The two mice in the cage sniff each other intensely – first the tail, then the nose, then the rear end. Hanna Hörnberg watches them on her monitor. Tracking software creates a grid of digital dots over the animals’ bodies, meticulously following and recording their every move. “It’s a bit like spying,” she says. “We can see what the mice are doing 24/7 without disturbing them. We know when they sleep, how often they eat, how they interact with each other, and how they react to changes.”
When analyzed together, the information provides a fairly accurate picture of the mice’s personalities – including, for example, whether they are prone to stress or show depressive-like behaviors. “In both humans and mice, stress is an important risk factor for depression,” says Hanna Hörnberg, a tall woman with a clear gaze. “We want to understand why some mice develop signs of depressive-like behavior and others don’t.” She is talking, in her unassuming manner, about the most complex organ that evolution has brought forth: the brain.
Hanna Hörnberg is a neurobiologist and behavioral scientist. In 2020, at the age of 36, she joined the Max Delbrück Center as a junior group leader. With her team in the Molecular and Cellular Basis of Behavior Lab, she studies the behavioral changes associated with neuropsychiatric and neurodevelopmental conditions like depression, schizophrenia, and autism. But she doesn’t just observe from the outside; she delves deep into the processes that take place inside the brain’s neurons and that underlie behavior.
To investigate social anxiety behavior in mice, for example, she places animals that do not know each other in a cage and tracks their reactions with the help of cameras and computational analysis methods. She then looks for biological differences between the brains of the mice that exhibit a stressed response to the unfamiliar mice and those that behave more relaxed, like the one in the video.
“Anxiety and depression likely have many different causes. One hypothesis is that depression involves blunted response to dopamine, which functions as a neurotransmitter in the brain,” she says. “But we are also looking at the brain’s immune cells called microglia, as there is a clear link between the immune system and depression.” If we are able to find molecular changes that are associated with depressive behavior, Hanna Hörnberg explains, this could lead to the development of more targeted therapies.
“I wanted to know why I am the way I am”
Had she realized one of her many childhood dreams, she would not currently be working in a lab on the Berlin-Buch research campus – instead, she would be working as a veterinarian on farms in northern Sweden. But one day at her school in Stockholm, where she grew up, Hanna Hörnberg attended a talk by a geneticist. The woman told her that she had studied zoology and was now researching genetically modified animals in the lab. “I thought this sounded so exciting,” she recalls. “That day, I decided that I too would study zoology.”
I was excited to learn how genetic factors help to determine who we are and how we behave and live our lives
But already as an undergraduate, she realized she was far more interested in laboratory work than zoological field research. She wanted to peer inside cells rather than observe organisms from the outside. “I was excited to learn how genetic factors help to determine who we are and how we behave and live our lives,” Hanna Hörnberg says. “I guess I wanted to understand why I am the way I am – and how I ended up with different interests and a different personality compared to my sister, despite our very similar upbringings and experiences.”
So she wrote an email to the renowned neuroscientist and developmental biologist Professor Christine Holt at Cambridge University to apply as a doctoral student – and she was accepted. Holt studies the growth of axons: neuronal projections that conduct electrical impulses. As an embryo develops, these axons must extend across great distances to reach their final destination in the brain – for example, from the eye to the midbrain. “They know which trajectory to take and when they need to stop growing in order to form synapses,” Hanna Hörnberg explains. “I really wanted to understand how these complex processes work at the cellular level.” She found that a particular RNA-binding protein is responsible for the expression of receptors at the axons’ tips that steer them toward specific cells – thereby guiding their growth in the right direction.
In Cambridge, she laid important foundations for her future scientific work – and for her private life. She met her husband, who is also a neuroscientist, and made many friends. “Christine Holt was an important mentor for me,” Hanna Hörnberg says. “She showed me that you can have a career in science and still have a family and a happy life. And she showed me that it pays to pursue unusual ideas.”
A protein that influences social interaction
After four years she was drawn increasingly back to the study of observable behavior, leading her to move from Cambridge to Switzerland. For her postdoctoral research at Biozentrum of the University of Basel, Hanna Hörnberg observed the social behavior of autism mouse models. “We studied how they respond to new social interactions and what changes occur when we switch off certain genes,” she says.
She discovered that mice need dopaminergic neurons – the nerve cells located in the brain’s reward center – to respond with curiosity to new social interactions. “Mice where the activity of these neurons has been turned off fail to distinguish between familiar and unfamiliar mice,” Hanna Hörnberg says.
She also learned that a certain protein – neuroligin-3 – plays a critical role in the mice’s altered social behavior. When it is not produced in the dopaminergic neurons, the rodents behave as if the neurons themselves are turned off; that is, they are not interested in changes in their social environment. The reason is simple enough: Without neuroligin-3, the neurons are unable to respond to oxytocin. This neurotransmitter, often called the “happy hormone,” is crucial for certain kinds of social interaction, especially when it comes to responding to new social situations.
In search of a way to re-activate the nerve cell’s response to oxytocin, Hanna Hörnberg examined the molecular differences between dopaminergic neurons in mice lacking neuroligin-3 and wild type mice, and found that dopamine neurons lacking neuroligin-3 made much more proteins. She then conducted tests with a drug designed for cancer treatment that inhibits protein production. Her experiment was a success: The drug reduced the excess protein production in the mice lacking neuroligin-3. “After applying this treatment, the dopaminergic neurons were again able to respond to oxytocin,” Hanna Hörnberg says, “and the mice behaved similar to wild type mice.” In the future, this finding could point toward new treatments for people with neurodevelopmental conditions.
Yet she believes it is impossible to unequivocally determine whether a person would benefit from treatment or not. “Basically, there is no such thing as a bad brain, and drug treatments should not be designed to change who people are,” Hanna Hörnberg says. “But if a person is chronically stressed or depressed, medication can provide tremendous relief by helping them feel better, achieve their goals, or make their life easier. But it should be up to each individual to determine if they want treatment or not”
Studying anxiety at the molecular level
Hanna Hörnberg is now expanding the scope of her research. With her team at the Max Delbrück Center, she seeks to understand how behavior and emotions like social withdrawal and anxiety are manifested at the molecular and cellular level in developmental and neuropsychiatric conditions. To do this, they are working with different environmental and genetically engineered mouse models and are continuously improving methods to observe and evaluate mice behavior using artificial intelligence. “We want to observe the mice behavior in an environment as natural as possible,” she says. In addition to video tracking analysis, the scientists use implanted chips to record the animals’ movements with utmost precision.
“The Max Delbrück Center is the perfect place for my research, because there are excellent neuroscience and molecular biology groups here,” says Hanna Hörnberg, who is also a researcher at Berlin’s NeuroCure Cluster of Excellence. “I can have a good exchange about whether our findings can be translated from mice to humans.”
Understanding the brain mechanisms behind behavior is key to her ability to research mental health problems. However, she believes the complex nature of the brain prevents simple solutions. For example, she says, it might be possible to pinpoint the brain region and signaling pathways that cause a specific symptom, but it is difficult to target them in just one part of the brain. For example, although increasing the levels of neurotransmitters like serotonin can help with depression, they can also trigger adverse reactions. “It’s like with cancer therapies – they often have many side effects,” Hanna Hörnberg says. “Going forward, we want to identify targets with higher specificity to suppress unwanted symptoms while barely affecting the rest of the brain.”
Text: Mirco Lomoth