|Yiping He (Pathology), Anne West (Neurobiology)||
A Developmental Approach to the Pathophysiology of Pediatric Medulloblastoma
Although all cells in the body have the same DNA they use their genome in very different ways. During normal development genes are turned on or off to let each specialized cell develop its unique function. By contrast, aberrant regulation of the genome during development frequently leads to childhood cancers. Among these cancers is medulloblastoma, which is the most common brain tumor in infants and young children. This cancer frequently causes death or results in life-long disability both due to damage done by the tumor to the developing brain and from the toxicity of cancer treatments delivered to prolong the child’s life. Thus new ideas that might help to treat this cancer are desperately needed. Recent research has identified novel changes in the regulation of gene expression from the genome in medulloblastoma that may explain why normal brain cells become tumors in this disease. Here we propose to directly test whether these changes in genome regulation are sufficient to cause the formation of tumors and we will work toward developing a mouse model that could provide a means to test new ways to treat medulloblastoma based on this idea. Together these studies will provide important new insights into a fundamental molecular process of brain development that has importance for understanding brain tumors.
|Dwight Koeberl (Pediatrics), Mohamad Mikati (Pediatrics), Scott Moore (Psychiatry & Behavioral Sciences), Victor Nadler (Pharmacology & Cancer Biology)||
Mechanisms of Increased Hippocampal Excitability in the D801N Knock-in Mouse Model of Na/K ATPase Dysfunction an Rescue with AAV-mediated Gene Therapy
Fifty percent of the energy consumed by brain cells is expended by a cellular pump called the sodium potassium (Na/K) ATPase pump. This pump moves sodium and potassium ions across the cell membrane and, thus, is critical for maintaining the integrity of the brain cells and their normal function. It is also vulnerable and can malfunction under the stress of such conditions as epilepsy, stroke, decreased blood sugar, loss of oxygen and other conditions such as Alternating Hemiplegia of Childhood (AHC). AHC is a severe disorder with bouts of paralysis, spasms, and epileptic seizures. It is caused by mutations in the gene, Atp1a3, coding for a protein in this pump. We recently generated a mouse model bearing the most common mutation in AHC and it presents with the symptoms of AHC. In this study we propose to investigate the cell circuitry that regulates the balance between excitation and inhibition in the brain, and determine how this circuitry is altered by dysfunction of the Na/K ATPase pump. We also plan to use gene therapy to correct the manifestations of this disorder in our mouse model. This approach may lead to new therapies for humans suffering from AHC, epilepsy, and other related conditions.
|Greg Appelbaum (Psychiatry & Behavioral Sciences); Mary (Missy) Cummings (Mechanical Engineering and Materials Science)||
Real Time Workload Detection in Supervisory Control Applications Using fNIRS
With increasing use of automation in complex system operations like air traffic or nuclear plant control, the role of human operators is increasingly shifting from hands-on control to remote supervision, known as human supervisory control. When critical events occur, such as the need to scram a reactor or redirect an aircraft in distress, operators can be stressed by the sudden increase in workload, to the point of making erroneous decisions. The ability to remotely detect a psychophysiologic state that is likely to lead to problematic human performance would be especially useful for supervisors of such systems. By combining the measured hemodynamic and metabolic responses of brain and cognitive activity using functional Near-Infrared Spectroscopy (fNIRS), it is possible to determine a change in a subject’s cognitive activity while performing different tasks. Whether such data can be reliably connected to workload and performance in actual supervisory control settings, where most other psychophysiological efforts have failed, is an open question. Using fNIRS in a human supervisory control environment (in this case supervising multiple unmanned vehicles), this proposal will examine whether measured hemodynamic fNIRS data correlates to an actual change in low, moderate, and high workload in supervisory control settings, as well as whether this correlates to different human performance aspects such as decision quality and reaction time. Moreover, we will explore whether fNIRS data can be used by instructors to tailor individual training, and provide for quality control for existing training material.
