Molecular mechanisms that regulate aggressive behaviour
Final Report Abstract
Aggression is a robust innate stereotyped social behavior in many animals such as flies, mammals and humans. In the mouse, intra-male territorial aggression is initiated in the olfactory system by the detection of gender specific pheromones. However, the nature of the aggressionpromoting odorants, the sensory neurons that detect them as well as the neural circuits that process the behavioral information remain mysterious. To understand this type of social behavior, we have identified the sensory neurons in the olfactory system that detect aggression-promoting pheromones. We identified neurons in the vomeronasal organ that express the G-protein Gαo as an essential requirement for efficient transduction of aggression-pheromone detection. Conditional deletion of the Gαo gene are accompanied by striking deficits in pheromone detection and both male-male aggression were severely reduced, or absent. Therefore, our results reveal that Gαo is necessary for the neural coding of chemosensory cues that promote aggressive interactions in mice. We have further identify a family of neurons among Gαo-expressing neurons characterized by the expression of H2Mv genes, a family of nine nonclassical class I major histocompatibility complex genes. We deleted all 9 H2Mv genes by chromosome engineering and generated mouse strains deficient for all nine H2Mvs. These mutants displayed reduced sensitivity to chemostimuli and displayed pronounced deficits in aggressive behaviors. Surprisingly, not only male aggression but also maternal aggression in females was impaired on both H2Mv and Gαo mutants. We demonstrated that the same pheromones that initiate malemale aggression also induce maternal aggression in lactating females, and that this form of aggression depends on Gαo and H2Mv-expressing neurons. Our results in Gαo and H2Mv mutants also showed severe alterations in the signal transduction of pheromones implicated in other behavioral responses. Thus, we deviated from our initial focus on aggression and studied sexual behavior in females. We found that Gαo mutant females show severe alterations in sexual and reproductive behaviors. These include, timing of puberty onset, and estrous cycle, defective puberty acceleration and ovulation induction, reduced sexual receptivity and male preference. These results highlight that sensory neurons of the Gαo-expressing vomeronasal subsystem, together with the receptors they express and the molecular cues they detect, control a wide range of fundamental mating and reproductive behaviors in female mice. One step further, we addressed the logic of the circuitry of chemosignal-detecting olfactory neurons in the brain. We studied the neural pathways underlying avoidance to predators and found that innate odor-driven behavior driven by parallel olfactory subsystems converge in the ventromedial hypothalamus. We determined that innate predator-evoked avoidance is driven by parallel, non-redundant processing of volatile and nonvolatile predator odors through the activation of multiple olfactory subsystems including the Grueneberg ganglion, the vomeronasal organ, and the main olfactory epithelium. Stimulation of these different subsystems resulted in the activation of the same subnuclei of the medial amygdala and ventromedial hypothalamus, regions implicated in fear, anxiety and defensive behaviors. Thus, the mammalian olfactory system has evolved multiple, parallel mechanisms for predator detection that converge in the brain to facilitate a common behavioral response. Overall, our findings provide significant insights into the genetic substrates and circuit logic of odor-driven, innate behaviors and may serve as a valuable model for studying innate aggressive, sexual and fear behaviors, as well as human emotional disorders.
Publications
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G protein Gαo is essential for vomeronasal function and aggressive behavior in mice. Proc Natl Acad Sci USA. 2011 Aug 2;108(31):12898-903
Chamero P, Katsoulidou V, Hendrix P, Bufe B, Roberts R, Matsunami H, Abramowitz J, Birnbaumer L, Zufall F, Leiders-Zufall T
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Newborn interneurons in the accessory olfactory bulb promote mate recognition in female mice. Front Neurosci. 2011;5:113
Oboti L, Schellino R, Giachino C, Chamero P, Pyrski M, Leinders-Zufall T, Zufall F, Fasolo A, Peretto P
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From genes to social communication: molecular sensing by the vomeronasal organ. Trends Neurosci. 2012 Oct;35(10):597-606
Chamero P, Leiders-Zufall T, Zufall F
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A Family of Nonclassical Class I MHC Genes Contributes to Ultrasensitive Chemodetection by Mouse Vomeronasal Sensory Neurons. J Neurosci. 2014 Apr 9;34(15):5121-33
Leinders-Zufall T, Ishii T, Chamero P, Hendrix P, Oboti L, Schmid A, Kircher S, Akiyoshi S, Khan M, Vaes E, Zufall F, Mombaerts P
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Major contribution of Gαo-dependent vomeronasal chemoreception to sexual and reproductive behavior in female mice. BMC Biology 2014, 12:31
Oboti L, Pérez-Gómez A, Keller M, Jacobi E, Birnbaumer L, Leinders-Zufall T, Zufall F, Chamero P
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Signaling mechanisms and behavioral function of the mouse basal vomeronasal neuroepithelium. Front Neuroanat. 2014 Nov 26;8:135
Pérez Gómez A, Stein B, Leinders-Zufall T, Chamero P
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Innate Predator Odor Aversion Driven by Parallel Olfactory Subsystems that Converge in the Ventromedial Hypothalamus. Curr Biol. Volume 25, Issue 10, 18 May 2015, Pages 1340-1346
Pérez-Gómez A, Bleymehl K, Stein B, Pyrski M, Birnbaumer L, Munger SD, Leinders-Zufall T, Zufall F, Chamero P
