Brian D. Burrell - US grants

behavioral habituation /sensitization; behavioral /social science research tag;

Nociception refers to the ability to detect pain or injury-inducing stimuli, and is critical for an animal?s survival. How painful stimuli are transmitted to the brain can be changed by the brain itself. For example, damaged regions of a body become more sensitive to subsequent stimulation as a way to protect the body from further damage. Alternatively, gently rubbing a painful area of the body can temporarily reduce pain. The goal of this project is to understand the physiological processes that modulate the ways in which painful stimuli are transmitted to the brain, focusing on the effects of endocannabinoids, a class of neurotransmitters known to attenuate pain. In addition, the capacity for certain patterns of neural activity to stimulate the release of endocannabinoid transmitters will be examined. This project will include behavioral experiments, molecular genetic procedures and electrophysiological recordings of synaptic transmission by pain-sensing neurons (nociceptors). It is expected that (1) endocannabinoid transmitters will be found to decrease nociceptive synaptic signaling, which will lead to a decrease in pain-elicited behaviors and (2) that activation of non-pain, touch-sensitive neurons will stimulate the release of endocannabinoid transmitters resulting in a decrease in the effects of painful stimuli. The experiments in this project are critical to developing an understanding of a fundamental process in neurobiology, how the brain detects pain and how pain signaling can be altered by modulatory processes within the brain itself. This proposal also provides unique training opportunities for graduate and undergraduate students in behavioral, molecular genetics and electrophysiological recording techniques. Furthermore, this project will take place in a state (South Dakota) that is under-represented in terms of federally funded scientific research and at an institution (University of South Dakota) that serves a number of rural and/or first generation college students.

DESCRIPTION (provided by applicant): The proposed training program will support an undergraduate summer research experience at an institution (the University of South Dakota) that enrolls a high percentage of first generation college students (over one third) from a primarily rural environment. This program addresses a critical need of promoting rigorous research education in areas related to substance abuse and mental health issues throughout the country, and will better prepare students in South Dakota for post-graduate careers in basic science or clinical research fields.

