Mark W. Miller - US grants

9353130 Zuazaga The proposal requests funds to establish an Imaging Center for the Institute of Neurobiology. Four instruments to perform major cell image analysis or tissue processing are requested: 1) a photometry/microscope system for quantitative fluorescence analysis, 2) a confocal microscope, 3) a ultramicrotome for serial sectioning, and 4) a three-dimensional reconstruction and morphometry system. The equipment will expand capabilities of eight research projects involving ten of the Institute's resident investigators, four of them Hispanic women, their students, and collaborators from mainland institutions. The development of cell imaging research will not only enhance current research at the Institute but will also further involve minority students in state- of-the-art neurobiological research. ***

Lay Abstract PI: Miller, Mark Proposal Number: IBN-9722349 Many goal-oriented behaviors are said to be "motivated" as their occurrence depends upon both extrinsic factors (such as the presence of food) and the intrinsic state of the organism (such as the level of hunger or satiety). This investigation relates the activities of specific brain cells and the connections between them to the generation of complex motivated patterns of behavior. The project focuses on the role of chemical substances called neuropeptides, which modulate the activity of these nervous system cells during motivated behavior such as eating. The studies are conducted as part of an undergraduate summer program at the Institute of Neurobiology in San Juan, Puerto Rico so that every step of the research program involves undergraduates. Most organisms, including humans, exhibit a variety of motivated behaviors. This project investigates the fundamental principles underlying the brain mechanisms controlling such behaviors. By coupling the research to the undergraduate summer research program, the project provides students with access to hands-on research opportunities and experiences that were previously inaccessible to students at the host institution.

cockroach

neurotransmitters; motor neurons; brain regulatory center; gamma aminobutyrate; motivation; interneurons; aquatic organism; Mollusca; nutrition related tag; immunocytochemistry; field study; electrophysiology;

A grant has been awarded to Dr. Mark W. Miller at the University of Puerto Rico Medical Sciences Campus to establish a Laser Scanning Confocal Microscope (LSCM) facility at the Institute of Neurobiology. This facility will be shared by the investigators and students of the ten laboratories that comprise the Institute. These laboratories utilize a variety of model systems, ranging from synapse development and specification in the cockroach to retinal aging in the human, to address some of the most challenging issues facing modern Neuroscience. While diverse in scope, these research programs are unified by certain methodological considerations and limitations. In particular, they share a need to localize specific proteins, messenger RNAs, or physiological events, within highly complex tissues. The elaborate three-dimensional structures of neurons, their remarkable phenotypic heterogeneity, and their intricate sorting and trafficking capabilities present formidable obstacles to studies requiring the precise localization of fluorescent signals or markers. In many cases, however, the limitations previously imposed by these factors have been overcome by the introduction of the confocal microscope, an instrument that enables investigators to detect and localize fluorescent signals with a resolution that greatly exceeds the capabilities of traditional microscopy.
The research conducted at the Institute of Neurobiology is dedicated increasing our understanding of the structure and function of nervous systems. Specific programs include: (1) Neuropeptide Y and GABA Expression in the Aging Ground Squirrel Circadian System (Dr. N. Lugo), (2) Dendritic Remodeling of Ganglion Cells after Optic Nerve Injury (Dr. R. Blanco), Survival and Regeneration of Human Spinal Cord Neurons (Dr. D. Kuffler), (4) Ultra-fast Imaging of Subcellular Calcium Signals in Vascular Smooth Muscle (Dr. L. Santana), (5) Role of Engrailed Paralogues in Specification of Neuronal Anatomy and Synaptic Connections (Dr. J.M. Blagburn), (6) Cotransmitters and the Regulation of Complex Behavior (Dr. M. W. Miller), (7) Retinal Aging in Human Populations in Puerto Rico (Dr. E. Kicliter), and (8) Functional Role of Metabotropic Glutamate Receptors in a Rhythm-generating Neuronal Network (Dr. W. Krenz).
In addition to the direct enhancement of these research projects, the proposed facility will have a broad impact on the educational goals and capabilities of the Institute of Neurobiology. Numerous graduate students affiliated with the University of Puerto Rico School of Medicine and the Department of Biology at the UPR Rio Piedras campus conduct their research at the Institute. Moreover, many advanced undergraduate students receive research training by participating in an Independent Investigation course, for which they may receive both credit and funding. Finally, the Institute hosts a summer program in Tropical Neuroethology that brings undergraduate students from around the country to Puerto Rico for an intensive 5-week research experience. The creation of a shared Laser Scanning Confocal Microscope facility will clearly enrich these educational programs and enhance the training objectives of the Institute of Neurobiology.

