Yu Lab C. Ron Yu, Ph.D. Assistant Investigator cry@stowers-institute.org Yu Lab Research Website

     We are interested in the mechanisms of sensory information processing in the brain. We study the neural circuits and their physiological functions in the mouse olfactory and vomeronasal systems to reveal how the nervous system detects, parses, and integrates sensory information and generates meaningful behaviors. The lab employs a combination of modern technologies that include molecular genetics, optical imaging, electrophysiology, and behavioral assays.

     In terrestrial vertebrates, the sense of smell provides important information about the environment and enables the animals to detect food, avoid predators, and find mates. Odors are detected by the sensory neurons in the olfactory epithelia in the nose, which pass the information to the main olfactory bulb (MOB) for further processing. Pheromones, a set of chemical signals emitted by the animals for intra-species chemo-communication, convey information about the sexual, social, and reproductive status of other individuals. Pheromones trigger a restricted repertoire of innate and stereotyped behaviors such as mating rituals, territorial aggression, and neuroendocrine responses. Pheromones are detected by their receptor neurons in the vomeronasal organ (VNO), which project axons to the accessory olfactory bulb (AOB). The olfactory circuits are largely genetically determined, but they are subject to plastic changes through experience. There is an intrinsic link between sensory input and behavioral output in the olfactory circuits, making them an attractive and tractable system to study sensory processing and developmental changes in the circuitry.

We are currently engaged in the following areas of research:

Pheromone detection and sensory processing in the vomeronasal pathway.

Signaling mechanism of pheromone detection:

     Our investigation of the ionic mechanisms of pheromone activation reveals that VNO signaling is mediated by Trp2, a cationic channel exclusively expressed in the VNO, and SK3, a small-conductance calcium-activated potassium channel. We also discovered an unusual compartmentalized ionic environment in the VNO. The VNO mucus, where the neuronal dendrites reside, contains a high concentration of potassium, while the somas are in a low potassium environment. Due to this unusual potassium environment, activation of the SK3 channel in the dendrites allows potassium flux into cells and augments the depolarization mediated by Trp2. We are investigating the mechanistic link between pheromone receptor activation and the depolarization of the neurons using electrophysiology approaches, including field potential recording, single cell extracellular recording and patch clamp techniques.

Representation of pheromones in the vomeronasal organ and in the brain:

     We are interested in the representation of pheromone activation in the brain. We first address this problem in the VNO by generating transgenic animals expressing genetically encoded calcium sensors. Our initial experiments indicate that male and female pheromones activate distinct but overlapping populations of vomeronasal neurons. A small subset of cells is specifically tuned to male pheromones while another is tuned to female pheromones. We also found cells that respond to both male and female pheromones but with different temporal profiles. Thus, pheromone information is initially encoded in the differential activation of VNO sensory neurons and this is likely to be transformed into a topographic representation in the AOB to elicit innate behaviors. We will investigate how this differential activation is reflected in the AOB using our state-of-the-art Zeiss LSM 510 META confocal system.

Behavioral consequences of altered pheromone detection:

     We have made targeted perturbations in pheromone detection in the VNO by genetically eliminating Trp2 and SK3 channels. Mice lacking either of these channels show marked defects in displaying normal aggressive behavior. Mating behaviors are also altered. Trp2 -/- mice show significantly increased male-male mounting while male-female mounting is not affected. The SK3 -/- mutants, however, show no increased male-male mounting but there is a significant delay in male-female mounting. We are using genetic methods to selectively inactivate different neuronal pathways involved in pheromone information processing to further reveal the contribution of different part of the circuits to animal innate behaviors.

Activity-dependent mechanism of circuit formation in the main olfactory system.

The role neural activity plays in establishing and maintaining the olfactory connections:

     In previous experiments, we used genetic methods to selectively dampen neural excitability in the olfactory epithelial neurons. As a result of electrical silencing in large numbers of neurons, olfactory axons in the transgenic mice show a developmental delay in comparison to axons from wild-type mice. Moreover, the silenced olfactory neurons fail to target to the proper glomeruli in the olfactory bulb such that neurons expressing the same receptor genes innervate numerous glomeruli rather than the two fixed ones seen in the wild-type. We are further investigating the role of neural activity plays in establishing specific connections between the sensory neurons and the mitral cells.

Molecular mechanism of activity dependent circuit formation:

     Electrical activity is likely to impinge on the molecular machineries that recognize guidance cues to establish and maintain proper connections. We are taking several approaches, including microarray technology to identify the molecules that are specifically regulated by neural activity. We are comparing gene expression profiles between olfactory neurons that are silenced by the overexpression of the Kir2.1 channel and that of wild-type olfactory neurons. A differential expression in genes is likely to result from electrical silencing of these neurons. These genes, therefore, are potential candidates regulated by neural activity that may be involved in axonal targeting.

Academic Appointment: Assistant Professor, Department of Anatomy & Cell Biology, The University of Kansas School of Medicine

Leypold BG, Yu CR, Leinders-Zufall T, Kim MM, Zufall F, Axel R. Altered sexual and social behaviors in trp2 mutant mice. Proc Natl Acad Sci U S A. 2002;99:6376-6381. Abstract

Yu CR, Power J, Barnea G, O'Donnell S, Brown HE, Osborne J, Axel R, Gogos JA. Spontaneous neural activity is required for the establishment and maintenance of the olfactory sensory map. Neuron. 2004;42:553-566. Abstract