Stephen J. Liberles, PhD

Institution: HHMI, Harvard Medical School
Research: Internal and external senses
Grants & Publications: Harvard Catalyst
Categories: HHMI, HMS

We study internal sensory systems using molecular and genetic approaches. The vagus nerve is an essential body-brain communication axis that controls vital functions of the respiratory, cardiovascular, digestive, and immune systems. Despite their importance, vagal sensory mechanisms are largely unresolved. We led efforts to (1) chart vagal sensory neuron diversity, (2) adapt genetic tools to map, image, control, and ablate different sensory neuron types, and (3) identify neuronal sensory receptors involved in interoception. We characterized a myriad of sensory neurons that innervate the lungs, stomach, intestine, heart, arteries, and larynx, and control breathing, protect airway integrity, detect blood pressure changes, and monitor meal volume and content. In a collaborative effort with Ardem Patapoutian, we identified a critical role for Piezo mechanoreceptors in the sensation of airway stretch and neuronal sensation of blood pressure underlying the baroreceptor reflex. We also used similar approaches to chart brainstem neurons that mediate nausea-related behaviors. Identifying neurons and receptors that control autonomic physiology builds an essential foundation for mechanistic study and therapy design.

Olfaction is one of our five basic external senses, and a principal mechanism by which we perceive the external world. Sensory receptors define our capacity for perception, and we identified novel olfactory receptor families (TAARs, FPRs), opening up new avenues of research to probe the neuronal basis of perception and behavior. We discovered ligands for many TAARs, including ethological odors derived from carnivores, male mice, and carrion that evoke innate aversion or attraction responses. We also identified a pheromone of juvenile mice that inhibits adult sexual behavior, and uncovered a noncanonical mechanism for sweet taste detection in hummingbirds that involved transformation of the ancestral umami receptor. Together, our work provides a molecular framework for understanding how sensory inputs are processed to evoke variable and complex behaviors.