Stephen Liberles
Assistant Professor of Cell Biology

Molecules, receptors, and neural circuits involved in olfaction and instinctive behavior.

Harvard Medical School
240 Longwood Avenue
Seeley Mudd Building, Room 529
Boston, Massachussetts 02115
Tel: 617-432-7283

Lab Size: Between 5 and 10

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 responses. First, we study olfactory cues, such as pheromones, food odors, and predator odors that elicit innate mating, foraging, and avoidance responses in mice. Second, we are identifying hypothalamic genes that control feeding behavior and other instinctive drives.

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 113 in zebrafish. These receptors likely evolved from receptors for aminergic neurotransmitters and hormones that control behavior and emotion. Several TAAR ligands are metabolites that occur naturally in urine, a rich source of social odors for many mammals. Furthermore, the biosynthesis of some TAAR ligands is highly dynamic, varying with age, gender, or behavioral state. One TAAR ligand is a reported pheromone, raising the possibility that some TAARs are pheromone receptors that stimulate innate behaviors and physiological responses. 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.

The hypothalamus is an important regulator of instinctive behaviors- such as feeding, sleep, aggression, and sex. Studying the neural circuits that control these instinctive behaviors at a molecular level has presented a great challenge, in part because of limited technology. To study instinctive behaviors, we have developed a strategy of first purifying hypothalamic neurons that are activated during various behavioral states by flow cytometry, and then asking what genes they express by PCR.
Initial experiments have focused on characterizing neurons in the feeding control center of the hypothalamus, the arcuate nucleus. Specific neurons in the arcuate nucleus sense gut-derived feeding signals- such as insulin, leptin, and ghrelin- and respond by inducing a neural cascade that influences feeding behavior.  We have been able to isolate hunger-activated neurons, and are beginning to search for novel genes expressed in these cells. In particular, we are focusing on cell surface receptors- such as GPCRs and tyrosine kinase receptors- that may serve as receptors for additional gut-derived signals. If the technique proves successful for identifying genes involved in appetite control, future projects will involve searching for genes that control other instinctive behaviors mediated by the hypothalamus.

Ferrero, D.M., et al, “Detection and avoidance of a carnivore odor by prey,” (2011), PNAS

Liberles, S.D., et al, “Formyl peptide receptors are candidate chemosensory receptors in the vomeronasal organ”, (2009), PNAS, 106 (24): 9842-9847

Liberles, S.D. and Buck, L.B., “A second class of chemosensory receptors in the olfactory epithelium”, (2006) Nature, 442 (7103), 645-650