by integrating information from other areas of the brain, like context clues (The tiger can’t reach us.) or prior memories (This is a zoo. We’ve been to a zoo before), and signals the amygdala to, essentially, calm down.

“The disruption of this circuit is going to lead to maladaptive behaviors,” Honeycutt says. “That’s where you start to see increasing anxiety-like behaviors even in the absence of something that could be anxiety-provoking.”

The connections between the amygdala and the prefrontal cortex develop throughout childhood and adolescence. Research has demonstrated, however, that these connections seemed to develop abnormally in children who had experienced severe neglect and later developed anxiety-like disorders.

“This circuit was showing accelerated maturation,” says Heather Brenhouse, an associate professor of psychology at Northeastern. “It was as if the brain was trying to adapt to the experience of early trauma and maybe predict later threats, and which could translate into being hyper-responsive.”

The researchers injected a dye into the each rat’s brain so they could trace the neurons connecting the amygdala to the prefrontal cortex. Photo by Ruby Wallau/Northeastern University

To figure out the exact mechanism behind this change, the researchers needed to be able to examine brains more directly. In neuroscience research, that means they needed rats.

“What a young rat, just like a young human, needs the most for its well-being is proper caretaking and nurturing,” Brenhouse says. “If you disturb the infant-mother relationship somehow, that’s the way to best model early life adversity.”

The researchers removed male and female rat pups from their mothers for three to four hours every day during their infancy. The pups were separated into warm areas with bedding that smelled like their mother and littermates, but without any physical contact or caretaking.

“It mimics very much the situation for those institutionalized children, where they were in little individual cribs, left alone and not being taken care of for a long period of time,” Brenhouse says. “That induces a lot of the same stress response changes and behavior changes and brain changes that map on fairly well to what we see in humans.”

To see how the connections in the rats’ brains were developing, the researchers injected a dye into each animal’s basolateral amygdala. As those neurons extended from the amygdala to the prefrontal cortex, they would become stained with the dye, allowing researchers to identify them.

The researchers examined the rats’ brains at different points in development. They found marked differences between males and females. In female rats that were separated from their mother, an excess of new connections grew rapidly between the amygdala and the prefrontal cortex early on in development. Males saw some of this same nerve growth (known as innervation), but not until much later on.

The researchers also used an fMRI to examine the activity patterns of the animals’ brains when they were at rest. Animals with this excess innervation had abnormal communication between the amygdala and the prefrontal cortex.

“These excess neural connections were disturbing the efficiency of that circuit,” Brenhouse says. “Basically, the circuit didn’t work as well, and it didn’t mature as well.”

The animals whose brains developed abnormally also behaved differently. The researchers tested them for anxiety-like behaviors by placing the rats on an elevated plus-shaped platform. Two of the arms of the platform had walls, creating a more secure space, while the other arms were wide open. Rats with excess connections between the amygdala and the prefrontal cortex spent more time huddling in the areas with protective walls.

The early development of this circuit seemed to be creating a sense of hyper-vigilance in these animals.

“It’s the first time we’ve really seen a sex-specific circuitry change over development after early life stress,” Brenhouse says. “Early life trauma is actually setting up the circuit to develop differently.”

As for why females are more vulnerable to these changes, the researchers say they aren’t sure yet. Male and female brains mature differently, so this type of stress may be hitting females at a critical point in their development. Differences in hormones or immune systems could also play a role, or perhaps males and females simply experience stress in different ways.

“There’s a long list of theories that we want to follow up on,” Brenhouse says. “We know males are impacted by early life stress in other ways, but the circuit that we tested seems to be more impacted in females.”

The important thing, though, is that these changes don’t have to be permanent.

Understanding the differences in how male and female brains develop, and the impact of neglect on this process, could help improve treatments and interventions for children before mental illnesses begin to manifest themselves.

“I’m always worried when we talk about early life trauma that it sounds like once you experience it, then you’re broken,” Brenhouse says. “But the truth is, our brain continues to be plastic throughout our lives. Maladaptive circuitry can certainly be molded by later enrichment, interventions, and treatments.”

This story was originally published on News@Northeastern on February 20, 2020

Cephalopods—the group of animals that includes octopus, squid, and cuttlefish—are well known for their incredible color-changing abilities. But these tentacled weirdos have also played a vital role in our evolving understanding of the human nervous system.
In honor of #CephalopodWeek, we spoke with Jade Zee, who directs Northeastern’s program in behavioral neuroscience, about what these animals can teach us.

“Among invertebrates, they stand very much apart. They’ve evolved a much larger nervous system,” says Zee. “Their body plan is completely different from ours, but they share many of the same fundamental principles in how the nervous system actually underlies behaviors.”

What have we discovered from studying cephalopods?

Neuroscience has really benefited from cephalopods. The very first action potential, which is the electrical activity of a neuron, was recorded in a squid.

Jade Zee directs Northeastern’s program in behavioral neuroscience. Photo by Matthew Modoono/Northeastern University

We humans have white matter, which causes electrical signals to travel much, much faster in our neurons. Invertebrates don’t have that. So the invertebrate solution, if you want electrical signals travel faster, is to have a wider diameter axon of a neuron.
The very first action potentials were recorded in what’s called the squid giant axon. It’s about a millimeter in diameter, which I know still sounds small, but that’s actually really, really big compared to other nerves.
With the early techniques we had to record electrical activity, it was necessary to find some kind of system where the axon was physically bigger, so you could actually impale electrodes in it and record this electrical activity.
This recording of an action potential in the squid giant axon is pretty fundamental. It’s what I teach in my neurobiology course and in biological psychology.

Why is the axon so big?

