Kyung-An Han - US grants

DESCRIPTION: (Adapted From The Applicant's Abstract) Neuromodulation is important for behavioral plasticity. The overall goal of this study is to explore the molecular and biochemical nature of this link. Novel dopamine and octopamine receptors of Drosophila have been isolated and shown to have highly enriched expression in the mushroom bodies, a brain structure indispensable for olfactory learning. The receptors produce increases in cAMP and intracellular Ca2+, key mediators of signal transduction pathways crucial for synaptic plasticity. Using recently isolated receptor mutants, the studies will focus on addressing three fundamental questions. 1) Do the receptors play a role in associative learning? 2) Do the receptor mutants fail at all types of learning or is there a selective deficit? 3) Which effector systems, cAMP and/or Ca2+, are responsible for any behavioral deficits observed? Given the diversity and complexity of behavior, comparative studies of the receptor mutants in behavioral paradigms should help dissect the elaborate physiological processes underlying behavioral plasticity. These studies may help to understand the roles for biogenic amines in human diseases, such as schizophrenia, and the actions of biogenic amine receptors in cognition.

[unreadable] DESCRIPTION (provided by applicant): Octopamine (OA) is a major monoamine in invertebrates and is functionally similar to norepinephrine (NE) of mammals. The Drosophila OA receptor (OAMB) activates cAMP and intracellular calcium increases and is highly enriched not only in subsets of neurons in the brain and the thoracico-abdominal ganglion, but also in the female reproductive system. To investigate OAMB's physiological functions, we generated OAMB mutants including hypomorphic and null alleles. Remarkably, OAMB mutant females were defective in ovulation and thus contained abnormally retained mature eggs in their ovaries. By employing powerful genetic tools and tremendous resources of Drosophila, the proposed studies are aimed at identifying the anatomical site(s) in which OAMB regulates ovulation and the downstream effectors that functionally interact with OAMB for this process. These will be primarily accomplished by adopting the binary GAL4/UAS expression system and the genetic suppressor screen. Knowledge obtained from the proposed and follow-up studies will help unravel physiological and cellular mechanisms by which OAMB and perhaps other adrenergic receptors (ARs) regulate ovulation in Drosophila and other animals. NE, for example, exerts profound effects on many aspects of female reproduction by acting on distinct ARs in nervous and reproductive systems of mammals including humans. Moreover, drugs commonly used for the control of hypertension, asthma and depression target or greatly affect adrenergic systems. Considering a remarkable functional conservation of key molecules and signal transduction pathways between Drosophila and mammals, information obtained from the proposed studies in Drosophila may enhance our understanding of how adrenergic systems influence reproductive physiology and health in humans. [unreadable] [unreadable]

