Mice use pheromones, compounds emitted and detected by members of the same species, as cues to regulate social behaviours such as pup suckling, aggression and mating1. Neurons that detect pheromones are thought to reside in at least two separate organs within the nasal cavity: the vomeronasal organ (VNO) and the main olfactory epithelium (MOE)2. Each pheromone ligand is thought to activate a dedicated subset of these sensory neurons. However, the nature of the pheromone cues and the identity of the responding neurons that regulate specific social behaviours are largely unknown. Here we show, by direct activation of sensory neurons and analysis of behaviour, that at least two chemically distinct ligands are sufficient to promote male–male aggression and stimulate VNO neurons. We have purified and analysed one of these classes of ligand and found its specific aggression-promoting activity to be dependent on the presence of the protein component of the major urinary protein (MUP) complex, which is known to comprise specialized lipocalin proteins bound to small organic molecules1, 3, 4. Using calcium imaging of dissociated vomeronasal neurons (VNs), we have determined that the MUP protein activates a sensory neuron subfamily characterized by the expression of the G-protein Gαo subunit (also known as Gnao) and Vmn2r putative pheromone receptors (V2Rs). Genomic analysis indicates species-specific co-expansions of MUPs and V2Rs, as would be expected among pheromone-signalling components. Finally, we show that the aggressive behaviour induced by the MUPs occurs exclusively through VNO neuronal circuits. Our results substantiate the idea of MUP proteins as pheromone ligands that mediate male–male aggression through the accessory olfactory neural pathway.

•A variety of mammalian pheromones have recently been isolated from the mouse.•Mouse pheromones, cognate sensory neurons, and their elicited behaviors are diverse.•Main olfactory epithelium and vomeronasal sensory neurons detect pheromones.•The logic of why two olfactory organs function to detect pheromones remains unknown.The concept of mammalian pheromones was established decades before the discovery of any bioactive ligands. Therefore, their molecular identity, native sources, and the meaning of their detection has been largely speculative. There has been recent success in identifying a variety of candidate mouse pheromones and other specialized odors. These discoveries reveal that mammalian pheromones come in a variety of ligand types and they are detected by sensory neurons that are pre-set to promote an array of social and survival behaviors. Importantly, recent findings show that they activate molecularly diverse sensory neurons that differ from canonical odorant detectors. These novel sensory neurons hold future promise to unlock the mystery of how their detection is hardwired to generate behavior.

•The same pheromone can evoke different behaviors in different recipients.•State-dependent control of pheromone responses occurs in both the periphery and brain.•Hormones and experience sculpt pheromone responses in the limbic system.A single sensory cue can evoke different behaviors that vary by recipient. Responses may be influenced by sex, internal state, experience, genotype, and coincident environmental stimuli. Pheromones are powerful inducers of mouse behavior, yet pheromone responses are not always stereotyped. For example, male and female mice respond differently to sex pheromones while mothers and virgin females respond differently to pup cues. Here, we review the origins of variability in responses to reproductive pheromones. Recent advances have indicated how response variability may arise through modulation at different levels of pheromone-processing circuitry, from sensory neurons in the periphery to central neurons in the vomeronasal amygdala. Understanding mechanisms underlying conditional pheromone responses should reveal how neural circuits can be flexibly sculpted to alter behavior.

Aggression and fear are often thought to be distinct behavioral states, yet they share several common output responses. In the mouse, both can be initiated by specialized odor cues. How these cues signal through the olfactory system to promote behavior is largely unknown. Recent experiments have started to uncover the relevant signaling ligands, chemosensory receptors, and responsive sensory neurons that together enable the precise manipulation of behaviorally relevant neural circuits. Moreover, the use of molecular genetics and new experimental strategies has begun to reveal how the central nervous system processes olfactory information to initiate aggression and fear. A sensory-initiated comparative study of these two fundamental threat reactions promises to offer new mechanistic insight.Highlights► Olfactory cues promote innate fear and aggression. ► Candidate aggression and fear promoting odorant receptors have been identified. ► Overlapping and distinct brain regions mediate innate threat behaviors. ► Genetics underlying innate threat responses may offer mechanistic insight.

Investigation of how specialized olfactory cues, such as pheromones, are detected has primarily focused on the function of receptor neurons within a subsystem of the nasal cavity, the vomeronasal organ (VNO). Behavioral analyses have long indicated that additional, non-VNO olfactory neurons are similarly necessary for pheromone detection; however, the identity of these neurons has been a mystery. Recent molecular, behavioral, and genomic approaches have led to the identification of multiple atypical sensory circuits that display characteristics suggestive of a specialized function. This review focuses on these non-VNO receptors and neurons, and evaluates their potential for mediating stereotyped olfactory behavior in mammals.

What makes males and females behave differently? Although genetic master-regulators commonly underlie physical differences, sexually dimorphic behavior is additionally influenced by sensory input such as olfactory cues. Olfaction requires both ligands for signaling and sensory neural circuits for detection. Specialized subsets of each interact to generate gender-dimorphic behavior. It has long been accepted that males and females emit sex-specific odor compounds that function as pheromones to promote stereotypic behavior. Significant advances have now been made in purifying and isolating several of these sex-specific olfactory ligands. In contrast, the neural mechanisms that enable a gender-dimorphic response to these odors remain largely unknown. However, first progress has been made in identifying components of sexually dimorphic olfactory circuits in both Drosophila and the mouse.