[unreadable] DESCRIPTION (provided by applicant): Posttraumatic Stress Disorder (PTSD) is a debilitating psychiatric condition defined by re-experiencing, avoidance, numbing, and hyperarousal symptoms that develop in response to a psychologically traumatic event. Theorists have suggested that the hyperarousal symptoms, which include sleep difficulties, anger, concentration problems, hypervigilance, and exaggerated startle response, reflect alterations in functioning of the hypothalamic-pituitary-adrenal (HPA)-axis. Understanding the mechanisms of these symptoms and their neurobiological underpinnings is essential to our understanding of the disorder and the advancement of assessment and treatment techniques for individuals with PTSD. The proposed research builds on a body of work suggesting a link between amplitude of the startle reflex and activity of the HPA-axis and is designed to examine the hypothesis that there is a relationship between the symptom of exaggerated startle and abnormalities in function of the HPA-axis in patients with PTSD. To do so, we propose to pharmacologically manipulate cortisol levels via administration of hydrocortisone in combat veterans with and without PTSD and examine resultant effects on amplitude of the startle reflex. The immediate objectives are, first, to replicate the finding that increasing systemic cortisol via hydrocortisone administration attenuates startle reflex amplitude in humans (Buchanan, Brechtel, Sollers, & Lovallo, 2001). Second, to extend this work to a sample of patients with PTSD where cortisol manipulations are expected to exert more pronounced effects on the startle reflex via enhanced negative feedback inhibition (Yehuda, 2001). Third, to examine the hypothesis that in individuals with PTSD, there will be an association between the amplitude of the startle reflex and the degree to which basal cortisol levels are suppressed relative to controls, (i.e., individuals with the lowest basal cortisol levels will exhibit the largest overall startle responses). Evidence in support of the these hypotheses would suggest a link between HPA-axis activity and startle amplitude, provide support for the hypothesis of enhanced negative feedback of cortisol in PTSD (Yehuda, 2001), and contribute to the development of startle reflex methodology as a behavioral tool for indexing inter- and intra- individual differences in HPA-axis function. [unreadable] [unreadable]

Our present understanding of several neurological movement disorders relates to pathologies of specific neurotransmitter systems. For example, substantial evidence indicates that the motor deficits associated with Parkinson's Disease result from the degeneration of the dopaminergic nigrostriatal pathway. In Huntington's Disease, motor deficits are associated with degeneration of striatal GABAergic neurons. Our most effective treatments for these disorders rely on agents that are thought to exert their effects on the synaptic signaling mediated by these neurotransmitters. Relating the activities of such neurotransmitter systems and therapeutic agents directly to human behavior, however, poses formidable challenges. The tong-term objective of this research program is to examine interactions between two major neurotransmitters, dopamine (DA) and GABA, in the regulation of feeding behavior. These two "conventional" neurotransmitters are thought to play key roles in the regulation of appetite, satiation, consummatory behaviors, and food reward in species ranging from invertebrates to man. The proposed studies will use an experimentally favorable model, Aplysia, in which it is possible to identify neurons that exhibit a specific transmitter phenotype, and to relate the activity of those neurons to specific behavior patterns. The three Specific Aims focus on the union of these two neurotransmitter systems in five specific identified interneurons in which DA and GABA are colocalized. The proposed experiments will (1) determine the contributions of colocalized DA and GABA to synaptic signaling, (2) explore the roles of DA and GABA in the modulation of intrinsic synaptic plasticities (metaplasticity), (3) investigate interactions between the cells in which DA and GABA are colocalized and other neurons that converge on common postsynaptic targets (heterosynaptic modulation). Recent advances in our understanding of behaviors related to feeding underscore the utility of this approach. In common with most organisms, the ingestive and egestive behaviors of this system are mediated by a single peripheral "physical plant" that is differentially activated by a multi-functional central pattern generator (CPG) circuit. The capability of a single CPG to achieve such motor program switching is often attributable to neuromodulatory cotransmitters that produce broad and coordinated reconfiguration of patterned motor output. Consequently, by increasing our understanding of cotransmission in this system, these experiments can be expected to reveal mechanistic and organizational principles that are applicable to the performance and dysfunction of motor behavior in more complex nervous systems.