Octopamine is a major invertebrate monoamine and is considered a counterpart of mammalian norepinephrine. To understand how octopamine regulates adaptive behaviors of the fruit fly Drosophila melanogaster, the current project focuses on a major receptor for octopamine OAMB that displays prominent expression in the mushroom bodies, brain structures crucial for learning and memory. Thus, the major objective of this research is to test the hypothesis that OAMB activates key cellular signaling pathways in the mushroom bodies, which underlies associative learning and memory. Preliminary data revealed that oamb mutants showed poor learning in reward conditioning (capacity to learn and remember the odor previously associated with sugar) and impaired short-term memory in conditioned courtship (courtship suppression of rejected males). In the present studies, oamb mutants and their transgenic variants will be further examined to elucidate specific roles of OAMB in learning and memory, the brain structure(s) that requires OAMB for those functions, and intracellular signaling molecules activated by OAMB. These studies together will help delineate the cellular mechanisms underlying reward learning and conditioned courtship. Considering a remarkable functional conservation of key molecules between Drosophila and other animals, knowledge obtained from the proposed studies will ultimately provide significant insights into how different environmental factors and genetic components affect learning and memory processes in other animals including humans. The present studies employ diverse experimental approaches including molecular, cellular, genetic, biochemical, statistical, and behavioral analyses and thus will offer multidisciplinary training and learning opportunities for students. Indeed, the PI has been actively engaged in training diverse groups of students including underrepresented minorities and women as well as offering research opportunities for high school students and various summer program participants. Thus, this project will have broader impact by enhancing participation of diverse student groups in research and integrating research into education.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Public health issues that result from nervous and/or metabolic system dysregulation are highly significant for the residents of El Paso and its surrounding communities. The University of Texas at El Paso (UTEP), a premier minority-serving institution on the U.S./Mexico border, has a robust basic research program made possible by the RCMI support of our Border Biomedical Research Center (BBRC). Within the BBRC the Neuroscience and Metabolic Disorders Project (NMDP) pursues collaborative research that investigates neurological and metabolic mechanisms that contribute to complex diseases that are highly expressed in this region. Our vision is that ongoin and new collaborations, and pilot research grants under our proposed new themes for research (neurological and metabolic dysregulation, neurotoxicology, neurodegeneration and recovery, and cellular mechanisms and cancer), will promote multidisciplinary research and permit future translational studies into therapeutics and interventions for border-relevant health conditions such as depression, addiction, diabetes and obesity, and cancer. Scientists in the NMDP enhance their productivity through the use of outstanding Core facilities which contain specilized equipment and technical support. Opportunities for investigators and programs to become more established and move in directions that likely would not otherwise be possible will result from the proposed activities. New faculty hires will build on the momentum gained through independent projects, pilot research grants and the use of the Core facilities, promoting synergy and expansion within the NMDP and between the NMDP and the other BBRC Projects (Toxicology and Infectious Diseases and Immunology). Positive outcomes of this new research strategy will be: 1) increased success in securing extramural funding;2) a concurrent decrease in our dependence on RCMI funds;3) the development and pursuit of multi-investigator and/or program project-type grant applications;and 4) a productive environment for training young scientists from underrepresented groups. Through this research plan, we will achieve our mission to contribute substantially to the health and education of people in the El Paso/Ciudad Juarez community as well as the missions of the NIH and NCRR.

DESCRIPTION (provided by applicant): Behavioral disinhibition such as increased impulsivity and aggression is typically observed in inebriated humans and alcoholics. Moreover, trait behavioral disinhibition strong correlates with alcohol addiction and abuse, suggesting that disinhibition and alcohol addiction have overlapping genetic or neural components. However, the neurobiological basis corroborating this notion is poorly understood. We found that Drosophila males exhibit disinhibited inter-male courtship, a type of cognitive behavioral disinhibition, with recurring ethanol treatment and dopamine neuronal activity is crucial for this phenomenon. Furthermore, the flies lacking dopamine transporter (DAT) display disinhibited motor behavior under the simultaneous influence of ethanol and social stress. These findings are novel and provide a unique system to unravel the neural and cellular mechanisms underlying ethanol-induced disinhibition. By employing powerful genetic resources available in Drosophila, the proposed research is directed at elucidating the mechanisms by which dopamine mediates ethanol-induced disinhibition. To achieve the goal, we will clarify the neural substrates and specific receptors mediating dopamine's functions in cognitive and motor disinhibition. The neuroanatomically simple and genetically amenable Drosophila offers tremendous advantages for this task. Numerous studies reveal striking similarities of various ethanol effects and the molecules mediating those effects in Drosophila and mammals. Notably, behavioral disinhibition is also observed in dopamine-related disorders such as attention deficit hyperactivity disorder, schizophrenia, Parkinson's disease, and substance abuse and addiction. Knowledge obtained in the proposed research will advance our understanding of behavioral disinhibition induced not only by ethanol but also by other addictive substances, genetic and social factors. PUBLIC HEALTH RELEVANCE: Behavioral disinhibition is typically associated with inebriated humans and alcoholics; however, its underlying mechanism is poorly understood. The proposed research is aimed at elucidating the neural and cellular mechanisms underlying ethanol-induced motor and courtship disinhibition.