If you think in terms of evolution, the behaviors that need to happen fast would generally be escape behaviors. Having this giant axon that was wider and thicker would allow electrical signals to travel faster in their bodies, and that would help them escape dangerous situations or predators.

How are cephalopods used in neuroscience today? Are researchers still studying that axon?

While it might have started out as just a great fundamental system to understand nervous system physiology, it has really branched out, in part because of their complex behaviors, and also because they have very interesting sensory capabilities.
Cephalopods do have a small brain, but their nervous system is not like a central nervous system. The neurons are clustered all over the place, kind of in a network. Those clusters are called ganglia. And from there, they have some independent control of a segment of the body. There are clusters of neurons located out in the arms that are responsible for a lot of the really interesting behaviors and motor control.
And for someone like me, who’s interested in the neural basis of behavior, there’s a lot of sort of quirky stories in the news about how complex their cognitive ability is. I don’t work on cephalopods, but I appreciate them as a neuroscientist.

A study came out last fall where researchers dosed octopuses with ecstasy (MDMA) to see how their behavior would change. What can we learn from studies like this?

The scientists who research this are actually conducting some experiments in the “Neural Systems and Behavior” course I co-direct at the Marine Biological Laboratory in Woods Hole.
We know, with humans, ecstasy promotes what we call pro-social behaviors. Their question was to ask whether or not the same sort of mechanism happens in cephalopods. And that turns out to be the case.
They used a species of octopus that is mostly solitary. When they were treated with ecstasy, they started being less interested in toys and more interested in each other. They were more gregarious. What it actually showed us was that they have a very similar system underlied by serotonin, which is exactly why humans also like MDMA.
MDMA is currently being tested in terms of its potential therapeutic benefits for treating PTSD. It’s useful to know that what’s happening from a neurochemical standpoint in humans is also happening in cephalopods.
This story was originally published on News@Northeastern on June 27, 2019.

Northeastern professor Dagmar Sternad is studying ballet dancers to understand how to help people regain their balance in old age. Her findings could help us improve our mobility, design better robots, and discover how to more effectively treat stroke patients.

Amanda Stroiney, who is developing a mobile app that delivers personalized treatment information to people with breast cancer, and who is applying to medical school with an eye toward oncology, never expected to work in the field of cancer research.
She studied behavioral neuroscience and criminal justice at Northeastern and planned to study brains.
But then she did a co-op at the Dana-Farber Cancer Institute through a Northeastern program that created opportunities for undergraduate students to gain hands-on training in cancer nanomedicine. The program allowed her to work with top cancer researchers at Dana-Farber, which is one of the leading cancer treatment and research centers in the world. And her experience changed everything.
Since its inception in 2015, 75 students have completed the same program Stroiney did—called Cancer Nanomedicine Co-ops for Undergraduate Research Experiences, or CaNCURE, for short.

“I really believe CaNCURE launched my career,” says Amanda Stroiney, who recently applied to medical school with an eye toward oncology. Photo by Matthew Modoono/Northeastern University

“What we’re doing is putting together our great students with the world’s best researchers in nanomedicine, training them to become cancer researchers,” says Srinivas Sridhar, University Distinguished Professor of Physics at Northeastern, who directs the program.

And, it appears to be working. “Over two-thirds of our alumni have stated that what they learned in CaNCURE helped them land their first job or get into medical school,” says Anne van de Ven, who is a research assistant professor of physics and the associate director of the program.
Stroiney was among the first students to take advantage of the program, just before she graduated in 2016.
She worked in the radiology department at Dana-Farber, studying two different imaging techniques that are used to diagnose a patient’s cancer.

Toward the end of her final year at Northeastern, Stroiney got two job offers on the same day. The first offer was related to her major, doing neurological behavioral studies. It’s the job she probably would’ve seen herself in, as a freshman. The second offer was for a clinical research position within the Center for Immuno-Oncology at Dana-Farber, and more aligned with what she did in CaNCURE.
She chose Dana-Farber.

“I really believe CaNCURE launched my career,” Stroiney says, three years after that fork-in-the-road

Inspired by her experience in CaNCURE, Stroiney is also helping to create a mobile app for breast cancer patients, seen here. Photo by Matthew Modoono/Northeastern University

day. She was sitting in the bustling co-working space in Cambridge, Massachusetts, out of which she’s working to create a personalized cancer treatment app.

Hers is a sentiment echoed by other CaNCURE alumni, including Sarah Sherman.
Sherman, who graduated from Northeastern in 2017 with a combined degree in biology and English, says she applied to the CaNCURE program because she wanted to gain experience in research, knowing it was a common career path for people in science fields.
She worked at Massachusetts General Hospital in a molecular imaging lab, where she was put in charge of testing a new breast cancer treatment to determine if it would be effective enough for clinical trials. It wasn’t, but Sherman says the experience inspired her profoundly. After she graduated, Sherman won a prestigious Fulbright Scholarship to do cancer research in Botswana. Since then, she’s worked at a small biomedical company that’s seeking to transform how diseases are detected.

“CaNCURE was pretty pivotal for me, particularly because before the program, I hadn’t done research outside a classroom setting,” Sherman says. “Without that initial opportunity to gain skills, I wouldn’t have felt as confident to take advantage of other opportunities along the way that have led me here.”

Sherman and Stroiney are among several students, faculty, staff, and alumni in the nanomedical field whose work will be highlighted at the fifth annual Nanomedicine Day at Northeastern on Thursday, June 13 in the Raytheon Amphitheater. Registration is not required to attend. A full agenda for the day can be found online.
This story was originally published on News @ Northeastern on June 12th, 2019.