|Murali Doraiswamy (Psychiatry & Behavioral Sciences), Tobias Egner (Psychology & Neuroscience), Scott Huettel (Psychology & Neuroscience), Walter Sinnott-Armstrong (Philosophy and the Kenan Institute for Ethics)||
Measuring Implicit Moral Attitudes
When a psychopath kills a stranger for money, does he have any sense that his act is immoral—as most of us would? Do people who say sincerely that nothing is wrong with homosexual sodomy actually have an implicit negative attitude that they need to overcome? Do people who lie have any inclination to think that lying is immoral? Are all of our moral judgments ultimately based on such implicit moral attitudes? To answer such questions, we need some way to determine who has an implicit moral attitude and, if so, how strong it is. Unfortunately, no such test exists yet. Our goal is to develop several measures of implicit attitudes, using reaction times, accuracy rates, subliminal primes, eye movements, and brain activity. We plan to develop, refine, and validate these varied tests by comparing their results to each other as well as to independent measures of moral judgment. These new tests will enable us to test popular theories in moral psychology, to study the effects of implicit moral attitudes on behaviors in a variety of contexts, and eventually to improve the diagnosis, treatment, and prediction of recidivism in psychopaths and other mental illnesses associated with deficits in moral judgment and behavior. These new tools could thereby aid both theory and practice.
|Marc G. Caron (Cell Biology), Arthur Moseley (Proteomics), Scott H. Soderling (Cell Biology)||
Translation-Dependent Molecular Signature of Synaptic Plasticity
We are all in part defined by the memories of our experiences, which not only record our past, but also inform how we react to present actions and predict future events. A remarkable feature of our memory is its longevity. Multiple lines of evidence spanning a half-century of research suggest it is the alteration and modification of specific connections (synapses) between neurons that enable for the long-term coding of experience into memory in a process termed synaptic plasticity. Moreover, abnormalities in this process are thought to underlie many of our most devastating neurodevelopmental disorders, including intellectual disability and autism spectrum disorders. One mechanism that has emerged to modify neuronal synapses is the specific translation (production) of proteins at sites of neuronal communication, enabling a long-term enhancement of their connectivity. Mutations in genes, such as FMR1 disrupt this process leading to Fragile X Syndrome in humans and related phenotypes in mice. Unfortunately, it has previously not been possible to decode the identity of proteins that are translated at the synapse, severely hampering our understanding of the mechanisms of synaptic plasticity and the basis for disorders related to its disruption.
|Geraldine Dawson (Psychiatry & Behavioral Sciences); Helen Egger (Psychiatry & Behavioral Sciences); Cynthia Kuhn (Pharmacology & Cancer Biology); Kevin LaBar (Psychology & Neuroscience); Patrick Seed (Pediatrics); Nancy Zucker (Psychiatry & Behavioral Sciences)||
The Role of Microbiota in the Treatment of Anxiety and Abdominal Pain in Young Children
Emerging preclinical evidence in animal models suggests that changes in the composition of the gut microbiome can both indirectly and directly influence CNS function. Evidence of “bottom-up modulation” has been demonstrated: treatments that alter the microbiome, such as probiotics, can influence anxiety and stress reactivity. Evidence of “top-down modulation” has also been demonstrated. For example, stress has been found to impact the composition of the microbiome. These preclinical findings have led researchers to the intriguing speculation that altering the composition of gut-microbiome in humans may affect psychiatric conditions such as anxiety. The use of probiotics as a clinical tool has yielded mixed findings with the most robust effects seen in the domain of pain perception/abdominal discomfort in individuals with irritable bowel syndrome. There remain numerous questions about the potential efficacy and mechanism of gut-CNS relationships. Part of this confusion and these conflicting results may be due to the developmental periods in which probiotic administration has been conducted. In animal models, alterations in HPA-axis reactivity, a marker of stress reactivity, were more sustained when interventions with probiotics occurred during the post-natal period. Similar findings support that gut-brain manipulations have more potent influence earlier in development. In this high-risk, high-impact study, we conduct the first trial open-label trial of probiotics in 30 young children with anxiety and abdominal pain. We examine changes in anxiety, pain/visceral sensitivity, and stress reactivity. Further, we will conduct exploratory analyses to compare the composition of the gut microbiome at baseline to typically developing children.
