Meet Rose Bagot, one of the Principal Investigators at the Ludmer Centre for Neuroinformatics and Mental Health. Prof. Bagot investigates mouse models of stress, with the ultimate hope that it can lead to a better understanding and treatment of stress-related disorders, such as depression and anxiety. In a recent interview, we got to learn more about her lab and recent findings.
Can you tell us about yourself and your academic journey leading up to now?
My name is Rose Bagot, and I鈥檓 an associate professor and a behavioural neuroscientist in the Department of Psychology at 不良研究所. I did my undergraduate degree in Psychology at the University of New South Wales in Sydney, Australia, intending to become a clinical psychologist. Along the way, I took a learning and memory course and had the opportunity to work in basic research with rats. I realized I was more passionate about understanding the 鈥渨hy,鈥� and the 鈥渉ow,鈥� than to work in clinical settings.
I pursued my PhD with Michael Meaney and Tak Pan Wong at 不良研究所, studying how early life experience can lead to different vulnerabilities in adulthood. In my postdoc at Mount Sinai Icahn School of Medicine in New York, I focused on preclinical models of depression and the neural circuit and the molecular changes in mouse models of stress exposure and adapting to understand what happens when an animal shows susceptibility, or rather, resilience, towards stress. This led to my own lab鈥檚 trajectory of understanding stress-related changes in the brain.
What are some of the techniques you use in your lab to study stress pathways?
I enjoy following a question across the different layers, from the behaviour to the underlying molecular mechanism. We use a range of in-vivo and post-mortem techniques to connect the dots and get the whole picture. We invest in, develop, and establish robust behavioural paradigms, and use imaging techniques to observe what鈥檚 happening in the brain of awake, behaving animals. One of these techniques is fibre photometry, which uses fluorescent calcium sensors implanted in the neurons. When the neuron is active, the calcium sensor emits a fluorescence signal which we can pick up as a proxy of neural activity. We also use different kinds of single-cell imaging, where we implant a miniature microscope to obtain videos of individual cells flashing on and off as the animal is engaged in behavioural tasks. This helps us understand how neurons respond during a task. There is also new technology called multi-scope, where we can record cellular activity from multiple brain regions simultaneously. We also use optogenetics to simulate brain activity, which allows us to follow a neuron鈥檚 projection and see how it leads to changes along the neural circuitry. In post-mortem tissue, we use single-cell sequencing to understand gene regulation in individual cells and how that changes with stress or reward. We can also use viruses to manipulate gene expression. We can increase the activity of a specific cell type and see how the animal adapts to stress or processes information about reward.
What led to the decision to come back to Montreal?
I really wanted to come back, but I also needed to know that I would have what I needed to build my dream lab. I applied widely to universities in Canada and the USA and had a number of offers, but the Ludmer Centre was pivotal in me coming back to 不良研究所. The Centre contributed towards my startup, which made it possible to accept 不良研究所鈥檚 offer. This additional funding gave me the flexibility to grow the lab quickly and to follow bold ideas and not worry about having enough funds to pay the students or recruit lab managers. It鈥檚 been really important in empowering the science that we do.
Tell us about an exciting new finding from your lab.
We recently conducted a study on the neural mechanisms of threat processing and how projections from both the prefrontal cortex (PFC) and the ventral hippocampus (vHPC) are encoded in the nucleus accumbens (NAcc). In previous work, we had seen that both neural circuits were encoding threat/no threat stimuli in male and female mice. What we found with this new study was that there was a sex difference in the processing of no threat stimulus. In male mice, the vHPC increased its activity to threat stimulus only. However, in female mice, both threat and no threat stimulus were associated with increased vHPC activity, and the differentiation between the two was done by the PFC. Consistent with these findings, we found that when we silenced the vHPC, male mice struggled with their discrimination between the threat/no threat stimuli, but there was no effect in female mice. Conversely, silencing the PFC impacted the female and not the male mice. This was surprising because behaviourally, the male and female mice seem to have similar discrimination between the threat/no threat stimuli. This is a very exciting new discovery from our lab, and we only found this difference because we routinely study both male and female mice.
What could these results mean?
This points to differences in vulnerability to anxiety and stress. We know that women are far more likely to have anxiety disorders than men. Very speculatively, it could be that the PFC is important in preventing excessive generalization of threat. If the PFC or its pathway is compromised by stress, then the individual is more likely to have disruptions in regulating responses to threat. We also know there are sex difference in cellular excitability of the vHPC neurons projected to the NAcc. These neurons are generally more easily activated in females, which can lead to a less specific response to threat/no threat stimuli. Whereas males have a low-level excitability of the vHPC neurons and a more specific response to the threat stimulus. It鈥檚 a humble reminder that if we don鈥檛 recognize these differences in the underlying mechanisms of a behaviour, we won鈥檛 be able to develop equally effective therapies for everyone.
How can these research paradigms lead to better treatment of stress-related disorders?
The work we do in the preclinical realm sets the foundation to empower future discoveries. Understanding molecular information can lead to tractable ways to intervene and influence brain functions. With single-cell sequencing, we can gain very detailed understanding of the molecular identity of a cell and the role it plays in a behavioural response. We can then target a specific cell type to modulate its activity, reverse maladaptive gene expression or induce resilient-like gene expression.
It also leads to higher-level fundamental knowledge. As mentioned earlier, our recent findings suggested that the PFC is especially important in female mice in maintaining an adaptive response to threat. This could lead to developing behavioural interventions to strengthen PFC recruitment. There are many possibilities.
How do you collaborate with other researchers to enhance what you do in your lab?
We eventually get to a point where we want to go beyond our area of expertise and techniques, and collaboration allows us to pursue that. As just one example in the context of the Ludmer Centre, I work with Claudia Kleinman, PhD, who is an expert in human genetics and in bioinformatics. Working with her has been instrumental in how we鈥檝e developed our single cell sequencing analysis protocols. She helps us push the envelope and critically assess our potential approach.
What are the biggest challenges you face in your work?
There is the very real issue of the changing political climate of instability. We are facing barriers in recruiting great people and supporting diverse scientists. In an institute where we promote diversity and equity, these aren鈥檛 just values about representation. In my lab, we have people from different training and cultural backgrounds working together and learning from one another. This creates a stimulating and productive environment where we generate different ideas that we wouldn鈥檛 have otherwise thought of with a single worldview. Bringing diverse ways of thinking into science has tangible benefits to our institution, and there are walls being put around it. I find that deeply troubling.
What鈥檚 next for your lab?
We obtained a grant to continue studying the mechanisms of sex differences in neural circuitry of threat/no threat stimuli. We also have a suite of projects examining how the brain processes reward and how that鈥檚 changed during stress. In a different line, we鈥檙e looking at the mechanisms of psilocybin as a potential antidepressant treatment. I鈥檓 also really excited about our calcium imaging projects and using this technique to understand how the neural circuit is integrating information in real time in an awake animal during a behavioural task.
What advice would you have for people who are early on in their academic and scientific career?
To find a balance between following your curiosity, and being practical. If you align your career path with your passion, I believe you can lead a happy life. But do make sure to have other elements in your life. Something very grounding for me is my family, which places a counterweight on my time and work. Having this balance in my life enriches how I approach my work. I come back each morning with renewed enthusiasm and interest in what I鈥檓 doing.