DESCRIPTION (provided by applicant): Negative conflict behavior (NCB) in intimate relationships is a problem of daily living that has profound effects on the mental health functioning of relationship partners, the children exposed to NCBs, and society at large. The aim of the proposed study will be to examine, for the first time, the influence of select candidate genes on this novel behavioral phenotype in a sample with well-documented rates of NCB, male combat veterans, and their female partners. NCB will be defined here as a dimension of negative interpersonal behavior ranging in severity from nonverbal expression of hostility to overt acts of violence. It will be measured via a state-of-the-art, multimethod array of self- and partner-reports and through the coding of verbal and nonverbal behavior during a semi-structured conflict discussion between partners in the laboratory. The primary aim of the proposed study will be to examine the direct and indirect effects of psychopathology-linked candidate genes on NCB and the mediating influence of internalizing and externalizing posttraumatic psychopathology on NCB. Analyses will test two primary hypotheses: First, genetic association analyses are expected to show that dopamine and monoamine oxidase (MAOA) polymorphisms exert direct effects on NCB and indirect effects on this outcome mediated by externalizing psychopathology. Second, serotonin and HPA-axis-related polymorphisms are expected to exert direct effects on NCB and indirect effects on this outcome mediated by internalizing psychopathology. Evidence in support of the study hypotheses implicating distinct psychopathological pathways to NCBs could aid in the development and refinement of interventions for NCBs which, to date, have shown only modest effects. In the future, information about genes could be used to inform the selection of pharmacologic agents and guide efforts to match treatments to patients on the basis of their unique genetic architectures.

DESCRIPTION (provided by applicant): The Institute of Neurobiology is a research and teaching component of the University of Puerto Rico Medical Sciences Campus, a minority institution. Its eleven faculty members are engaged in basic research in the neurosciences, and in training students to do so. The present application is to apply for the funds to continue and extend the highly successful program that was begun almost thirteen years ago. Funding under M-RISP has made it possible to provide badly needed administrative support, thus freeing investigators from some of these duties. It is further affording opportunities for selected faculty members to develop themselves as fully competitive members of the world scientific community, as well as role models for their minority students. The objectives of this application are: 1) to provide institutional research development support to enhance the infrastructure that will facilitate development of basic mental health research projects based on molecular, cellular and integrative studies of the nervous system, and to offer advanced training and experience for faculty members and students by supporting workshops and exchange visits between the Institute faculty and experts from other institutions. 2) to provide support for four individual investigator research projects which are basic to the Institute's goal of developing a critical mass of active investigators conducting research in neuroscience. This will enable not only the development of these research areas, but also the training of minority research assistants at the graduate and undergraduate levels; 3) to give an opportunity to minority undergraduate and graduate research assistants to become involved in mental health related research.

This project is for partial support of the Moluscan Neuroscience 2009 conference to be held February 13-16, 2009 at the Institute of Neurobiology, a free-standing unit of the University of Puerto Rico Medical Sciences Campus. This is the third conference dedicated exclusively to Molluscan Neuroscience since 1997. The other conferences were the Cell and Molecular Biology of Aplysia and Related Invertebrates meetings held at the Cold Spring Harbor Laboratory (CSHL) in 1992 and 1997. This meeting has as one of its goals to enhance interaction among investigators in the field with a format and scale modeled on the CSHL meetings held in the 90's. The meeting will bring together world experts and students in an environment geared towards interaction, participation and discussion of the latest ideas and findings in the field. It will assemble the international community of neuroscientists and students who use molluscan models to investigate a wide spectrum of fundamental neurobiological problems.

Sessions and symposia will address specific thematic areas in which this field has been most influential. These include: Learning and Memory, Central Pattern Generators, Evolution of Neural Circuits and Behaviors, Development, Neuromodulation, Ion Channels, and Signal Transduction. Emphasis will be placed on platforms designed to increase the accessibility of these resources to the broader Neuroscience community. Workshops will be organized to discuss the use of new tools such as the emerging Genome Projects for Aplysia and related gastropods, cephalopod genomics, genomic and microchemical analysis of single cells and cell compartments, and NeuronBank.org initiatives for archiving identified neurons and their homologs across species.

NSF funds will enable multiple educational and outreach initiatives by providing travel, housing, and registration support for graduate students and postdoctoral fellows who could not otherwise attend. Emphasis will be placed on promoting participation of junior investigators, women, local students from Puerto Rico, and members of other groups that are under-represented in this field. This outreach reflects a firm conviction that the greatest beneficiary of such broadened participation will be the field of Molluscan Neuroscience itself. The host institution will provide administrative support and all funds related to the conference venue.