|James Burke (Neurology); Scott Cousins (Ophthalmology); Sina Farsiu (Biomedical Engineering and Ophthalmology); Eleonora Lad (Ophthalmology); Guy Potter (Psychiatry & Behavioral Sciences); and Heather Whitson (Medicine, Geriatrics)||
Novel Retinal Imaging Biomarkers in Early Alzheimer’s Disease
Imaging of the retina, an extension of the brain, is becoming increasingly used for the diagnosis of neurodegenerative disorders such as multiple sclerosis. Recent studies have shown that retinal changes occur in Alzheimer’s disease (AD). We believe that retinal changes can be utilized for early diagnosis of AD and have the great advantages of being more sensitive, cheaper and significantly less invasive than other diagnostic techniques. We believe that both retina and the brain in AD undergo inflammation, which results in specific retinal changes that can be quantified using automated software developed by our group. The goal of this study is to compare retinal images between normal subjects and subjects with different stages of AD and to confirm that specific retinal changes occur in subjects with early AD. Novel imaging systems to quantify these retinal abnormalities will facilitate early diagnosis as well as fast and convenient monitoring of dementia progression in AD patients. In addition, quantification of these specific retinal changes can be employed to monitor efficacy of future therapies for AD.
|Ute Hochsgeschwender (Neurobiology); Marc Sommer (Biomedical Engineering); Henry Yin (Psychology & Neuroscience)||
Combining Bioluminescence and Optogenetics for Noninvasive Photonic Control of Neurons
A revolutionary advance in studying the brain has come from a technique called “optogenetics”. Scientists program nerve cells within the brain to become light-sensitive, just like the nerve cells within the eye. The activity of such modified nerve cells can then be controlled with exquisite spatial and temporal precision using safe, low-energy lasers and other discrete light sources. Applying this method to nerve cells near the surface of the brain is easy: one can simply shine a laser at the brain area of interest. But many important brain areas are nestled in the wrinkles of the brain, or hidden below the gray matter, in the middle of the head. Hence, to study deeper areas, scientists need to use fiber optics, the same as used in telecommunication cables. These fiber optics cause damage and are impractical for many potentially important experiments. We propose a replacement to fiber optics that will permit the expansion of optogenetics methods. Instead of providing light from external sources, we create the light within the brain. Using genes from fireflies or marine organisms, we can introduce one protein into a nerve cell (called a luciferase) that normally is inactive, but when exposed to a certain chemical (for example, one called luciferin) produces safe, low-energy light. The light-triggering chemical can be introduced with a simple IV injection (it crosses the blood-brain barrier). This project will advance the fundamentals of this new method for non-fiber optic, non-brain-invasive optogenetics.
|Kafui Dzirasa (Psychiatry & Behavioral Sciences); Yong-hui Jiang (Pediatrics & Medical Genetics); William Wetsel (Psychiatry & Behavioral Sciences)||
A Novel Neural Circuit Analysis Paradigm to Model Autism in Mice
Currently, there is no effective treatment for autism spectrum disorders (ASD) that targets the underlying biological mechanism because little is known about the pathophysiology. The apparent technical challenge in human studies renders mutant mice with targeted mutations equivalent to humans a unique opportunity because it allows manipulation at molecular and circuit levels. However, the current analytic paradigm of analyzing synaptic development and function in ASD mouse models has offered little insight into the behavioral impairments in these mice. Human genetic studies have supported SHANK3 synaptic protein as one of the best causative genes for ASD. Shank3 mutant mice recapitulate the core behavioral impairments in ASD and then provide an exciting opportunity to develop a novel analytic approach of dissecting circuit dysfunction. The long term goal of this project is to define dysfunctional circuit underlying ASD behaviors. The central hypothesis is that the ASD-like behaviors in Shank3 deficient mice originate from aberrant neurophysiological activities of multiple neural circuits. The broad objective of this project is to establish a novel paradigm of dissecting and repairing the neural-circuit mechanisms underlying ASD-like behaviors. The specific objective is to identify and repair the dysfunctional neural circuits underlying social deficits and repetitive behaviors in Shank3 deficient mice by utilizing multi-circuit neurophysiological recording, optogenetic tools, and behavioral testing concurrently. The use of this approach in Shank3 mutant mice will be first to examine the circuit dysfunction in valid ASD mouse models. The knowledge about circuit dysfunctions in Shank3 models will provide insight to develop more effective interventions.
