Internal and External Sensory Systems

Neural circuits that generate perception and control behavior are poorly understood at a molecular level. We are interested in understanding how the brain processes external sensory and internal homeostatic signals to initiate behavioral and physiological responses. We study how our senses of smell and taste process different environmental cues (like pheromones, food cues, predator odors) to elicit innate mating, foraging, and avoidance responses. In recent efforts, we are also investigating internal sensory modalities of the vagus nerve.

1. Olfaction and pheromone signaling in mammals

Many social behaviors of the mouse, such as mating, fighting, and nurturing of young, involve the transmission and detection of pheromones. Sensory neurons in the mouse nose detect odors and pheromones using ~1,600 different G Protein-Coupled Receptors (GPCRs). We recently identified two novel families of mammalian olfactory receptors, termed trace amine-associated receptors (TAARs) and formyl peptide receptors (FPRs), some of which are prime candidates to detect semiochemicals such as pheromones and predator odors.

Trace amine-associated receptors

TAARs are olfactory receptors in diverse vertebrates- there are 15 in mice, 6 in human, and 112 in zebrafish. TAARs are G Protein-Coupled Receptors distantly related to biogenic amine receptors. Like odorant receptors, TAARs are expressed in sparse olfactory sensory neurons via monoallelic receptor choice. We identified ligands for many olfactory TAARs, and each detects different combinations of volatile amines, including ethological odors from carnivores (TAAR4; 2-phenylethylamine), male mice (TAAR5; trimethylamine) and carrion (cadaverine; TAAR13c). TAARs provide a powerful model system for unraveling the molecular basis of odor aversion and attraction behavior. We are studying all aspects of TAAR-mediated signaling, from the identity of natural product ligands to the characterization of neural pathways that influence behavior.

Formyl peptide receptors

FPRs are key mediators of the innate immune response to invasive bacteria. The Fpr gene family underwent sudden and recent expansion in rodents but not other placental mammals, creating novel rodent Fpr genes of unknown function. We recently found that five mouse FPRs acquired a distinct physiological role, as chemosensory receptors in the vomeronasal organ (VNO). Like other VNO receptors, these FPRs are selectively expressed in dispersed subsets of VNO sensory neurons. Immune system FPRs recognize formylated peptides, which are synthesized by bacteria, mitochondria, and chloroplasts, and would represent a novel VNO ligand class, distinct from other VNO-activating peptides, such as MHC peptides and various urine- and gland-derived peptides. We are interested in identifying ligands for VNO FPRs, and more broadly, defining a general role for the VNO in detecting biogenic peptides that stimulate innate behaviors and serve as social cues related to gender, age, social status, and individuality.

2. Sensory modalities of the vagus nerve

Internal sensory systems of the vagus nerve control basic respiratory, cardiovascular, immune, and digestive functions. Surprisingly, despite medical importance, each sensory modality of the vagus nerve remains poorly defined at a molecular and cellular level. Using molecular and genetic approaches, we systematically identified receptors and cell types of the vagus nerve with different autonomic functions. We developed a collection of genetic reagents to study vagal sensory neuron subtypes, and adapted tools based on Cre/loxP technology for anatomical mapping, in vivo imaging, and remote control of neural activity. Identifying neurons and receptors that mediate particular physiological drives builds an important foundation for mechanistic study and therapy design.