Department of Cell BiologyHarvard Medical School
250 Longwood Ave.
Seeley Mudd Building, Room 529
Boston, MA 02115
Lab Members: 2 postdoctoral fellows, 3 graduate students
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Molecular basis of instinctive animal behavior
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.
(1) 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.
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 occur naturally in urine, a rich source of social odors for many mammals. The biosynthesis of some TAAR ligands is highly dynamic, varying with age, gender, or behavioral state. Furthermore, 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.
(2) Charting neural circuits that control appetite
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.
Last Update: 8/22/2013