|Donald Beskind (Law); R. McKell Carter (Cognitive Neuroscience); John Pearson (Neurobiology & Neurosurgery); J.H. Pate Skene (Neurobiology); Neil Vidmar (Law)||
A Neurobiological Basis for Decision Making
In the United States legal system, rules of procedure and rules of evidence work to limit the harmful effects of biases in human decision-making. But these rules are based on centuries of common law tradition and have not always been linked to research on decision-making, bias, and the strategies decision makers use when weighing evidence. Our research group brings together legal experts and neuroscientists to answer these questions by conducting large-scale web-based studies to measure the decision strategies used by jurors, judges, and prosecutors when weighing evidence. We will use neuroimaging to investigate the brain processes that give rise to these strategies, including unconscious biases. Our ultimate goal is to establish a scientific body of knowledge on biases and heuristics in legal decision-making that will contribute to the goal of a more informed, rational, and humane justice system.
|Greg Appelbaum (Psychiatry & Behavioral Sciences); Rachel Brady (Computer Science & Electrical & Computer Engineering); Scott Huettel (Psychology & Neuroscience); Jordynn Jack (English & Comparative Literature, UNC, Chapel Hill); James Moody (Sociology); Alex Rosenberg (Philosophy)||
Mapping the Intrinsic Structure of Neuroscience
Over the recent decades, the field of neuroscience has increased massively in scope and scale. While once seen simply as an extension of biology, neuroscience has matured into an interdisciplinary venture that collaborates with numerous other fields (e.g., computer science, linguistics, psychology, and economics). Given this growth, there is a profound need for new approaches that synthesize across the larger literature, by identifying common relationships across thousands of studies. In the present application, we expand on a recently developed semantic network approach that maps the relationships between terms and concepts that appear in the larger neuroscience literature. By implementing network text analyses in representative corpora of published neuroscience papers, we will map the historical and current state of knowledge. This approach holds promise for revealing key principles that may not be evident in individual studies. Changes in conceptual maps will be examined over many years to create quantitative models of how the discipline changes over time, which in turn can generate predictions for future research. We will apply these approaches to several sub- disciplines (e.g., systems vs. cognitive) to map the boundaries between different areas of specialization, thereby evaluating how different approaches to neuroscience lead to different understandings of brain function. Given the novelty of this approach for neuroscience, this project seeks to build a unique community at Duke that combines expertise in neuroscience, humanistic inquiry, and network analysis – thereby positioning Duke as a leader in this emerging field.
|David Beratan (Chemistry); Warren Grill (Biomedical Engineering); Wolfgang Liedtke (Medicine, Division of Neurology); Thomas McIntosh (Cell Biology); Scott Moore (Psychiatry & Behavioral Sciences); Angel Peterchev (Psychiatry & Behavioral Sciences); Sridhar Raghavachari (Neurobiology)||
Characterization, Mechanisms, and Modeling of Static Magnetic Field Effects on Neuronal Excitability
Recent scientific studies have shown that the field generated by simple permanent magnets (like fridge magnets but stronger) can alter brain activity when such a magnet is placed on a person’s head for a few minutes. This is an exciting discovery that can lead to various new applications of magnetic fields in science and medicine. Strong magnetic fields are also encountered is some environments like medical MRI scanners. However, it is not understood why this type of magnetic field affects the brain and exactly how the brain cells respond to fields of various strengths, directions, and length of application. This project will explore in detail how the magnetic field affects brain tissue. Specifically, we will combine experimental measurements of how brain cells respond to various magnetic field characteristics, with theoretical and computational models of potential mechanisms underlying these effects. The outcome of this effort will provide a foundation to develop static magnetic field stimulation as a tool for neural research and as a potential safe and cost-effective treatment for brain disorders.
