- Monika Gulia-Nuss: Cytochrome P450 G subfamily memory as a putative odor degrading enzyme in yellow fever mosquito, Aedes aegypti
Nicholas Murray: The influence of repetitive head impacts on motion perception
Repetitive head impacts (RHIs), independent of concussion, are low magnitude blows to the head, neck or body that rarely elicit clinical signs or symptoms of concussion. Recent evidence suggests RHI from a single season of collegiate football can lead to a reduction in midbrain white matter integrity. These findings are consistent with other neuroimaging studies which have identified alterations in brain structure/function over the course of a single-collision sports season. Our goal is to determine the lasting consequences of RHI on motion perception and oculomotor responses following a single season of collision sports. This goal will be accomplished by evaluating motion perception using moving adaptive procedures DVA task while recording eye movements.
Maryam Raeeszadeh-Sarmazdeh: Engineering selective metalloproteinases inhibitors for developing new therapeutics for neurodegenerative diseases
Targeting new pathogenic biomarkers of neurodegenerative diseases is critical as there are limited efficient therapeutics available to control such diseases. The metzincin superfamily, including matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinases (ADAMs), play multifaceted roles in physiological and pathological processes in the central nervous system and therefore are therapeutic targets to limit neurodegeneration in diseases such as Huntington disease, Parkinson’s disease (PD), and Alzheimer’s disease (AD). Given the significance of recognizing enzymes that play a central role in neurodegenerative disease as novel neurodegenerative therapeutics, enzyme inhibitors with high selectivity are desired. Overexpression of MMP-9 plays a significant role in several neurodegenerative disorders, while ADAM-10 helps block progression of AD. Our long-term goal is to develop selective protein-based therapeutics based on MMP inhibitors or similar scaffolds. These studies will lay the foundation for preclinical in vivo models and novel therapeutic strategies for neurodegenerative and other MMP-related diseases.
Floris van Breugel: Temporal integration of olfactory and wind information in plume tracking insects
How animals integrate multiple sensory modalities across time and space in natural environments to make complex sequences of decisions remains poorly understood. A classic behavior that requires such computations is chemical or odor plume tracking in turbulent fluids, and organisms ranging in scale from sperm to sperm whales solve this task with remarkable efficiency. A major obstacle that has stymied prior efforts to determine the mechanistic basis for their decision making has been the inability to independently manipulate odor concentration and fluid flow. To overcome this obstacle, my lab has developed a new method for spatially controlling remote activation of olfactory receptor neurons to create a virtual odor plume independent of the wind to study plume tracking behavior in flying fruit flies. The aim of this project is to determine how temporal and spatial integration of odor and wind information are involved in plume tracking decisions using our virtual odor plume technology.
Jennifer Hoy: Experience-dependent plasticity in superior colliculus circuitry
Our long term goal is to identify and understand the mechanisms underlying plasticity in visual stimulus detection and visually-guided pursuit. Plasticity in these visuospatial orienting behaviors are perturbed in both neurodevelopmental disorders such as autism as well as neurological disorders resulting from traumatic experiences such as PTSD. Thus, development and plasticity of these visual orienting behaviors critically impact healthy visual processing. To better understand the mechanisms that underlie visual stimulus detection and pursuit behaviors more fundamentally, we will investigate the development and sensory experience-dependent plasticity of function of specific cell types of the superior colliculus in the mouse as they relate to specific changes in visual stimulus detection and pursuit behavior.
The superior colliculus is a key subcortical visual system that processes salient environmental stimuli, receives substantial input from cortex and mediates rapid spatial orienting behavior in all mammals. The function of cells in this structure are also sensitive to visual experience and change significantly over development, yet it remains unclear whether specific circuits are the sites of experience-dependent plasticity or how specific circuits in the colliculus change function over development. To address these questions, we will study the functional development of two classes of cells in the superior colliculus known as the wide- and narrow-field neurons. These two cell types define distinct circuits that differentially impact visual stimulus detection versus pursuit. We will measure stimulus representation in these cell types as they relate to behavior as a function of development and specific natural experiences. Overall, this work will advance our understanding of the neural circuit mechanisms underlying successful spatial orienting behaviors that are essential for visual perception.
