The never-ending curiosity and joy of discovery drive the young researcher, Dr. Barbara Fülöp, PhD student at the Department of Pharmacology and Pharmacotherapy, who spends long hours looking through the microscope in one of the department's research laboratories. She is holding slides in her right hand, projecting their images to a computer monitor to see what cell changes they show. She is passionately explaining what the brownish spots in the mouse brains mean, what the changes indicate and what conclusions can be drawn. She wanted to become a clinician, but then got carried away by research. Her mentors and the positive feedback she receives during scientific presentations help maintain her persistence.
Written by Rita Schweier
"I am from Veszprém, I applied for a computer science class in high school, and until the tenth grade I thought I would become a computer programmer. Then, in the 11th grade, my form teacher called my attention to the TM camp, called Talent Movement at the time, at the University of Pécs, which prepared high school students for the matura examination. Although the exam seemed distant to me, I went anyway. The biology class was held by a sixth-year student who was doing his obstetrics and gynaecology practice at the time. He explained very passionately what happens when a baby is born and how grateful he is to be able to see it because it is a miracle. Well, I decided then and there that this was what I wanted to do. His enthusiasm completely captivated me," Barbara begins telling me her story.
Although she had her ups and downs during her university years, none of them discouraged her from achieving her goal. After completing her pharmacology final exam, she approached Professor Zsuzsa Helyes with the intention of conducting research. Her supervisors were Dr. Éva Borbély, senior lecturer, and Dr. Ágnes Hunyady, a PhD student at the time, both of whom impressed her with their engaging personalities and showed her all the possible research methods. Barbara is also grateful to them for supporting her as a mother as well because she had plenty to do with her three children, now aged seven, four and two. She considers herself fortunate to have the help of her husband, Dr. Balázs Fülöp, who is also a doctor and a teacher at the Department of Anatomy and Department of Primary Health Care, and also her family, since the grandparents are always there for them.
"As a research topic, I was most interested in endometriosis and the TRPV1 receptor, which is also the research profile of the department, however, when I applied there was no vacancy in this area, but a new project was just starting: the "tubing experiments", as we call them, and they were looking for new coworkers. The idea is to put mice in a well-ventilated but very restrictive tube for six hours a day for several weeks, stress them and then measure them. We test their behaviour, observe what happens to their different pain qualities, how their motor coordination changes in response to stress, and what happens to their desire to explore. Usually, if the mouse shows depression-like symptoms, it does not want to go out into the light or explore new areas, but instead it stops and waits until the test is finished. These behavioural tests, such as when mice are restrained by their tails and can only hang, are used to test the effects of antidepressants. In these cases, we observe whether the animals want to cope with acute stress, whether they want to escape. The ones showing depression-like symptoms do nothing, they accept the situation and just hang. They behave in a similar way when they are put in water, not fighting for their lives. The differences between the behaviour of mice with depression-like symptoms and those receiving antidepressants are very striking," she says.
Currently, the focus of their research is monitoring the pain thresholds of genetically different animals. They are looking at whether they behave differently in various stressful situations if they lack certain proteins or receptors. Functional measurements are made of their pain response to cold stimuli and touch, and then they examine what brain processes are involved in response to stress and whether they differ between genotypes. She says that in two strains of genetically modified mice they found that after two weeks of tubing, they became very stressed and showed pain response much earlier, called hyperalgesia. This means that they responded to even a mildly painful stimulus with proportionally large pain. However, mice from which the IL-1 (interleukin) protein had been genetically knocked out of, i.e. they lacked the IL-1 alpha-beta gene during embryonic development, did not show increased sensitivity. One method of testing the sensation of pain is to dip the hind legs of mice in ice water. When the cold causes pain to them, they either jerk their legs away or defend themselves in some way. The other method is to stimulate them with a blunt needle, pressing up to ten grams into their paws. Sometimes they already pull away or lick or hide their feet at 6-8 grams of pressure. So, they look at how quickly they respond to pressure stimulus with pain.
"Slides of the mice's brains are prepared after stressing them for two weeks. We stain their immune cells, the astrocytes and microglia, perhaps the two most important immune cells in the central nervous system. When these two cells are activated, it is called neuroinflammation. We want to know how these cells change under stress, whether they become activated, and if we take the IL-1 out of the system, whether the same process occurs or whether the outcome is different," she explains.
In March 2023, Dr. Barbara Fülöp published her first first-author article showing that in mice, after two weeks of stress without any other intervention, pain develops, which is associated with increased microglial and astrocyte activation in brain areas involved in both stress and pain. Mice lacking an important inflammatory cytokine, interleukin-1, do not develop stress-induced pain and central nervous system glial activation. A correlation between these two parameters is therefore possible. The aim is to demonstrate with the help of animal experiments that blocking IL-1 does not induce stress-induced pain. If this could be confirmed, developing a drug that prevents microglial and astrocyte activation and the associated pain sensitization could be initiated. In the case of humans, it could be used for chronic primary pain, perhaps the best known of which is fibromyalgia. This is a disease mainly involving the central nervous system, with musculoskeletal pain, where there is a disturbance in the perception and processing of pain, but it is not known what causes it exactly. Stress is thought to play a significant role or exacerbate pre-existing symptoms. Patients with this condition also experience painful stimuli as pain.
Dr. Barbara Fülöp is most excited when the results are what she expected, or rather the opposite because then she can passionately start looking for causes and correlations. Her enthusiasm is supported by her supervisors and the scientific forums where she can participate and present her research.
Photos:
Dávid VERÉBI