|Blanche Capel (Cell Biology); Debra Silver (Molecular Genetics & Microbiology); Greg Wray (Biology)||
Identifying the Genetic Basis for Uniquely Human Features of Cortical Development
The human brain performs a variety of remarkable feats that underlie our unique mental abilities. In particular, the cerebral cortex is essential for many complex brain functions including cognitive function, sensory perception and consciousness. In terms of evolution, the cerebral cortex is the most recently acquired structure of the mammalian forebrain. Moreover, relative to other structures of the brain, the neocortex is dramatically expanded in humans and this expansion is thought to be responsible for our higher cognitive functions. Many psychiatric disorders, such as autism, bipolar disorder, and schizophrenia are thought to result from dysfunction in the neocortex. In addition, disruption of neocortical development results in broad classes of developmental disorders including microcephaly (reduced brain size). Despite the importance of the neocortex in our evolution, behavior, and mental disease, we know little of the human-specific genetic changes that distinguish the human neocortex from all other mammals. Our project seeks to address this gap in knowledge by identifying genes that are common to all mammals, but whose function has been uniquely co- opted for human brain development. We will focus on those changes acquired in the human lineage that influence gene expression rather than encode a specific protein. We will dissect how these regulatory changes control gene expression in the stem cells that build the neocortex and control the process of brain development. Our long-term goal is to discover the broad repertoire of human-specific genetic changes that impact neocortical development. Significantly, this project will help to understand the genetic mechanisms underlying brain size, cognition, and psychiatric and neurodevelopmental disorders.
|Roberto Cabeza (Psychology & Neuroscience); Sarah H. Lisanby (Psychiatry & Behavioral Sciences); Bruce Luber (Psychiatry & Behavioral Sciences)||
Age-related Changes in Network Organization Investigated with Concurrent TMS-fMRI
The aging brain does not endure anatomical and physiological decline passively; it actively attempts to counteract this decline by reorganizing its functions. In one example of this we have studied using MRI brain imaging, young adults will activate their right frontal lobes when performing a memory task, while older adults (OAs) will also use the left frontal lobes as well, and how much they do this is related to how well they do. The ability of OAs to use both hemispheres may be related to how strongly they are connected. One new way of testing this connection is by using transcranial magnetic stimulation (TMS), which produces a magnetic field in a coil placed outside the head to stimulate the brain directly below it. If used while MRIs are being recorded, the activation throughout the brain caused by the TMS can be measured, including the opposite brain hemisphere. This provides a direct measure of connectivity, which can be compared to how well OAs perform a memory task. Certain forms of TMS can enhance ability to perform a memory task. We will apply this form of TMS to the opposite hemisphere in OAs to test whether it helps their performance in a memory task, and compare that with their measures of brain connectivity. We will then give OAs TMS for two weeks, to test whether that would help make the memory enhancements last at least three months. We hope the results will lay the groundwork for further study leading to therapies for memory deficits in the elderly using TMS.
|Greg Crawford (Pediatrics); Uwe Ohler (Biostatistics & Bioinformatics); and Anne West (Neurobiology)||
Epigenomic Regulation of Neuronal Differentiation
Although the brain is comprised of many different kinds of neurons, all of these diverse cells share the same genomic DNA, and, ultimately, during development they all arose from a single common precursor cell. Understanding the molecular mechanisms that underlie the generation of different kinds of neurons during the development of the brain is important because defects in this process due to genetic mutations or environmental insults can result in devastating neurodevelopmental disorders. The differences in gene expression that define specific kinds of neurons arise during development as a result of modifications layered on top of the DNA sequence that change the structure and thus the accessibility of genomic DNA. New high throughput DNA sequencing technologies have revolutionized our understanding of this process by providing a means to visualize the cell-type specific architecture of DNA. However because the generation of specific kinds of neurons requires specialized techniques, very little is known about the role of DNA structure in the formation of these cells. Here we propose to overcome this limitation by bringing together an interdisciplinary group of investigators to study this aspect of neuronal development. By leveraging the collective expertise of a neuronal cell biologist, a genome biologist, and a computational biologist we are uniquely positioned to witness for the first time how DNA structure changes as a cell becomes a neuron. These studies have the potential to fundamentally reshape our knowledge of the molecular mechanisms of brain development.