An award is made to the University of Texas at El Paso (UTEP) to develop a high-speed optical microscope for imaging fluorescent objects and simultaneously tracking their fast motion in three-dimensional (3D) space. This interdisciplinary project enriches undergraduate and graduate students' education by providing frontier research experience in the fields of biology, chemistry, physics, and electrical engineering. It also trains postdoctoral researchers who will form the next generation of instrumentalists. This project gives scientists in biology and chemistry a strong background in the development and use of innovative and contemporary
instruments, significantly enhancing their ability to conduct cutting-edge research. The developed microscope will serve as the cornerstone of a Biophotonics core facility that will promote collaborative research, education and outreach activities. Underrepresented minority students at UTEP, a Hispanic-majority (almost 80%) institution, and regional users will be invited to participate in workshops and research activities using this facility.

This project is an innovation in the field of fluorescence microscopy. By integrating two ultrafast laser techniques, temporal focusing and pulse shaping, this new microscope has the capability of acquiring 3D volumetric images at an unprecedented high-speed (50 volumes/s, volume size 100um × 100um × 100um). This microscope eliminates the current laser beam scanning mechanisms typically used in confocal and two-photon microscopes with temporal focusing, and adds depth scanning capability by integrating the pulse shaping technique. This project will also develop a computerized image processing system that will automatically analyze high-speed videos. These capabilities, i.e. high-speed and 3D volumetric imaging, will enable researchers to explore and analyze previously unobtainable fast dynamic information from this automatic image analysis systems. Initial applications are in the areas of marine virus infection, nanoparticle transportation, and fly brain imaging. Applications could extend to many other fields where it is hard to study fast 3D dynamic processes using current laser beam scanning fluorescence microscopes.

DESCRIPTION (provided by applicant): Behavioral disinhibition such as increased impulsivity and aggression is typically observed in inebriated humans and alcoholics. Moreover, trait behavioral disinhibition strong correlates with alcohol addiction and abuse, suggesting that disinhibition and alcohol addiction have overlapping genetic or neural components. However, the neurobiological basis corroborating this notion is poorly understood. We found that Drosophila males exhibit disinhibited inter-male courtship, a type of cognitive behavioral disinhibition, with recurring ethanol treatment and dopamine neuronal activity is crucial for this phenomenon. Furthermore, the flies lacking dopamine transporter (DAT) display disinhibited motor behavior under the simultaneous influence of ethanol and social stress. These findings are novel and provide a unique system to unravel the neural and cellular mechanisms underlying ethanol-induced disinhibition. By employing powerful genetic resources available in Drosophila, the proposed research is directed at elucidating the mechanisms by which dopamine mediates ethanol-induced disinhibition. To achieve the goal, we will clarify the neural substrates and specific receptors mediating dopamine's functions in cognitive and motor disinhibition. The neuroanatomically simple and genetically amenable Drosophila offers tremendous advantages for this task. Numerous studies reveal striking similarities of various ethanol effects and the molecules mediating those effects in Drosophila and mammals. Notably, behavioral disinhibition is also observed in dopamine-related disorders such as attention deficit hyperactivity disorder, schizophrenia, Parkinson's disease, and substance abuse and addiction. Knowledge obtained in the proposed research will advance our understanding of behavioral disinhibition induced not only by ethanol but also by other addictive substances, genetic and social factors. PUBLIC HEALTH RELEVANCE: Behavioral disinhibition is typically associated with inebriated humans and alcoholics; however, its underlying mechanism is poorly understood. The proposed research is aimed at elucidating the neural and cellular mechanisms underlying ethanol-induced motor and courtship disinhibition.