Simon Pieraut: Regulation of Parvalbumin interneuron connectivity by Slit2
Among the varied inhibitory cell types present in mammalian brains, Parvalbumin-expressing (PV+) interneurons (INs) exert a strong influence on excitatory cell function. While subtle perturbation of their network contributes to the pathophysiology of mental disorders, the molecular and cellular mechanisms regulating their connectivity are poorly understood. We propose to investigate the regulation of PV+ INs connectivity by Slit2. Slit2 is a member of the slit family of secreted glycoproteins involved in axon guidance during embryonic development. We found that conditional deletion of Slit2 in PV+ INs leads to physiological and morphological changes affecting PV+ interneuron population. Altogether, our preliminary data support a model in which connectivity of PV+ neurons is mediated by Slit2. We believe that, if altered, this pathway will lead to perturbed information processing and ultimately behavioral deficits. Using a combination of in vivo and in vitro electrophysiological approaches, imaging of synaptic sites, and behavioral analysis, we propose to determine the role of Slit2 in controlling PV+ INs inputs and outputs and characterize the effect of conditional Slit2 deletion at the circuit and behavioral level. This study will lead to advancements in the field of synapse development and plasticity. Slit2 function during postnatal development is unknown and characterizing a new role for this secreted molecule in central synapses will have a strong impact in the field. The proposed work will shed light on an unidentified pathway governing PV+ INs connectivity which is, when altered, involved in the physiopathology of neurodevelopmental brain disorders.
Josette El Zaklit: Toward the Potential Application of CANCAN Electrostimulation for Neuromodulation
Electrical stimulation applied to specific regions in the brain by surgically implanted electrodes is currently being used as one treatment option for various neurological disorders. Non-invasive technologies such as transcranial magnetic stimulation (TMS) are available; however, they are inefficient due to their limited penetration depth and precision. Deep-penetrating but non-invasive electrostimulation techniques are not yet available. Novel technologies have recently emerged with the potential to enable deep-tissue focusing of nanosecond-duration pulsed electric fields (nsPEFs) for non-invasive nerve and cardiac myocyte stimulation. Moreover, bipolar (BP) nsPEFs have been shown to reduce or even cancel certain biological effects, such as the uptake of Ca2+, elicited by monopolar (MP) pulses in a phenomenon known as "bipolar cancellation". A possible application of this bipolar cancellation is remote stimulation by a “cancellation of cancellation” (CANCAN) effect. This new concept offers the unique opportunity to drive the transfer of electrical energy to a much smaller area and deeper into biological tissues due to the high frequency content of nsPEFs. Thus, CANCAN could provide new means to alter neural cell excitability, serving as a reversible, focused, and non-invasive method for neuromodulation. The objective of this study is to examine the potential for nsPEFs to serve as a novel bioelectric modality to stimulate neurosecretion by studying the response of excitable adrenal chromaffin cells to MP and BP nsPEFs. We will analyze and compare MP and BP (2-100 ns, 3-16 MV/m) nsPEF-induced effects on membrane depolarization, intracellular Ca2+ levels, and exocytosis using a combination of experimental and numerical modeling approaches. We will determine whether the responses elicited by MP nsPEFs can be cancelled or attenuated by BP nsPEFs. The project will provide a proof-of-concept for the use of BP nsPEFs as a novel and safe modality for neuromodulation. In addition, our research will investigate a novel paradigm in which nsPEF-induced biological effects can be reduced by reversing the electric field polarity, and will offer novel tools to modulate cell excitability through the use of CANCAN electrostimulation.
Mark Lescroart: How Does Attention Affect Human Scene-Selective Areas?