An award has been made to the University of Puerto Rico Medical Sciences Campus to establish an NSF Undergraduate Research and Mentoring (URM) program at the institution, in order to provide opportunities for undergraduate students to obtain research and mentoring experience in the field of neurobiology. Each year, for the first four years of the project, four students will be recruited to participate in the program, and the students will be provided NSF support for a period of two years. Over the five-year period of the grant, a total of sixteen students will participate in the program. Students from groups that are under-represented in neurobiology will be recruited following their second year of undergraduate study. Existing local networking mechanisms will be utilized to identify students from universities throughout Puerto Rico. Students will be engaged in ongoing faculty research programs on a year-round basis, with the objective of getting students to present and/or publish their work. The areas of research cover a broad range of topics, but are unified by the interdisciplinary goal of using the methods of neurobiology to increase our understanding of nervous system structure and function. Each program investigator has considerable mentoring experience, and the structure of faculty research programs enable undergraduate students to become rapidly involved in publication-quality research. The program mentoring strategy consists of personalized "hands-on" technical guidance that exposes students to state-of-the-art physiological, molecular and imaging approaches and equipment. Students are mentored in the scientific method, learning how to formulate hypotheses that are testable and appropriate to the questions they wish to answer. They are involved in all aspects of the research effort, including design of experiments, data collection, analysis, and communication of results. The importance of trust, cooperation, and teamwork within the "laboratory culture" is emphasized throughout the students' training. This individual mentoring experience is integrated within a highly interactive group setting that conveys and instills the excitement and enthusiasm of scientific exploration. Additional information is available at http://www.neuro.upr.edu/nsf-urm.html, or by contacting Dr. Mark Miller, at mark.miller@upr.edu.

DESCRIPTION (provided by applicant): The broad, long-term objective of this research is to understand how neurotransmitter systems control motor activity. The present study will address the mechanistic and functional consequences of signaling by neurons that contain multiple neurotransmitters. It will utilize an experimentally favorable model in which it is possible to identify specific neurons that exhibit a particular transmitter phenotype and to determine the contribution of those neurons to the generation of complex motor patterns. Experiments conducted to date have 1) localized the neurons that contain GABA and dopamine (DA) in Aplysia, 2) demonstrated that the overlap, or colocalization, of these major neurotransmitter systems occurs in only five neurons, all of which participate in the central pattern generator (CPG) circuit that controls feeding, and 3) localized GABA-DA coexistence to identified interneurons that can specify the functional configuration of this multifunctional CPG. Methods integrating neurophysiology, neuroanatomy, and pharmacology will test the central hypothesis of this study: GABA-DA interneurons that are intrinsic to a multifunctional CPG circuit can specify functional motor patterns via modulatory signaling. The proposed experiments address three specific aims that test this hypothesis: 1) determine the contributions of DA and GABA to rapid and slow synaptic signaling by the neurons in which they are colocalized, 2) explore the roles of colocalized DA and GABA in the regulation of multiple forms of synaptic plasticity that these interneurons display, and 3) determine the respective contributions of colocalized DA and GABA to the modulation of intrinsic membrane properties of postsynaptic motor neurons. These studies promise to lead to insights and principles that will have applicability to motor control in more complex brains, including the human central nervous system. In view of the pivotal role of dopaminergic and GABAergic neurotransmitter systems in our present understanding of major neurological movement disorders, these principles should also inform efforts to develop therapeutic and treatment strategies. The developmental objectives of this project will enable the PI to continue his efforts to acquire competitive research support. In view of positive evaluations of recent proposals, it is anticipated that this objective will be achieved during this grant period. Public Health Relevance: Several major neurological movement disorders, such as Parkinson's Disease and Huntington's Disease, are currently attributed to the malfunctioning or imbalance of specific brain pathways. This project will examine the contributions of brain cells that contain specific signaling molecules, or neurotransmitters, to the control of movement. This investigation will increase our understanding of how brain circuits control motor behavior and how major movement disorders result when these circuits are compromised.

This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5).

Founded as an Institute within the University of Puerto Rico in 1967 by the renowned neuroscientist José del Castillo, the Institute of Neurobiology (INB) was established with the goal of using simple organisms to understand neural structure and function. UPR is a major minority-serving institution, and the INB graduate student population is predominantly Hispanic. The focus on Poikliothermic model systems holds new significance in furthering the understanding of the impact of climate change (seawater temperature, salinity, etc.) on ecosystems. The institution is focusing on simple organisms, and common interests such as neural plasticity, temperature adaptation, and signaling molecules. Funds are provided to correct significant deficiencies including 1) an antiquated air conditioning system and 2) an obsolete network cyberinfrastructure. The rejuvenation of the INB will significantly improve ongoing and planned research opportunities and create new opportunities for collaborative research. The renovations will have immediate broader impacts including: 1) significant benefit to the minority student body served by the University of Puerto Rico; 2) an innovative approach to "ecological neurobiology" that will provide the first wave of researchers equipped to deal with the emerging and important issues of global climate change; 3) the establishment of a Neurobiology Education Center that will serve to educate teachers, children and the public about the study of neuroscience, and the special relevance of these studies to Puerto Rico's tropical ecosystem.

