Vidita Vaidya has been delving into the depths of the mind for answers on stress, adversity and trauma. The neuroscientist from Tata Institute of Fundamental Research in Mumbai has been dissecting stress and mood disorders long before awareness on mental health increased in the past few years. “I think we are seeing a revolution in mental health research,” said Vaidya, who was awarded the 2022 Infosys Prize in Life Sciences on 6 January.
Two decades of research have only heightened Vaidya’s sense of awe over the tiny molecules and chemicals that determine human behaviour under stress.
“The enormous complexity of the brain makes it a very difficult place to study and understand normal and abnormal functions,” said Mriganka Sur, famed neuroscientist and jury chair of the Life Sciences category of the Infosys Prize, to ThePrint.
On choosing Vaidya’s work for the $100,000 prize, Sur said the jury was impressed by the detailed commitment to understanding the mechanism that will one day lead to useful drugs for various mental health conditions.
Serotonin and stress
Vaidya’s work focuses on serotonin and she is deeply interested in the mechanisms that regulate variations in people’s vulnerability and resilience to stress.
Every person has a stress response to an adverse event, and how they react (behavioural changes) is shaped by the duration of and exposure to stress during critical, early developmental years.
“We see this most obviously at a behavioural level,” Vaidya explained. “When going through stress, changes occur in behaviour, and when stress is withdrawn, the brain reverts to a baseline [the state of no stress].” This could take days or weeks or even months, depending on the person’s previous exposure to stress.
For people who have faced trauma early in their lives, the baseline seems to be set much higher. They respond differently to adverse events and also take longer to revert to their baseline.
It is well-established in medical literature that adverse early childhood experiences are a common risk factor for psychiatric disorders including schizophrenia, substance abuse, obsessive-compulsive disorder (OCD), anxiety, or depression.
Vaidya studies the neuromechanisms behind this kind of stress-adaptation in mice models, which generally work similar to the human body.
In mammals, stress response is mediated by the hypothalamic-pituitary-adrenal (HPA) axis or the interaction between these three glands. It is a neuroendocrine system and regulates many metabolic processes such as digestion, energy expenditure, sexual activity, the immune system, as well as mood and emotions. It is the primary pathway to respond to acute, short-lived stressors for which a response can be mounted, and then terminated, Vaidya explained.
“It is not designed for sustained, chronic, long-term stress,” she said. “HPA axis is responsible for the adrenal glands secreting cortisol (stress hormone), which bind to receptors in the brain. For animals that have gone through early adversity, the feedback regulation of the HPA axis function is deteriorated. So switching back to baseline is longer and different.”
She and her team focussed on the functional responses to the serotonin receptor 5-HT2A and found that even with the same amount of receptors, the response is heightened (more material flows from hormone into receptor) and signalling is significantly enhanced under stress.
A similar response was previously recorded independently when fluoxetine (Prozac) was given to mice that were less than two weeks old, which resulted in the antidepressant enhancing anxiety and despair instead. It had also been found in a model of autism spectrum disorder previously.
So Vaidya’s team experimented with the receptor, blocking it in early developmental windows and then exposing young mice to stress by separating them from the mother. This prevented serotonin from working on the receptors. Then, after several months, the team exposed the mice to stressful behaviour as adults, and noticed that they did not show any anxiety or despair.
They further refined their findings by identifying a neurotransmitter pathway, where when they amplified the signals between the cells, it resulted in increased anxiety and despair and brain patterns similar to schizophrenia.
When these experiments were done on adult mice with no previous trauma, the stress response was well-regulated. But with those who had early trauma, “there’s interesting collapse everywhere” in the brain during a secondary stress response.
Vaidya’s work is crucial from a pharmacological point of view today, more than ever.
“Mental health through the three years of Covid has emerged as a very big challenge,” said Sur. “We are remarkably social creatures, and our isolation has led to a major mental health crisis, bringing the problem to the forefront in a big way.”
A better understanding of what triggers stress responses at a molecular level enables the discovery or synthesis of molecules that could act as potential drugs or treatments for psychiatric disorders.
