Towards the identification of a mesoscale neural systems logic underlying innate behaviors - Project Summary/Abstract Innate behaviors, also known as instincts, are essential for the survival of all species in the animal kingdom, including humans. Of great interest is understanding how the experience-induced behavioral plasticity observed in innate behaviors can lead to maladaptive behavioral expressions, including uncontrolled aggression, sex offenses, and generalized anxiety. Such mental disorders carry a substantial emotional and financial burden to families and society, rendering the development of effective therapeutic approaches of high significance. The neural substrates of innate behaviors are distributed across numerous brain regions. An essential step towards understanding how the brain orchestrates behavior is to identify how inter-region interactions of neural activity influence behavior in freely moving animals. However, methodological limitations have largely restricted such investigations to single nuclei, while the deep brain remains to date inaccessible to in vivo mesoscale neural recordings in freely moving animals. The research proposed here uses custom-designed technology to break this methodological barrier, making possible recordings with single-unit resolution across twenty subregions of the deep brain (hypothalamus) in freely moving, innate behavior-expressing mice. In Aim 1, using this technology, I will investigate the presence of behavior-specific mesoscale hypothalamic neural features in the innate and learned expressions of social and fear-related behaviors. I will test whether the activity of specific brain regions can predict specific behaviors, and I will identify the spatial distribution of hypothalamic clusters exhibiting behavior-tuning or mixed selectivity. In Aim 2, I will dissect how aggression- or fear-conditioning alters mesoscale neural activity dynamics and test the effect of chronic administration of pharmacological reagents known to reduce the expression of maladaptive social and fear behaviors. Lastly, in Aim 3 – the independent phase of the award, I will expand the use of these tools to investigate mesoscale neural activity dynamics across diverse areas of the corticolimbic system, seeking to identify local and global principles that guide the expression of the physiological and maladaptive forms of innate behaviors. Collectively, the above approaches target the development of an experimental and analytical platform to address fundamental questions of systems neuroscience on the mesoscale mechanisms that govern the expression of innate behaviors. Following these initial steps, this work will be complemented by experimentation aiming to test whether the identified neural features in the behaviors of interest have a causal role. Through the mentored phase of this award, my vision is to build a highly complementary skillset to the one I acquired during my graduate training, and create a unique, state-of-the-art independent research program. By pursuing work spanning diverse disciplines, including molecular, cellular, systems neuroscience, behavioral and computational approaches, I am committed to developing a mechanistic understanding of the neural basis of innate behaviors, with the potential to lead to advanced therapeutic solutions.