Human activities are altering the environment at an alarming rate. A multidisciplinary approach is essential to understand the complex interplay between molecular, cellular, and behavioral responses by organisms under these increasingly stressful conditions. The nervous system is the interface between an organism and its environment.

The Puerto Rico Center for Environmental Neuroscience (PRCEN) will combine neuroscience (the study of the nervous system and behavior) and environmental science (the study of local ecosystem environments) to tackle environmental issues in Puerto Rico's tropical setting. The Center will combine neuroscientists from the Institute of Neurobiology and the Dept. of Anatomy of the University of Puerto (UPR) Medical Sciences campus and environmental scientists from the Environmental Sciences Program and the Depts. of Biology and Chemistry of the UPR Rio Piedras. The alliance will bring together cutting-edge techniques normally associated with cellular and molecular neuroscience with expertise in local ecosystems and environmental science to create a novel field that will require participants to move outside of their comfort zones and learn about entirely new areas of research.

Objectives of the center will be to: (1) establish research programs in the new field of environmental neuroscience, (2) enhance research productivity through faculty and infrastructure development, (3) increase the numbers of minority students attaining advanced degrees in interdisciplinary science, and (4) generate community understanding of the work being done in the Center.

The research subprojects focus on four local ecosystems: terrestrial, freshwater rivers, estuaries, and marine systems. The habitats under study are intimately connected: contaminants in the mountains make their way into rivers, pass through the estuaries, and end up in the sea.

The oceans subproject is designed to understand the consequences of environmental pressures on tropical corals, using state of the art molecular-cellular techniques.

The estuaries project will focus on the blue crab, which supports one of the largest fisheries industries in the United States. This project will use high resolution monitoring to track the presence of contaminants and other environmental stressors, and correlate the resulting environmental data with physiological monitoring of heart and endocrine functioning in this crab.

The freshwater studies will monitor contaminants in three representative Puerto Rican rivers. Four animal models (zebrafish, mosquitofish, and two types of prawn) will be exposed to pollutants found in the three rivers, and a range of physiological and behavioral parameters will be examined.

Finally, the terrestrial project will use sophisticated molecular biology and electro-physiology to examine the nervous systems of fruit flies from different habitats in Puerto Rico. The standard laboratory-reared fruit fly (Drosophila) is a prized and widely-used model system in neurobiology laboratories throughout the world. However, there is a paucity of studies examining this animal in the wild, especially with respect to the specific habitats in which they are living.

Intellectual Merit
The conceptual linchpin of the PRCEN is that the nervous system is the interface between an organism and its environment; a multidisciplinary approach is essential to understand the complex interplay of molecular, cellular, organismal, and ecosystem dynamics faced by organisms under the increasingly stressful conditions created by human impacts on the environment. We refer to this approach as environmental neuroscience. The program will be unified by the central hypothesis that a full understanding of the consequences of pollution and climate change requires dialogue between investigators monitoring environmental conditions and organismal biologists using that information to determine how environment affects function.

Broader Impact
The PRCEN center will change the way we look at environmental problems, and will create a new category of scientists prepared for the environmental challenges developing from human activities. The Center will impact a large number of minority students by tapping into the collective student population of over 19,000. Our undergraduate participants will integrate closely with ongoing NSF sponsored mentorship initiatives such as the Lewis Stokes Alliance for Minority Participation, the Research Experience for Undergraduates Program, and the Undergraduate Research Mentoring Program. Our graduate students will have access to broad training here, and will also be given the opportunity to take courses and train stateside at places like the Marine Biological Laboratory in Woods Hole, MA. Finally, our studies will integrate with local organizations such as the San Juan Bay Estuary Program to coordinate community outreach targeting K-12 education.

An award has been made to the University of Puerto Rico Medical Sciences Campus (UPR MSC) to acquire a state-of-the-art Laser Scanning Confocal Microscope (LSCM). This instrument overcomes obstacles that previously limited the detection and precise localization of fluorescent signals within nervous systems and other complex three-dimensional structures. The LSCM will be housed at the Institute of Neurobiology (IN), a freestanding unit of the UPR MSC. Eleven laboratories that comprise the IN utilize a variety of model systems, ranging from the neuromuscular junction of Drosophila to mammalian neurons in cell culture, to address some of the most challenging issues facing modern neuroscience. The LSCM will benefit the entire neuroscience community of Puerto Rico as well as investigators in other disciplines that require precise spatial localization of fluorescent markers within biological tissues.