Chronic pain is a major health care burden in the US, affecting approximately 100 million people at an annual cost of $635 billion. This proposal will examine modulation in pain signaling (nociception) as a form of learning and memory. Acquisition of a nociceptive memory represents a form of sensitization-type learning involving either an increased response to nociceptive stimuli (hyperalgesia) or having non-nociceptive stimuli elicit a painful response (allodynia). Habituation, on the other hand, is a potential mechanism to erase a nociceptive memory and may represent an unrecognized process contributing to forms of analgesic modulation such as gate-control of pain or stress-induced analgesia. This approach has benefits not only in understanding how pain- induced sensitization develops, but also in potentially using learning-based approaches to reduce pain, such as using habituation to reduce activity in nociceptive circuits. We have identified a modulatory process, specifically endocannabinoids acting through Transient Receptor Potential Vanilloid (TRPV) channels, that contributes to both pain-related sensitization and habituation of pain- evoked behaviors. Endocannabinoids are lipid neurotransmitters that activate either metabotropic cannabinoid receptors (CB1 and CB2) or TRPV channels (in which case endocannabinoids are sometimes referred to as endovanilloids). While there is considerable interest in cannabinoid-based therapies, their effectiveness in treating chronic pain is questionable. This is, in part, because endocannabinoids can exert both anti-nociceptive and pro-nociceptive effects. Endocannabinoids can depress nociceptive synapses (an anti-nociceptive effect) and we have evidence that this modulatory process contributes the ability of repetitive non-painful stimuli to reduce responses to painful stimuli, a form of transfer of habituation. Endocannabinoids also mediate synaptic disinhibition/potentiation of non-nociceptive synapses, a pro-nociceptive effect that may contribute to pain- induced sensitization. In this study, we will examine the role of endocannabinoids and TRPV signaling during nociception-related sensitization and habituation using Hirudo verbana (the medicinal leech). This approach takes advantage of the well-characterized nervous system of Hirudo in which we have already identified distinct synapses that undergo either endocannabinoid/TRPV-mediated depression or disinhibition/potentiation. An additional advantage is that Hirudo lacks CB1 and CB2 receptors, so it is possible to isolate the role of endocannabinoids acting via TRPV. In Aim 1, the cellular mechanisms mediating endocannabinoid/TRPV- induced potentiation of non-nociceptive synapses will be examined as well as how this plasticity contributes to sensitization to non-painful stimuli (allodynia). In Aim 2, the role of endocannabinoid/TRPV-mediated depression of nociceptive synapses during habituation will be studied as well as whether this habituation can reverse injury- induced sensitization. Aim 3 will address the question of what controls whether the anti-nociceptive or pro- nociceptive forms of endocannabinoid/TRPV modulation are initiated. This will focus on the potential roles of distinct sources of endocannabinoid transmitters and how different patterns of afferent activity can trigger either gene expression of proteins responsible for endocannabinoid synthesis or post-translational modification of these same proteins. These studies will have the following impact. First, using habituation approaches to ?erase? a nociceptive memory is a novel approach and one that could be used immediately in humans by modifying existing medical device therapies, e.g., transcutaneous electrical nerve stimulation (TENS) therapy, making them more effective. Second, the idea that endocannabinoids contribute to the neuromodulatory processes initiated by TENS therapies may provide an avenue for combining endocannabinoid-based drugs (which have failed to date) with this medical device-based therapy, producing an analgesic effect that neither approach can produce on its own. Finally, questions about the effectiveness of cannabinoid-based therapies is undoubtedly based on their ability to both increase and decrease activity by nociceptive circuits. Resolving the cellular mechanisms that mediate these opposing effects is critical if cannabinoid-based therapies are to be effective for treating pain.

The environment facing today's graduate students in STEM fields is changing rapidly. The number of STEM PhD students obtaining tenure-track jobs in academia is decreasing, and consequently, STEM graduate degree holders are increasingly finding jobs in non-academic fields. This means that the model for training STEM graduate students needs to change to accommodate the potential career paths that current and future generations of these students may enter. These include training in topics such as science policy, project management, finance, entrepreneurship, understanding intellectual property rights and technology transfer, and how to work in interdisciplinary teams. This National Science Foundation Research Traineeship (NRT) award to the University of South Dakota will develop a training plan that incorporates a truly interdisciplinary vision of research with the development of professional skills to enhance students' preparation for and success in careers inside and outside of academia. The project anticipates training forty (40) MS and PhD graduate students, including twenty (20) funded trainees, from the departments of Chemistry and Basic Biomedical Sciences.

Students will receive interdisciplinary research training that will focus on the development and application of nanotechnology-based tools to better understand brain function and develop treatments for brain disorders. Graduate students engaged in these projects will receive both classroom and laboratory training in nanotechnology-based chemistry and neuroscience research skills. What is novel about the STEM training in this program is that the student trainees will themselves be developing interdisciplinary expertise as part of their training, as opposed to the traditional, discipline-specific approach. The research will be complemented by the development of professional skills that include training to improve communication to both scientific and general audiences, sessions with scientists representing non-academic careers, and a series of classes (microtracks) from the University of South Dakota Beacom School of Business. These microtrack courses will be in themes such as finance, product development, entrepreneurship, and intellectual property rights. Finally, students will have the opportunity to participate in internships with both regional and national companies that utilize STEM expertise. This training program will develop a cadre of STEM graduate students with both the research and professional skills to better address current and future STEM workforce requirements.

The NSF Research Traineeship (NRT) Program is designed to encourage the development and implementation of bold, new potentially transformative models for STEM graduate education training. The Traineeship Track is dedicated to effective training of STEM graduate students in high priority interdisciplinary research areas, through the comprehensive traineeship model that is innovative, evidence-based, and aligned with changing workforce and research needs.

