Annegret Falkner, an Assistant Professor in the Princeton Neuroscience Institute, has been awarded an NIH Director’s New Innovator Award. The award supports exceptionally creative early-career investigators pursuing innovative, high-impact research projects. It is one of the most competitive grants awarded by the National Institutes of Health and carries with it $1.5 million in research funding over a five-year period.
The focus of Falkner’s research is understanding how social experiences, including social dominance and defeat, lead to the generation of negative persistent affective states, such as depression. To tackle these challenging questions, Falkner takes a multi-pronged approach, both quantitatively observing animal behavior and recording and manipulating neural activity during social experience.
Like so many projects at PNI, Falkner’s awarded proposal was born out of an interlab collaboration, in this case with Professor Ilana Witten and spearheaded by graduate student Lindsay Willmore. “I would have never thought of this idea without Lindsay in the lab,” says Falkner.
Falkner’s proposal centers on identifying both behavioral and neural signatures of resilience, the quality of being robust to social stress, and manipulating the neural activity of animals that lack resilience to make them more resilient. Historically, research into individual susceptibility to negative affective states has focused on genetic and epigenetic predictors, or neural activity without respect to ongoing behavior. “Maybe it's not that some animals are destined to be resilient based on their genes,” says Falkner. “Maybe they're actually just doing something differently when they're experiencing social stress. Perhaps they have slightly better or more varied behavioral strategies to deal with stress.”
To identify and manipulate the signatures of resilience, Falkner is developing cutting-edge technologies for quantitatively measuring animal behavior and neural activity when animals are engaged socially. She uses deep-learning based methods to catalogue the actions of large cohorts of animals to identify the key behaviors that resilient animals express when they are being attacked by another animal. Then, she deploys this technology in conjunction with targeted neural stimulation, to co-activate, in real-time, dopamine neurons in animals that show a lack of resilience at critical moments when they are exhibiting these resilient behaviors. “Maybe we can teach animals to become more resilient by reinforcing these particular behaviors in an online fashion,” says Falkner. “We're giving them a little burst of hedonic value every time they do something that seems to be good for them.”
In the second phase of the project, Falkner plans to perform massively parallel neural recordings using implanted optical fibers in up to twenty poorly understood brain regions that constitute the social behavior brain network, an endeavor that has never been attempted either in scale or in freely-behaving animals. Then, she plans to use these recordings to identify the neural signatures of resilience, just as she did using animal behavior, and use targeted neural manipulation to pattern this activity into the brains of animals that are not displaying resilience. Falkner hopes that by “steering” the animal's behavior with targeted behavioral or neural manipulation, it might allow them to prevent depression by pushing the animals into more pro-resilient states.
Falkner joined the faculty of the Princeton Neuroscience Institute in the summer of 2018 following stints at Columbia University as a PhD student and NYU Medical Center as a postdoctoral researcher. “I wanted to come to Princeton in large part because of its strength in quantitative behavior, and especially looking at natural behavior,” says Falkner. “If I were at some other institution, I’d be doing much more cut-and-dry circuit stuff, probably boring myself and boring everybody else. Being here has made me think bigger about the kind of projects I want to tackle.”
by Brian DePasquale