|Peter Klopfer (Biology and Evolutionary Anthropology); Andrew Krystal (Psychiatry & Behavioral Sciences); Richard Moon (Anesthesiology); Greg Wray (Biology and Evolutionary Biology); and Anne Yoder (Biology)||
The Neurobiology of Hibernation: Neurophysiologic, Neuroendocrinologic, and Genetic Mechanisms
We have assembled a multi-disciplinary research team to elucidate the neurobiology of hibernation. This team will have the unique opportunity to access the closest genetic relative to humans that hibernates, the fat-tailed dwarf lemur (Cheirogaleus medius), which only exists in the Duke Lemur Center and in the wild in Madagascar. The proposed research program will examine mechanisms associated with the shift from being warm-blooded to the hibernation state, a change which is marked by such drastic alterations in metabolic-rate and body temperature that they are fatal to non-hibernators and to hibernators when not in hibernation season. In order to study the changes in physiology that trigger hibernation and allow animals to survive this state, we propose to evaluate differences in brain electrical activity (EEG), blood thyroid hormone levels, and the expression of genes that are known to regulate metabolism, in waking, sleep, and hibernation. This work has the potential to not only improve our understanding of hibernation mechanisms but also to provide insight into the regulation of temperature and metabolism, and the functions and regulators of sleep. Further, by identifying hibernation-related genes in the closest genetic relative to humans that hibernates, the proposed work promises to be the most important step to date towards determining whether it might be possible to safely trigger hibernation in humans, a capacity which could improve the treatment of a host of human ailments, improve survival in extreme environmental conditions, and allow extended travel in space.
|Fan Wang (Cell Biology); Wolfgang Liedtke (Medicine, Division of Neurology)||
Transsynaptic Labeling and Functional Characterization of Sensorimotor Circuits in the Mouse Trigeminal System
The trigeminal sensory-motor system detects tactile and painful sensory stimuli experienced by the head and face, and also regulates diverse voluntary orofacial motor behaviors such as chewing, swallowing and vocalization. In this project, we will focus on understanding mouse trigeminal sensorimotor circuits underlying two key functions of this system: active touch sensation and mastication-related behaviors. Furthermore, we will examine the functional neuronal connectivity in both normal mice and in a mouse model of orofacial pain to determine whether chronic pain conditions alter the wiring of the sensorimotor circuits. We will employ mono-synaptic rabies assisted trans-synaptic tracing, electrophysiology, calcium- imaging, and behavioral analysis to dissect these neural circuits. These studies should not only provide insights into the neural basis of voluntary movement control and sensorimotor integration, but also establish the foundations for uncovering abnormally altered circuits in various neurological disorders.
|Vadim Arshavsky (Ophthalmology); Sina Farsiu (Ophthalmology); and Adam Wax (Biomedical Engineering)||
Non-invasive Monitoring and Diagnosis of Ocular Neurodegenerative Diseases Using Cell Density Measurement via Angle-resolved Low Coherence Interferometry
Early detection of disease is an overarching goal in medicine. The sooner a disease is found, the greater the options for treatment. In this project, we seek to develop a new method for detecting early stages of neurological diseases by examining cells in the eye. While previous efforts to detect diseases in the eye have used images, it can be difficult to achieve sufficient resolution to see the earliest changes, which occur at the cellular level, due to the limitations of the eye’s own lens. Instead, we seek to take another approach in this work by using light scattering to detect changes in the structure and organization of cells in the retina.
Light scattering has been shown to be a useful basis for diagnosis in several tissues and organs, notably for detecting early stage cancer in epithelial tissues, by measuring changes in cell structure and organization. To date, light scattering has not yet been applied to detecting cellular changes in the eye but has been successfully applied by our research group to detecting early stage cancer in the esophagus without the need for biopsy. In this project, we will demonstrate proof of principle measurements to show that a) cellular structure in the eye can be measured using light scattering and b) the information that is obtained can be used to determine changes in structure due to disease.
|Richard Auten (Pediatrics-Neonatology); Staci Bilbo (Psychology & Neuroscience); and Marie Lynn Miranda (Enviornmental Sciences and Policy)||
Cumulative Maternal Stressor Effects on Enduring Neural and Developmental Outcomes in Offspring
Poverty is associated with many kinds of environmental and psychological stressors, including lead exposure, poor air quality, minimum wage jobs, poor nutrition, and sub-standard housing. In this proposal, we are interested in investigating the potential connections between exposures to social and environmental stress during the prenatal and early postnatal period. We are using an animal (mouse) model that includes a significant social stressor (restricted bedding material) and an environmental exposure already known to affect health outcomes (air pollution). Recent studies suggest that asthma and mental health problems, such as mental retardation, developmental delay, and depression, are strongly linked. We are interested in making the connection between nerve, brain, and respiratory health effects that are associated with exposure to social and environmental stress. While we are using an animal model approach, we will also work concurrently to link the outcomes from this research with what is known about human exposures and outcomes.
