Thomas J. Park - US grants

DESCRIPTION: The conceptual issue addressed in this proposal is how neurons in the lateral superior olive (LSO) obtain their selectivity for interaural intensity disparities (IIDs), and whether neurons with different IID selectivities are arranged in an orderly fashion within isofrequency contours of the LSO. The impetus for this proposal derives from the success that investigators have had in discovering how medial superior olivary (MSO) neurons, and their avian analogue in the nucleus laminaris, obtain their selectivity for a particular interaural time disparity and how those features are systematically represented with those nuclei. In contrast, the way in which LSO cells obtain their individual sensitivity for a particular IID and the degree to which an orderly arrangement of IID sensitivities might exist in the LSO are issues that have received little attention and are poorly understood. Only Reed and Blum have proposed a hypothesis that addresses both the issue of how LSO cells obtain their individual IID selectivity and what structural features could also impart an orderly arrangement of IID selectivity within isofrequency contours. Their hypothesis, however, has never been tested experimentally. Moreover, it relies only on the differences in thresholds of the inputs from the two ears, and thus it does not incorporate a number of other important features of the LSO, such as latency and time-intensity trading. The aims of this proposal are to test the Reed and Blum hypothesis and fill in the gaps in our knowledge about how LSO neurons obtain their particular IID selectivity. The first series of experiments has two goals: 1) To survey the LSO and obtain an overall view of the prevalence of neurons whose IID selectivities are predicted by threshold differences between the excitatory and inhibitory ears. 2) To distinguish between the hypothesis based on threshold differences, and alternative hypotheses which predict that IID selectivity is determined by differences in the relative strengths of the excitatory and inhibitory inputs, differences in arrival times from the two ears, or by some combination of threshold, strength and latency differences. These hypotheses will be evaluated by obtaining indices of input thresholds, strengths and latencies for each ear and then confirming their relative contributions for creating the neuron s IID selectivity through time-intensity trading experiments. A second series of experiments will reveal the degree to which IID selectivities are arranged in an orderly fashion within one isofrequency contour in the LSO. These experiments will exploit the greatly hypertrophied 60 kHz isofrequency contour of the mustache bat s LSO, yielding data from a large number of cells within one isofrequency contour.

The objective of this project is to investigate adaptations in the peripheral and central nervous systems of the naked mole-rat. Naked mole-rats have an unusual lifestyle in that they combine a fully subterranean existence with extreme sociality, and a proclivity for living in large numbers. Thus, in their crowded burrows where many animals share a limited air supply, these animals are exposed to the challenges of breathing exceptionally high levels of carbon dioxide and exceptionally low levels of oxygen. Initial studies have revealed that, behaviorally, naked mole-rats are extremely resistant to high carbon dioxide and low oxygen. The goals of the project now are to better understand the underlying mechanisms that make this resistance possible. The project uses a variety of methods including behavioral, electrophysiological, anatomical, and molecular techniques with an emphasis on moving freely between experiments that focus on neural mechanisms and those that focus on natural behaviors. The project also relies heavily on comparative data from closely and distantly related species that have evolved under different carbon dioxide and oxygen conditions. The expected impacts of this project include contributing to the understanding of the nervous system in general, and to adaptations to environmental challenges in particular. Also, the project will develop a new model system for studying the evolution of the nervous system and behavior. The project will provide training opportunities in systems neuroscience for both graduate and undergraduate students. The project will also enhance laboratory courses in that several laboratory exercises have been developed with these animals.

This project will contribute to understanding tolerance of hypoxia (low oxygen levels) within the nervous system by studying the African naked mole-rat. This mammal lives in crowded, oxygen-starved burrows, and has evolved the ability to survive extended periods of oxygen deprivation without triggering brain cell death. This project will test new target genes that may protect brain cells from cell death resulting from exposure to hypoxia, with potential applications in designing new treatments for humans that experience oxygen deprivation during traumatic events like a stroke or heart attack. By studying the genome of the naked mole-rat, the investigators previously discovered changes in the genes of this species that likely reduce cell death from oxygen deprivation. The goal of the current project is to test each of those genes for its potential role in brain cell protection. The project will support two graduate students each year, who will help mentor a number of undergraduate student researchers recruited from existing programs targeting students from groups underrepresented in science. Information on the naked mole-rat will be shared via outreach to a local zoo and area high schools. <br/><br/>This project will investigate molecular, cellular, and physiological mechanisms in the brain that underly hypoxia tolerance and will contribute to understanding evolutionary adaptations to environmental challenges in general. The naked mole-rat will be developed as a model system for studying the molecular and genetic basis of hypoxia tolerance in the mammalian brain. Brain cells from the naked mole-rat display an intrinsic tolerance to hypoxia and a dramatic reduction in calcium accumulation during hypoxia compared with most other mammals, which is hypothesized to result from multiple adaptations that limit and buffer calcium currents. Additionally, there appears to be a significant neuroprotective role for the endocannabinoid system in the brain of the naked mole-rat. This project will specifically examine the neuroprotective function of the calcium channel TRPM7, NMDA glutamate-receptor ion channels, a calcium-related kinase, and the calcium-binding protein parvalbumin, as well as the endocannabinoid system. The investigators will use brain slice electrophysiology, mass spectrometry, and gene manipulation techniques to determine the molecular and genetic basis of hypoxia tolerance in the naked mole-rat. Experiments designed to introduce naked mole-rat-specific gene alterations into mouse cells will test the hypothesis that the changes in the naked mole-rat genes can also protect other species. Understanding how brain cells are protected from oxygen deprivation may ultimately lead to new therapeutic targets for heart attack and stroke victims. Several graduate and undergraduate student trainees will participate in the research, and results will be incorporated into undergraduate courses and outreach activities.<br/><br/>This award was co-funded by the Physiological Mechanisms and Biomechanics Program and the Neural Systems Cluster Organization Program in BIO-IOS.<br/><br/>This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.