Future of mental health research
Vaidya’s next step is to follow a serendipitous discovery in her lab: serotonin regulating the mitochondria and making it produce more energy as well as increase its quantity.
“In hindsight, it seems obvious we should have looked at plant literature,” she laughed. Plants have high levels of serotonin and their antioxidant effects help them stay healthy and alive, as do other life forms.
“It’s a really old molecule,” said Vaidya. “It existed when there were no brain cells and no receptors for it 3 billion years ago.” The nervous system came into existence about 700 million years ago, and evolution co-opted this serotonin molecule to become a neurotransmitter in animals, she added.
Her team is also collaborating with other researchers to start studying the effects of serotonin in the gut.
Vaidya also works with psychedelics, whose medical properties are once again seeing a resurgence in Euro research after decades of societal taboo. Psychedelics also stimulate serotonin receptors, and some do so without any hallucinogenic effects.
“These molecules work immediately,” she explained. “There’s been the prevalent view that plastic changes in the brain take time, but these drugs show remarkable recovery in mere hours.”
Vaidya will soon be going to New York City, to conduct experiments with LSD, psilocybin, and DMT. “It is impossible to get a Schedule 1 drug inside India. It’s easier to send me and my students outside,” she said with a smile.
“There are very interesting molecules that exert very potent effects fairly quickly, and have been used in major clinical trials. I think these findings are going to open up very interesting things, and I am cautiously optimistic right now,” she added.
Broad base for specialisation
Vaidya grew up reading about primates, through the works of famed primatologists Jane Goodall and Dian Fossey. With two clinical scientists as parents, she knew she wanted to become one too.
She obtained a life science and biochemistry undergraduate degree from St. Xavier’s, Mumbai, and developed great interest in a neuroscience course. She wanted to study the subject in vertebrate and mammalian systems, but most institutes in India during the 1990s focussed only on fly neuroscience. So she decided to move to the US.
She trained at Yale University for five years, which she says was the most enjoyable period of her academic life. “I really loved being at the Yale psychiatry department,” she said fondly. “We had clinicians, scientists, and everyone was talking to each other about their science. It is very enjoyable to be a young student in an environment where you see people decades ahead of you getting extremely excited about their work. It’s contagious.”
Vaidya said she always knew she wanted to come back to India, but neuroscience outside of the fly still hadn’t picked up enough. So she decided to make her transition “one jump at a time”.
After completing her PhD at the age of 26 from Yale, she went to the Karolinska Institute in Sweden for a year of post doctoral work, followed by two years at the University of Oxford.
In 2000, she returned to India and joined the Department of Biological Sciences at Tata Institute of Fundamental Research (TIFR), Mumbai.
At the time, she was the pioneer in the field, and had to set up facilities from scratch.
“I needed a large number of mice to work with. So I had to set up the first animal house,” she recalled.
Today, she is chair of the biological sciences department at TIFR and a professor of neurobiology.
When comparing her work at Yale to her 20 years in India, she said she missed the “critical mass”, the neurobiologists and especially the neuropsychopharmacologists around her she could talk to, as there aren’t many in India — definitely not enough for her to walk into an office like she could do at Yale. “But the other side of the coin is that I discovered wonderful collaborators in completely unexpected places. It’s a young and vibrant neuroscience community in the country.”
Vaidya went on to win the Shanti Swarup Bhatnagar Prize for Science and Technology for Medical Sciences in 2015, after having won the National Bioscience Award for Career Development in 2012.
“I always encourage anyone who’s young and looking for advice to take as broad a degree as possible to keep options wide,” said Vaidya. “I had done only one neuroscience course during my bachelor’s in chemistry and life sciences, but I knew I really liked it.”
Speaking about winning the Infosys Prize, the latest feather in her cap, she said “it feels wonderful”.
“When you choose to leave everything behind and come back to your country to start from scratch, you do it not for the recognition but for the excitement the work brings. Having worked with an amazing group of students and postdocs here for 20 years, I know we are all feeling recognised. We feel privileged and honoured.”
(Edited by Prashant)