|Herbert Covington and Kafui Dzirasa (Psychiatry & Behavioral Sciences)||Characterization of Brain Circuit Changes Underlying Chronic Social Defeat Stress|
|Nicole Calakos (Neurology); Kafui Dzirasa (Psychiatry & Behavioral Sciences); Christopher Lascola (Neuroradiology, Brain Imaging and Analysis Center); Sri Raghavachari (Neurobiology); and Henry Yin (Psychology & Neuroscience).||
Investigating the Neural Basis for Motor Learning Abnormalities in a Novel Mouse Model for Dystonia
Dystonia is an involuntary movement disorder that is a cause of significant disability. The pathogenesis of dystonia remains unclear. Consequently, current treatment modalities have both limited efficacy and significant side effects. We aim to identify the synaptic and circuit level dysfunction in a novel animal model based on a rare TOR1A sequence variant identified in an individual with late-onset, focal dystonia. This novel mouse model has the potential to provide critical insights into the relationship between TorsinA dysfunction, neural dysfunction, and behavioral sequelae. These studies will also advance our understanding of the contribution of this gene to dystonia and related neurological diseases.
|Tobias Egner (Psychology & Neuroscience, Center for Cognitive Neuroscience); Warren Grill (Biomedical Engineering); Michael Platt (Neurobiology, Center for Cognitive Neuroscience); and Marc Sommer (Biomedical Engineering, Center for Cognitive Neuroscience).||
Optimizing Transcranial Magnetic Stimulation in an Animal Model of Human Cognition
The application of brief magnetic pulses near the head can induce small electric currents in the neural tissue of the brain, a technique called ‘transcranial magnetic stimulation’ (TMS). Studies in humans suggest that TMS can temporarily inhibit or increase the activity in stimulated brain areas, and there is much interest in using TMS for human brain research and therapeutic purposes. A major impediment to these endeavors is that the exact way in which TMS affects neuronal activity and consequent cognitive function is currently not well understood. To overcome this limitation, we will optimize TMS for use in nonhuman primates, where we can directly measure its effects on the responses of single neurons, and to compare the behavioral consequences of stimulating particular brain regions in monkeys and humans. Results from our project will provide a scientifically sound basis for the development of research and therapeutic applications of TMS in humans.
|Adrian Angold (Psychiatry & Behavioral Sciences and the Center for Developmental Epidemiology); Philip Costanzo (Psychology & Neuroscience); Helen Egger (Psychiatry & Behavioral Sciences and the Center for Developmental Epidemiology); Richard Keefe (Psychiatry & Behavioral Sciences); Cynthia Kuhn (Pharmacology & Cancer Biology); Kevin LaBar (Psychology & Neuroscience, Center for Cognitive Neuroscience, Center for Neuroeconomic Studies, and the Brain Imaging and Analysis Center); Rhonda Merwin (Psychiatry & Behavioral Sciences); Steven Stanton (Center for Cognitive Neuroscience); James T. Voyvodic (Radiology and the Brain Imaging and Analysis Center); Martin H. Ulshen (Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition); Chongming Yang (Social Sciences Research Institute); and Nancy Zucker (Psychiatry & Behavioral Sciences and the Duke Eating Disorders Program)||
Interoception and the Development of Self-Regulation in Adolescence
It is well recognized that internal changes in bodily organs signal motivated states such as hunger, fear, passion, excitement. While such signals are logical accompaniments to these motivated states (e.g. feeling the intense pounding of your heart as you run from an attacker), yet the signals themselves can serve as cues to guide complex behavior (e.g. the intense pit of dread in your gut intensifies your opinions). Of interest, research in adults has demonstrated that individuals differ in their sensitivity to these somatic sensations. For example, while some may be exquisitely sensitive to even minor alterations from their gut, others often seem relatively unaware of these internal changes. Importantly, sensitivity to these somatic sensations has been associated with proficiency of emotional learning, the vividness of emotional memories, the intensity of emotional experience, and may help facilitate empathic attunement to others via the embodiment of their experiences. Sensitivity to somatic sensations may be related to intuitive problem solving (‘gut feelings’), strength of convictions, and may be related to the pleasure or aversion associated with drugs of abuse. Despite the importance of “interoceptive sensitivity,” researchers know surprisingly little about the development of adaptive and maladaptive trajectories of conscious somatic sensation. We aim to characterize the neural circuitry that supports the healthy development of interoceptive sensitivity during a vulnerable period of brain development: adolescence. This project will help us develop novel intervention strategies for psychosomatic disorders such as anorexia nervosa that principally emerge during the adolescent period, and will be used as the basis of a longitudinal investigation of the typical and atypical development of somatic sensitivity across adolescence.