In addition to enhancing research objectives, acquisition of cutting-edge imaging instrumentation will significantly impact the educational goals and capabilities of the University of Puerto Rico Medical Sciences Campus. The proposed instrumentation will benefit students associated with two major NSF-supported initiatives: the Undergraduate Research Mentoring (URM) program in Neural Networks and Behavior which supports year-round investigation by undergraduate students in neuroscience labs throughout the island, and the Center for Research Excellence in Science and Technology (CREST) in Environmental Neuroscience which partners neurobiologists with ecologists investigating the effects of anthropogenic factors on nervous system function. Finally, this instrumentation will promote collaborations between the UPR and leading international investigators, providing opportunities for students to receive a part of their training at major research institutions. Such experiences greatly expand their horizons and ultimately lead to broadened participation in the nation's STEM workforce.

DESCRIPTION (provided by applicant): With terrorism, natural disasters, mass shootings, war and other forms of horror and violence on the rise across the globe, understanding the mental health consequences of these events, and treating survivors, has become a major public health priority. Posttraumatic stress disorder (PTSD) is the most common psychiatric consequence for survivors of such trauma and a serious and potentially disabling condition that affects 8-10% of individuals in the U.S. population at some point during their lifetimes (Kessler et al., 2012; Kessler et al., 1995). In those exposed to intense and repeated trauma, such as military combat, lifetime prevalence is considerably higher (i.e., closer to 20%). Twin studies have shown that a substantial proportion of variation in PTSD risk is attributable to hereditable factors leading investigators to begin to explore the molecular genetic basis of these effects. Unfortunately, results of genetic association studies conducted to date have been inconsistent and the heritability of PTSD remains largely unexplained. Recently, however, our research group published the first genome-wide association study (GWAS) of PTSD which implicated the Retinoic Acid Orphan Receptor Alpha gene (RORA) as a significant risk locus for the development of PTSD after trauma exposure (Logue et al., 2012). The primary finding from that study was subsequently replicated by an independent research group (Amstadter et al., 2013). We believe that the basis for RORA's association with PTSD lies in its role in protecting neurons from the effects of oxidative stress (OXS) and inflammation (INF). Specifically, we hypothesize that individuals who carry the RORA risk variant(s) have a reduced capacity to mount a neuroprotective response to the OXS and INF associated with PTSD. As a result, they are more likely to incur damage to regions of the brain involved in emotion, memory, attention, and other psychiatrically-relevant processes where the loss of neural integrity alters brain function and yields symptoms of the disorder. The primary aim of this study is to test this and related hypotheses using data from the Translational Research Center for Traumatic Brain Injury and Stress Disorders at VA Boston Healthcare System (TRACTS). Specifically, we propose to study the intersection of RORA genotype, other OXS and INF genes, PTSD and other psychopathology, and structural brain parameters using existing genomic data from a high-density gene chip and high resolution structural magnetic resonance imaging (MRI) brain scans from 190 Caucasian OEF/OIF veterans. We will also explore associations between other aspects of psychiatric illness and abnormalities in brain morphology and examine effects of mild Traumatic Brain Injury (mTBI) on these parameters. Evidence in support of our primary hypotheses could pave the way towards the development of medications designed to enhance protective RORA and OXS and INF gene function-and in doing so promote neural resilience in individuals with genetic risk variants.

A major goal in the field of neuroscience is to understand how the brain evaluates its surroundings and implements a plan of action. Increasing our knowledge about decision-making could ultimately lead to improved strategies for solving problems in a more effective and adaptive fashion. This knowledge should also provide deep insight into certain behavioral and developmental disorders in which decision-making is compromised.

This PIRE project brings together of a consortium of U.S. and international faculty and students on four interdisciplinary subprojects that are unified by the goal of increasing our understanding of brain mechanisms mediating reward and decision processes. Each subproject will partner investigators and students from the University of Puerto Rico (UPR) and/or Oklahoma State University with a team of international researchers from Canada, Chile, Egypt, Italy, and/or Turkey. The Neural Mechanisms of Reward and Decision project will catalyze advances in research and education that could not occur without international collaboration. PIRE workshops and exchanges will cultivate interdisciplinary cooperation and identify common objectives among groups that investigate the role of dopamine in reward and decisions across a broad spectrum of phylogenetic and mechanistic levels. One subproject will study the impact of parasitic infection on neuromodulatory systems that regulate host behavior in a snail-schistosome system using transcriptomics and electrophysiological techniques. A second subproject will examine how isolation stress during adolescence differentially affects male and female dopamine circuitry and resultant learning, memory and behavior in rats. A third subproject will study the role of dopamine on plasticity of foraging behavior in different honeybee subspecies. The fourth subproject will examine the biophysical consequences of repeated exposure to stimulants on the activity of dopamine neurons. The PIRE project will make continuous efforts to integrate across the four subprojects to achieve a broad understanding of neural mechanisms of reward and decision processes.