Expanding opportunities for data-driven research and increasing requirements for data management in sponsored research have resulted in a growing need for retention of both long-term archival data sets that are infrequently accessed, as well as 'active archives' of data that are accessed periodically to revisit, revise, and share experimental results. For this project, the University of South Dakota will acquire, deploy, and maintain the South Dakota Data Store (SDDS), a network-accessible, sharable, multi-campus storage resource integrated with existing campus cyberinfrastructure. Initially, SDDS will support twelve STEM projects across eight departments at four institutions in South Dakota, including 30 faculty, 43 postdocs, and 303 students. SDDS will provide South Dakota researchers with a centralized, efficient, high-performance platform for both archival of and shared access to large quantities of electronic data.

SDDS includes two major services. The Sharing Tier provides high-reliability, high-availability, network-accessible storage for research requiring persistent access to large quantities of data. The Archival Tier provides long-term offsite archival-grade storage. SDDS will serve all faculty, staff, postdocs, students, and graduate students at the University of South Dakota. Through a partnership of multiple institutions, SDDS will also serve researchers at South Dakota State University, Black Hills State University, and the South Dakota School of Mines and Technology, with access open to further community adoption by all educational and not-for-profit noncommercial researchers. The project leverages prior investments at the University of South Dakota and South Dakota State University in dedicated Science DMZ networks. All participants will be able to access SDDS via existing 10Gb connectivity, and end-to-end performance measurement is ensured using existing PerfSONAR deployments at all involved institutions.

PROJECT SUMMARY ? G-RISE at the University of South Dakota (G-RISE USD): The Mission of the G- RISE USD program is to develop a biomedical doctoral training program that produces a highly qualified, diverse pool of biomedical scientists that reflects the makeup of South Dakota and prepares these trainees for a variety of career paths in the public and private sector. The Specific Objectives of this program are to: (1) Enhance the diversity of the USD Basic Biomedical Sciences (BBS) graduate program with an emphasis on non-majority groups characteristic of this region, i.e. American Indians, Latinos, 1st generation college students, rural students, and students from disadvantaged socioeconomic backgrounds. (2) Prepare the next generation of biomedical PhD students to be successful, independent scientists that are also prepared for a variety of career paths by integrating traditional elements of didactic instruction and mentor-driven research with professional development activities. (3) Develop effective mentoring skills in faculty (as well as staff and students) so that these mentors can carry out a more structured, but still personalized, training program for their mentees, understand how to incorporate principles of inclusive excellence into their training, and prepare students for career paths that may lead to careers outside of academia. The guiding Rationale for the G-RISE USD is that it can develop an inclusive biomedical research training program that reaches a unique set of underrepresented students and prepare them for a diverse set of potential careers. There are a large number of pipeline programs that can deliver highly trained students from diverse backgrounds and with diverse research interests to the BBS graduate program. There is also very strong institutional support for education and training of a diverse population of students including several social and cultural resources across campus. Key Activities include: Active recruitment of the targeted student groups and a holistic application process combined with practices to improve retention, e.g., cultural competency training for the student and faculty, and peer mentoring for students within the training program. Rigorous scientific training that promotes independent thinking and hypothesis-driven research, reproducibility, and responsible conduct in research. Development of written and oral communications skills including workshops on how to reach professional and general audiences. Professional development through ?microcredential? classes that allow students to take graduate courses in business, law, communication, and education, internships and informational interviews, and workshops on career development skills such as active interviewing and team-building. Improving the quality of faculty mentoring through a workshop using the Entering Mentoring curriculum. The intended trainee Outcomes of the G-RISE USD are to increase the proportion of BBS graduates students from the underrepresented groups described above, for trainees to have productive research careers at USD in terms of publications and presentations, and to have graduates of the program successfully enter a variety of careers in the public and private sector.