|Nell Cant (Neurobiology); Warren Grill (Biomedical Engineering); Jennifer Groh (Psychology & Neuroscience, Neurobiology, and the Center for Cognitive Neuroscience); Debara Tucci (Surgery, Division of Otolaryngology Head and Neck Surgery and the Duke Hearing Center); and Blake Wilson (Surgery, Division of Otolaryngology Head and Neck Surgery and the Duke Hearing Center)||Feasibility Studies of the Inferior Colliculus as a Prosthetic Site|
|Guoping Feng and Christopher Lascola (Radiology and the Brain Imaging and Analysis Center)||Quinolone Reductase II: A Novel Target for Neuroprotection|
|Guoping Feng; Yong-hui Jiang (Pediatrics, Division of Medical Genetics); Christopher Lascola (Radiology and the Brain Imaging and Analysis Center); Allen Song (Biomedical Engineering and the Brain Imaging and Analysis Center)||Using a Novel Approach for Functional Brain Imaging in Mouse Models of Psychiatric Disorders|
|Allison Ashley-Koch (Medicine and the Center for Human Genetics); Nicole Calakos (Neurology); Guoping Feng; and William Wetsel (Psychiatry & Behavioral Sciences)||Dissecting Synaptic and Circuitry Mechanisms of Bipolar Disorder|
|Marc Caron (Cell Biology); Michael Ehlers (Neurobiology); Richard Mooney (Neurobiology); William Wetsel (Psychiatry & Behavioral Sciences); Bruce Bean (Harvard Medical School, Neurobiology); and Richard Palmiter (University of Washington, Biochemistry)||Noninvasive Chemical Genetic Control of Neuronal Activity|
|George J. Augustine (Neurobiology); Lorena Beese (Biochemistry); and Homme Hellinga (Biochemistry)||Engineering Optogenetic Sensors and Actuators for Imaging and Controlling Brain Activity|
|Bruce Donald (Computer Science and Biochemistry); Gleb Finkelstein (Physics); and Richard Mooney (Neurobiology)||Multi-wall Carbon Nanotubes and MEMS Microrobots for Intracellular Neuronal Recordings|
|Vadim Arshavsky (Ophthalmology); and Joseph Izatt (Biomedical Engineering)||Non-invasive Optical Measurements of Spatially Resolved Electrical Activity in the Retina|
|R. Alison Adcock (Psychiatry & Behavioral Sciences); James Bettman (Marketing, Fuqua School of Business); Elizabeth Brannon (Psychology & Neuroscience and the Center for Cognitive Neuroscience); David Goldstein (Molecular Genetics & Microbiology); Scott Huettel (Psychology & Neuroscience, Brain Imaging and Analysis Center and the Center for Cognitive Neuroscience); Kevin LaBar (Psychology & Neuroscience and the Center for Cognitive Neuroscience); Mary Frances Luce (Marketing, Fuqua School of Business); John Payne (Management, Fuqua School of Business); Michael Platt (Neurobiology and the Center for Cognitive Neuroscience); Pate Skene (Neurobiology); and Nancy Zucker (Psychiatry & Behavioral Sciences)||Decisions Under Risk: From Phenotype to Mechanism|
|Martin Fischer (Chemistry) and Ryohei Yasuda (Neurobiology)||Noninvasive, High-speed, High-resolution Neuronal Imaging|