Student participants in the Neural Mechanisms of Reward and Decision project will conduct research in the labs of international partners as well as in U.S. labs; they will receive mentoring to develop their critical thinking proficiency and enhance their communication skills and professionalism. All mentors possess considerable experience with international collaboration and cooperation which will be shared and disseminated for the benefit of the entire program. This program also responds to the national need to increase diversity in the scientific workforce. The University of Puerto Rico has historically served as a rich source of talented students who pursue graduate degrees in institutions on the island and elsewhere. This program will enhance our ability to provide students with international research experiences that promote their global engagement. A great beneficiary of broadened global participation in the field of neuroscience will be the field itself.

DESCRIPTION (provided by applicant): The University of Puerto Rico (UPR) Medical Sciences Campus proposes to establish a COBRE Center that will significantly strengthen the research infrastructure of the institution and that will impact biomedical investigation throughout the island. The specific aims of this COBRE Center for Neuroplasticity at the University of Puerto Rico are to: 1) Foster development of junior investigators into competitive researchers working on projects with direct biomedical significance. An intensive mentoring program will be implemented with the goal of creating a culture of research comparable to that of major research-intensive universities. 2) Provide a Neuroimaging and Electrophysiology Facility (NIEF) that will offer state-of-the-art instrumentation, training, and expertise to the neuroscienc community of Puerto Rico. The NIEF will be located in the Institute of Neurobiology, but will incorporate ultra-high-end instrumentation in the new Biomolecular Sciences Building (BSB) after the COBRE has become well-established at the Institute; 3) Partner with IDeA Networks of Biomedical Research Excellence (INBRE) entities in Puerto Rico; 4) Support programmatic activities that increase interdisciplinary collaborations at the basic research level. The major strengths of the proposed COBRE include: 1) the PI, who is both an accomplished researcher with extensive funding and advisory activities within the NIH, and an experienced administrator with a history of successful initiation of research and training programs; 2) the team of young, aggressive and highly committed scientists; 3) enhanced mentorship possibilities provided by the current level of intellectual and scientific accomplishment present at the Institute of Neurobiology; 3) rational planning for the future by deployment of the new BSB as a centralized hub for integrated and collaborative research in the future of the COBRE Center for Neuroplasticity; 4) the full commitment of the UPR Administration toward assuring the stated goals of the project. This UPR COBRE Center should define pathways and benchmarks for basic and translational research across the UPR system for the next decades.

The Centers of Research Excellence in Science and Technology (CREST) program supports the enhancement of research capabilities of minority-serving institutions through the establishment of centers that effectively integrate education and research. CREST promotes the development of new knowledge, enhancements of the research productivity of individual faculty, and an expanded presence of students historically underrepresented in science, technology, engineering, and mathematics disciplines.

With National Science Foundation support, the University of Puerto Rico Medical Sciences Campus will continue development of its Phase II Center for Environmental Neuroscience. The Phase I Center for Environmental Neuroscience was established to bring together scientists from the traditionally separate fields of neuroscience and environmental science, recognizing the fact that the nervous system serves as the interface between an organism and its environment. Phase II Center investigators and students will explore the impact of anthropogenic environmental degradation on nervous systems at the structural, physiological and behavioral levels.

Responses of nervous systems to environmental degradation will be examined in three subprojects partitioned according to tropical habitats: 1) Marine and Estuaries, 2)Rivers and Freshwater, and 3) Terrestrial. Three objectives that encompass the subprojects will identify nervous system responses that will improve risk prediction or development of resilience strategies to diverse environmental stressors. These specific aims will 1) assess effects of environmental contaminants on nervous system structure and function, 2) determine impacts of climatic variation (acidification, temperature changes) on the molecular and cell biology of neurons, and 3) investigate the impact of anthropogenic stimuli (light, sound) on sensory systems and behavior.

Center educational and career development activities include a newly created course in Environmental Neuroscience, a Seminar Series, a Responsible Conduct in Research module, and the Yale Ciencia Academy for Career Development, a year-long on-line program that provides graduate students underrepresented in science, technology, engineering, and mathematics disciplines with opportunities for mentoring, peer support and networking. Institutional partnerships will also provide Center students and faculty with access to training and research programs at institutions of cutting-edge investigation in neurobiology and environmental science.

