Bio Patrika interviews Dr. Pati on his thoughts about “the relation between early changes in the brain to psychiatric disorders in adulthood”

Dr. Sthitapranjya Pati’s interview with Bio Patrika hosting “Vigyan Patrika”, a series of author interviews. Dr. Pati is currently a Research Fellow at Sainsbury Wellcome Centre for Neural Circuits and Behaviour, London. Work presented here is done as part of PhD in the lab of Prof. Vidita A. Vaidya at Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai. Dr. Pati published a paper titled “Chronic postnatal chemogenetic activation of forebrain excitatory neurons evokes persistent changes in mood behavior” in eLife (2020) as first and senior author.

How would you explain your paper’s key results to the non-scientific community?

Behavior is produced by brain circuits that are set up during the time surrounding birth (known as critical window). Both genes and the surrounding environment of the animal contribute towards building and tuning these brain networks. A stressful or adverse experience during early life can result in a long-lasting change in emotional behavior and can increase vulnerability towards developing psychiatric disorders in adulthood. There are diverse ways to model this long-term behavioral programming in animals, that include environmental perturbations (e.g., separating pups from their mothers or stressful experience during pregnancy), pharmacological treatments (e.g., exposure to specific drugs), and maternal immune activation (e.g., influenza infection during the third trimester of pregnancy). In the past couple of decades, studies from our lab and other research groups across the globe have demonstrated that an enhanced activity of excitatory neurons (cells in the brain that activate or fire up other cells) in the forebrain via a specific intracellular signaling pathway, are associated with the long-lasting changes observed in all these seemingly distinct perturbations that lead to an overlapping set of behavioral changes. These behavioral changes are often mood-related and associated with symptoms noted in anxiety disorders, depression, and schizophrenia.

Figure 1. Excitatory neurons in the cortex expressing the designer receptor, hM3Dq DREADD (in green).

We hypothesized that there could be common substrate in the brain where these diverse perturbations converge to modify key neuronal circuits during the ‘critical’ window. In our recent study, we examined whether increased activation of these forebrain excitatory neurons during the first two weeks following birth is enough to program these long-lasting changes in emotional behavior, in more formal terms if it is causal to such persistent alteration in mood. To answer this, we used genetically engineered mice that expressed engineered receptors specifically in forebrain excitatory neurons and these could be selectively activated by a designer drug that would otherwise not bind to any other endogenous receptors. In order to activate these, we fed this drug (mixed with sugar solution) to the mouse pups during the first two weeks after their birth and tested for its effects on different mood-related behaviors in adulthood. We noted increased anxiety and depression-like behavior in these mice that often persisted across their life span. These mice also showed impairment in the way they filter noise from sensory information, a hallmark symptom of schizophrenia. In addition to our major findings, we also established that (1) the time window immediately after birth is ‘critical’ for such long-term programming and if we perform the same activation experiment either in adolescent or adult mice, we do not see any effect on emotional behavior, (2) the behavioral alterations are associated with molecular, cellular, and neurophysiological changes that closely resemble to that observed in patients with these psychiatric disorders.

Figure 2. Blue: Nucleus, Green: Excitatory neurons in the cortex expressing the designer receptor, hM3Dq DREADD, Red: Marker for active neurons. Yellow neurons are the excitatory neurons that are active following DREADD activation.

“Our study furthers the understanding of the early changes in the brain that could underlie increased vulnerability to develop psychiatric disorders in adulthood.”

What are the possible consequences of these findings for your research area?

Our study furthers the understanding of the early changes in the brain that could underlie increased vulnerability to develop psychiatric disorders in adulthood. This is of importance to researchers who want to understand long-term programming of behavior and to design possible behavioral/ pharmacological interventions to ameliorate these diseases. We believe this work also has relevance for psychiatrists particularly focused on the mechanisms that underlie persistent consequences of early adversity.

What was the exciting moment (eureka moment) during your research?

I do not remember ‘a particular’ moment that was definitively eureka moment or set the study in motion. This study is a culmination of efforts by many past and present members of our lab at TIFR. The stage was already set for me and I just followed course, so it would be unfair of me to take credit for having come up with the idea. Needless to mention, with a study involving such big collaborative efforts of thirteen scientists from three premier research institutions of India and spanning more than six years, I had all the help I needed. We aimed to conduct an old-school, thorough biological study with substantial scientific rigor. I remember an afternoon in the lab when I was casually sitting by the center table of our lab and chatting with Vidita (my advisor and lead author of this study), standing a few feet away. We discussed how cool it would be to be able to do this experiment.

What do you hope to do next?

I recently started my postdoctoral research in the Sainsbury Wellcome Centre and currently looking at learning mechanisms. I hope to contribute to the ongoing effort to understand how the brain works and how it produces myriads of fascinating behaviors starting from a simple reflex to expressions conveying complex emotions. Many things excite me as scientist, so I am not really obsessed about a specific problem and will pursue whatever sparks my curiosity.

Where do you seek scientific inspiration?

Inspirations change as you age, I guess. I pursued science after my BTech because I did not want to do a job, I wanted to show off as being cool, and mostly it sounded like fun. I was utterly unaware about what it is and what a scientist is supposed to do. In the past nine years, hopefully I have become more serious and understand that I am very fortunate to be a part of something much bigger than myself. I hope to contribute to the best of my ability in the years to come.

My outlook and understanding of scientific inquiry have been mostly shaped by my advisor (I am extremely fortunate and grateful to be her student) and heavily influenced by some of my seniors both from our and other labs. While doing science, I would always thrive on being guided by the principles of kindness, honesty, and dignity (of all people I interact with).

How do you intend to help Indian science improve?

I intend to come back to my country at some point and hopefully start a lab. First and foremost, I would like to create an atmosphere of excellence in the lab without compromising on individual dignity and kindness. As a PhD student who has carried out research for several years in one of the best places in India, I have seen both the good and the bad. Indian scientists have been truly inspirational, producing some incredible work despite the administrative roadblocks, the scarcity of resources, and an extended timeline for almost all processes. I have seen a great effort by the support staff of multiple institutions going out of their way to help researchers. I have also been through some amazingly bad experiences (thankfully mostly administrative).

However, it often comes down to jugaad even in the best of the places in India and that’s not always a great thing. The physical infrastructure lacks in two aspects (1) Administrative will to make things happen (instead of coming up with things that will stop the process), and (2) Lack of a trained workforce and core facilities to build and produce things (like virus, transgenic mice, microscopes, sequencing, computation, manufacturing, and so on). I would admit that we have been making some good progress in the second front in the past decade. I wish to join the ongoing effort by fellow scientists in setting up the correct example and making things better for those who would come after me.

Reference

Pati S*, Saba K, Salvi SS, Tiwari P, Chaudhari PR, Verma V, Mukhopadhyay S, Kapri D, Suryavanshi S, Clement JP, Patel AB, Vaidya VA*. (2020). Chronic postnatal chemogenetic activation of forebrain excitatory neurons evokes persistent changes in mood behavior. Elife, 9, e56171.

Current affiliation

Research Fellow

Sainsbury Wellcome Centre for Neural Circuits and Behaviour, London

Email: s.pati@ucl.ac.uk

Read more about Prof. Vidita Vaidya research interests here: https://www.tifr.res.in/~dbs/faculty/vvlab/Research.html

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