Nanoindenter (indenting at a scale about thousand times finer than the human hair) is a highly versatile experimental tool for materials characterization that utilizes diamond indenter of 10-20 nanometers in diameter into the surface of materials to determine mechanical properties, including hardness, stiffness, adhesion strength, and wear. It also has the unique ability to rapidly and precisely make several hundred measurements for probing the surface properties of materials. These characteristics make nanoindentation an indispensable tool for research in disciplines ranging from Engineering to Biology, Chemistry, Geology and Medicine. The significance of the project relates to exploring at a fundamental level the mechanical behavior of materials that include the response at high impact, local hardness of thin films for electronic applications, and wear of biomedical implants. Furthermore, the project addresses the challenge of tailoring the surface properties of materials for a host of applications from susceptibility to scratching of electronic devices to adhesion of cells on biomedical implants, providing new directions in the development of next generation of advanced materials with superior mechanical performance and longer life. The project supports nanotechnology education in the Colleges of Science and Engineering at the University of Texas at El Paso and provides practical training to undergraduate and graduate students throughout the campus in a manner that will enable new understanding to emerge at the atomic or molecular level. The compact all-in-one configuration is envisioned to advance the research capabilities of more than 10 research groups, over 45 graduate students, 40 undergraduate students, and 5 post-doctoral researchers, in terms of new understanding at the nano or molecular level, thereby opening entirely new avenues of research in materials science and engineering, and biomaterials and biomedical engineering including the design of nanostructured materials, organic-inorganic hybrid materials, materials for nanoelectronics, and biomedical applications. The research team is committed to disseminate the educational resources on nanoindentation to facilitate broader participation of K-12 audience to scientific and engineering concepts on nanoindentation.

Strength is a fundamental property of the majority of materials systems. Automated, advanced nanoindentation and scratch experiments are appropriately suitable for this challenging task because of high spatial resolution and throughput. The acquisition and subsequent utilization of an automated nanoscale deformation system for materials research at the University of Texas at El Paso constitutes the scope of the project. The goals are to use nanoindention in areas of research that concern deformation mechanisms in nanostructured materials, mechanics of mechanically-induced surface deformation in thin films and polymer nanocomposites, nanomechanical characterization of 3D-printable materials, biomechanical properties of tissue engineered biomaterials including bone, cartilage and skin, adhesion strength of cells, and mechanical properties of ceramic proppants used for hydraulic fracturing. The approach and method involves use of different modules (ultra-low mechanical force, dynamic mechanical analysis, extended z-range, high temperature stage, high load transducer, high resolution imaging, and fluorescence microscope), enabling the researchers to acquire new understanding of the materials at the nanoscale.

Project Abstract Response inhibition refers to the ability to suppress ongoing motor actions that are no longer needed or appropriate and is a fundamental feature of executive function supporting flexible and goal-oriented behaviors. Dysfunctional response inhibition is a core deficit in a variety of mental disorders including attention deficit hyperactivity disorder (ADHD), schizophrenia, autism spectrum disorders, obsessive compulsive disorder, post traumatic stress disorder, bipolar disorder and drug addiction. The neural substrates and neuromodulatory systems involved in response inhibition are well characterized in human subjects and rodent models; however, the underlying cellular and molecular mechanisms are largely unknown. To address this, we investigated a simpler model system and found that Drosophila melanogaster manifests response inhibition. This is the first observation made in invertebrates and provides an excellent model to elucidate the neurobiological basis of inhibitory control. The overarching goal of the proposed study is to elucidate the neural, cellular and molecular mechanisms underlying response inhibition in Drosophila. The preliminary data point to dopamine as an important neuromodulator for response inhibition. The flies with enhanced dopamine signaling or with deficient dopamine transporter display abnormal response inhibition. Remarkably, this phenotype is induced by simultaneous exposure to environmental and social stimuli, but not to one factor alone. The proposed research is directed at identifying the dopamine receptor and neural substrate (Aim 1), dopamine neurons (Aim 1), and intracellular signals (Aim 3) crucial for response inhibition. This will provide a baseline to further delineate comprehensive neural, cellular and molecular mechanisms. The proposed study is innovative, has great potential to provide insights into neurobiology and evolution of response inhibition and help fill the knowledge gap in our understanding of dysfunctional inhibitory control associated with diverse mental disorders.