Project Summary. The Administrative Core forms the nucleus of the COBRE Phase II Center for Neuroplasticity at the University of Puerto Rico. As such, it will support the three-fold objectives of the COBRE Center: 1) Develop and maintain a nationally competitive biomedical research program focused on the theme of Neuroplasticity; 2) Facilitate the developmental trajectory of junior investigators toward their transition to independent research careers; 3) Support the COBRE NeuroImaging and Electrophysiology Facility (NIEF). The Administrative Core incorporates all programmatic facets of this initiative, including Faculty Career Development Activities (Laboratory Management, Grant Writing, Manuscript Preparation) and Neuroscience Research Infrastructure Enhancement programs (Seminar Series, Neuroscientist-in-Residence, Annual Puerto Rico Neuroscience Conference, Outreach Activities, and Academic Partnerships). The Administrative Core is composed of a team of individuals with proven track records and experience in the operation and management of large multi-faceted research and training programs. Oversight of the Core is the responsibility of the COBRE Associate Director, Dr. Mark Miller. Miller serves as liaison between the program and its Evaluation Module and he coordinates communication with NIGMS officials. The Administrative Support Office will continue to be staffed by a highly experienced and dedicated team including: Ms. Bethzaida Birriel, Grants Administrator; Ms. Brenda Caban, Accountant; and Ms. Sandra Felix, Purchasing Agent. All fiscal matters will be managed at the Institute of Neurobiology, a free- standing unit under the Deanship of Academic Affairs of the University of Puerto Rico Medical Sciences Campus. Institute personnel will handle most aspects of the post-award administration of funds, including hiring of technicians, postdocs, and students. Finally the Administrative Core will coordinate all program appraisal and assessment, including the participation of an independent external evaluation group from Cooperativa de Servicios de Evaluación e Investigación (CoopSEI). The Administrative Core team will organize the Annual COBRE Retreat and Assessment Activity that will enable all stakeholders to meet, exchange ideas, report progress, and plan future strategies. This meeting will serve as the principal forum for developing and disseminating data required for formative and summative evaluation of all COBRE Center research objectives and programmatic initiatives.

It is well established that parasites can promote their survival and proliferation by altering the physiology and behavior of their hosts. Large gaps exist, however, in our understanding of the cellular and molecular mechanisms that parasites target to modify their host nervous systems. This project explores how parasites can redirect host reproductive energy to meet their own demands for growth and multiplication. Experiments will be performed on gastropod snails of the genus Biomphalaria, intermediate hosts for larval schistosome flatworms. This project responds to several programmatic objectives of the NSF Organismal Systems and Infection Biology (OSIB) initiative. It will provide students at the University of Puerto Rico with unique opportunities to participate in research at the cutting edge of neurobiology, parasitology, and global health. Visiting experts will present modern approaches to parasite biology, gene editing, and neuroimaging technologies. Infection of Biomphalaria snails by larval schistosomes has major socioeconomic implications for developing countries due to its obligatory role in schistosomiasis, a pervasive tropical disease of poverty. A collaboration with the Theodor Bilharz Research Institute in Cairo, Egypt, thus expands the horizons of student participants, exposing them to the benefits of a global approach to scientific discovery. This project will increase the number of scientists from underrepresented groups that are trained to conduct interdisciplinary research at the nexus of neurobiology and parasitology. It will also contribute to forming a citizenry that is increasingly aware of global health issues and challenges.<br/><br/>Freshwater snails of the genus Biomphalaria serve as intermediate hosts for the digenetic trematode Schistosoma mansoni. Within the intermediate host, trematode larvae multiply and transform into the cercariae that can infect their mammalian definitive hosts. Larval proliferation is facilitated by modifications of host behavior and physiology, including a reduction of reproduction known as ‘parasitic castration’. As a simultaneous hermaphrodite, the male and female systems of each Biomphalaria specimen must be highly regulated and coordinated. Several neuropeptides are among the signaling systems that control gastropod reproduction. This study explores two neuropeptides that were recently described in Biomphalaria; a gonadotropin releasing hormone-related peptide that is proposed to regulate the female reproductive system and a family of FMRF-NH2 related peptides that control the male mating apparatus. Neuropeptide expression will be investigated across the prepatent phase of infection. The mRNA that encodes the peptide precursors will be detected using a novel in situ hybridization technique (Hybridization Chain Reaction) and the mature peptides will be localized with immunohistochemistry. Synaptic signaling through a FMRF-NH2 gated ion channel will be investigated using neurophysiological methods on identified neurons. This project responds to several programmatic objectives of the NSF Organismal Systems and Infection Biology (OSIB) initiative. The proposed experiments will provide new insights into 1) temporal dynamics of infectious processes, 2) parasitic manipulation of host behavior at the level of individual neurons, and 3) interactions between the immune and nervous systems in an under-studied model system. <br/><br/>This project is funded jointly by Division of Integrative Organismal Systems in the BIO Directorate and the Established Program to Stimulate Competitive Research (EPSCoR).<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.