Identification of the ligands and sensory neurons that mediate pheromone behavior

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DESCRIPTION (provided by applicant): Neural information processing utilizes an unfathomable number of discrete circuits composed of seemingly similar neurons dedicated to specific and diverse tasks. Elucidation of the temporal activity, spatial organization, or molecular differences among neurons that lead to distinct perceptual, neuroendocrine, or behavioral outcomes is critical to the design of effective therapeutic intervention. The molecular-genetics revolution of the investigation of chemosensory-mediated behavior has provided the potential to identify, manipulate, and reveal the mechanisms that underlie individual neural circuits. Though great progress has been made in identifying groups of receptors and neurons that participate in chemosensory information coding we do not know the specific ligands and neural circuits that mediate any defined behavior in a mammalian model. The objective of this research is to identify the pheromone ligands, responding sensory neurons, and necessary neuronal circuits that mediate a specific social behavior in the mouse. 1) We will use a novel chemical capture method to chemically tag, enrich, and profile small molecules of any physicochemical class to identify the specific pheromones that encode a single defined behavior. 2) We expect that an individual behavior is mediated by a dedicated subset of chemosensory neurons. We will use calcium imaging combined with molecular and histochemical methods to define the sensory neurons that promote the behavior. 3) Social behavior in rodents is plastic; the age and gender of the receiving animal determines whether it will respond. We predict that neuronal pathways that are active in responding animals are inactive, not present, or spatially distinct from those activated in non-responding animals. We will analyze mice expressing a novel genetic reporter of cFos activation to define and manipulate the neural circuit underlying a single behavior. We expect that at the completion of these aims we will have made an important first step that will allow us to predictably activate social behavior in mice and therefore define at the cellular and molecular level underlying mechanisms of neural function and dysfunction. PUBLIC HEALTH RELEVANCE In the mouse, sensory neurons that respond to pheromones activate nuclei in the medial amygdala and hypothalamus. These same nuclei have been implicated in regulating social behavior in humans. However, elucidation of the organization, functional significance, and specific mechanism of action of these centers is impeded by the lack of knowledge of the corresponding function of subsets of amygdala and hypothalamic neurons. We are defining components of the signals that elicit and regulate a known behavior. This important first step will allow us to predictably activate social responses in mice, and therefore define at the cellular and molecular level, the underlying mechanisms of neural function and dysfunction.