The proper functioning of the sensory and endocrine systems is essential for the health and well being of human beings. Sensory experiences often have direct influence on endocrine systems and many experience- induced endocrine responses are innate. However, the neural circuitry that controls these processes is not well understood. In the proposed project, we will study the mouse vomeronasal circuitry as a model system to elucidate the neural mechanism of sensory information processing and mechanism of sensory control of endocrine function. In vertebrates, innate behaviors such as mating rituals and territorial aggression are elicited by the detection of pheromone cues through the vomeronasal organ. These behaviors are robust and stereotyped, but their expression critically depends on the proper response to pheromones. The vomeronasal circuit connects directly to the endocrine systems and influences their output. These circuits are largely genetically determined and there is an intrinsic link between sensory input and the behavior and endocrine responses, making it an attractive and tractable circuitry to understand sensory processing and sensory control of endocrine changes. The objective of this application is to identify the sex pheromones, their receptors and trace the neural circuitry processing the information. We hypothesize that male and female pheromones elicit responses from distinct populations of cells in the VNO. This information is represented in the brain by the distinct spatial patterns of the sensory neuron projection and allows sex discrimination and differential endocrine changes in response.
In Aim 1, we will use transgenic animals expressing calcium indicators in the sensory neurons to identify cells that respond to specific pheromones in urine. Combining fluorescent imaging, mouse genetics and molecular biology, we will identify the pheromone receptor gene expressed by these cells. We will screen urine fractions to chemically identify the pheromones.
In Aim 2, we will trace the information flow by genetically labeling the neurons expressing the sex pheromone receptors.
In Aim 3, we will combine genetic experiments with behavioral assays to analyze pheromone control of endocrine responses. Animals have evolved specialized neural circuitry that links sensory input to endocrine responses. The complexity of sensory experiences makes it difficult to study sensory control of endocrine response in humans. The vomeronasal system is highly evolved in most vertebrate species and is specialized in controlling endocrine system and emotional states. Similar circuits exist in humans but may have been compacted during primate evolution to consist of mostly the main olfactory, and to include other sensory modalities. Insight gained from this study will help to elucidate control mechanism of endocrine systems and motivational states, as well as the processing of social communication.

Public Health Relevance

The proper functioning of the sensory and endocrine systems is crucial to the health and well being of humans. Social communications and the emotional well being are critically dependent on the proper processing of social information. Cognitive deficits in many psychiatric disorders are largely the results of defects in the brain circuits. The proposed study will allow us to understand the neural circuitry that mediates social communications among animals, which has a direct influence on the endocrine control of reproductive and aggressive behaviors. Elucidating the functional logic of this circuit will provide insights into the brain mechanisms for sensory information processing, social communications and endocrine control. This knowledge can be used for diagnostic and therapeutic applications.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
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Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
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Sullivan, Susan L
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Stowers Institute for Medical Research
Kansas City
United States
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Duyck, Kyle; DuTell, Vasha; Ma, Limei et al. (2017) Pronounced strain-specific chemosensory receptor gene expression in the mouse vomeronasal organ. BMC Genomics 18:965
Haga-Yamanaka, Sachiko; Ma, Limei; Yu, C Ron (2015) Tuning properties and dynamic range of type 1 vomeronasal receptors. Front Neurosci 9:244
Kim, SangSeong; Ma, Limei; Unruh, Jay et al. (2015) Intracellular chloride concentration of the mouse vomeronasal neuron. BMC Neurosci 16:90
Yu, C Ron (2015) TRICK or TRP? What Trpc2(-/-) mice tell us about vomeronasal organ mediated innate behaviors. Front Neurosci 9:221
Haga-Yamanaka, Sachiko; Ma, Limei; He, Jie et al. (2014) Integrated action of pheromone signals in promoting courtship behavior in male mice. Elife 3:e03025
Yu, C Ron (2013) Calcium imaging of vomeronasal organ response using slice preparations from transgenic mice expressing G-CaMP2. Methods Mol Biol 1068:211-20
Kim, SangSeong; Ma, Limei; Jensen, Kristi L et al. (2012) Paradoxical contribution of SK3 and GIRK channels to the activation of mouse vomeronasal organ. Nat Neurosci 15:1236-44
Kim, SangSeong; Ma, Limei; Yu, C Ron (2011) Requirement of calcium-activated chloride channels in the activation of mouse vomeronasal neurons. Nat Commun 2:365
Ma, Limei; Haga-Yamanaka, Sachiko; Yu, Qingfeng Elden et al. (2011) Imaging neuronal responses in slice preparations of vomeronasal organ expressing a genetically encoded calcium sensor. J Vis Exp :
He, Jie; Ma, Limei; Kim, Sangseong et al. (2010) Distinct signals conveyed by pheromone concentrations to the mouse vomeronasal organ. J Neurosci 30:7473-83

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