From the nose to the brain: pathways that control instinctive mouse behaviors
Neural circuits that control many complex behaviors are poorly understood at a molecular level. Recent advances in understanding the molecular logic of olfaction provide powerful inroads into studying a range of instinctive behaviors, such as appetite, sex, and aggression. We recently discovered a second class of chemosensory receptors in the olfactory epithelium termed trace amine-associated receptors or TAARs (1), and these receptors are prime candidates for influencing certain instinctive behaviors.
(1) Characterization of candidate mammalian pheromone receptors
The mammalian nose is a powerful chemosensor, capable of detecting and distinguishing a myriad of chemicals. Sensory neurons in the olfactory epithelium contain two types of receptors: odorant receptors (ORs), which comprise the largest gene family in mammals, and TAARs, a smaller family of receptors distantly related to biogenic amine receptors. Do TAARs play a specialized role in olfaction distinct from that of ORs? Genes encoding TAARs are found in diverse vertebrates- from fish to mice to humans- and like OR genes, are expressed in unique subsets of sensory neurons in the olfactory epithelium. TAAR ligands include a series of volatile amines, several of which are natural constituents of mouse urine, a rich source of rodent social cues. One chemical is linked to stress and two others are enriched in male versus female urine. Furthermore, one TAAR ligand is reported to be a pheromone.
Future research will explore the roles of TAARs in mammalian olfaction, and the hypothesis that some TAARs may be involved in detecting pheromones. Project aims include: (1) searching for novel TAAR agonists- (Are other agonists natural products in mice and are they produced by animals of certain genders, ages, or behavioral states?), (2) searching for agonists for human TAARs, (3) determining the behavioral consequence of TAAR activation by gene knockout or odor exposure, and (4) examining the neural circuits downstream of TAAR activation.
(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.
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