When humans navigate, we direct attention to particular features of the visual environment, such as walls and other boundaries of local space, landmark objects, and potential paths or walkways. Several areas in the human brain have been shown to represent information about these and other visual features of scenes. However, little is known about how (or whether) these representations change under the influence of attention. The principal goal of this proposal is to elucidate how attention affects the representation of navigationally relevant information in the human brain. We address this issue in a multi-session fMRI experiment. We will develop formal encoding models for many hypotheses from past work and evaluate each model (each hypothesis) based on its predictive power in withheld data. This approach, termed Voxelwise Modeling (VM), will result in estimates of the fraction of response variance that is explained in every voxel in the brain by models of visual scene features and by models of attention. It will also reveal how each voxel is modulated by changing task demands (tracking distance to a destination, estimating heading, and searching for an object). Thus, this project is likely to result in high-quality maps of the representation of navigationally relevant information in individual subjects. Such maps are likely to be of interest to clinicians, since navigation is commonly impaired in Alzheimers', Parkinson’s and other neurodegenerative diseases.
Nicholas Murray: Evaluation of Saccades during Fixed and Free Head Visual Tasks Post-Concussion
The objective of this application will be to evaluate saccadic eye movements during fixed and free head visual tasks immediately following a sport-related concussion (SRC) in Division I collegiate athletes. The specific aims of the project are (1) examine saccadic eye movements using gaze mapping (a projection of the gaze vector using motion capture synced with eye tracking) during both traditional (prosaccade and antisaccade) and novel functional sport-like visual tasks; and (2) examine the diagnostic accuracy of these visual tasks compared to the gold standard physician diagnosis. The proposed research is consistent with the National Institute of Neurological Disorders and Stroke mission to seek fundamental knowledge about the brain to use that knowledge to reduce the burden of neurological disease. Furthermore, it may fuel further neuroscience research in the area of gaze mapping. We hypothesize that our traditional visual tasks will not observe differences in saccadic gain, mean and peak velocity between SRC and matched controls, whereas our novel functional sport-like visual task will. We also hypothesize that the sport-like visual task will demonstrate high diagnostic accuracy when compared to the gold standard physician diagnosis. To test these hypotheses, the proposed research will recruit SRC and matched controls via our sports medicine partners. Twenty athletes with SRC will be enrolled in the study who are (a) between the ages of 18 and 25; and (b) are diagnosed with a SRC by the head team sport physician. We will then recruit matched controls on a rolling basis who will be paired by sport and gender. The participants will complete an antisaccade and prosaccade visual task with their head fixed along with a novel sport-like head free visual task while wearing a high frequency eye tracking system. Changes in eye movement characteristics will be analyzed in the horizontal and vertical directions using saccadic gain, mean and peak velocity. The project is innovative as it will investigate saccadic eye movements following SRC using gaze mapping and ecologically valid visual tasks. The proposed research is significant in that it will be the first to quantify and measure saccades using both traditional and novel approaches to further elucidate the impact that SRC has on the visual system. The data generated from this pilot project will enable us to apply for larger federal funding such as an R15 or R01.
Mihye Ahn: Statistical models for group comparison of functional MRI data
Recently, many large-scale neuroimaging datasets have been collected and analyzed in an attempt to elucidate brain activities including but not limited to the pathology of psychiatric disorders and cognitive brain functions. However, only a few approaches have been developed for simultaneously analyzing multi-subject neuroimaging data. In this project, we will propose statistical models for integrating functional connectivity pattern across subjects. We will consider two types of data collected in different ways: 1) multi-subject functional MRI data obtained from one or more populations, and 2) multi-subject repeated-measures fMRI data obtained from one or more populations. In summary, we will study statistical models to analyze multi-subject fMRI data collected in various ways, and also consider spatial-temporal correlations as well as high-dimensionality of the data for proposing new statistical procedures such as model selection criteria. The proposed research is important because it addresses the essential steps for analyzing highly correlated fMRI data for multi-subject and multi-group conditions. By applying the proposed models, we will be able to detect group differences with increased power. Moreover, the statistical models we will develop will help us to address research questions effectively in multi-subject fMRI studies.
Fang Jiang: Multisensory temporal processing in early deaf adults
The loss of one sense early in life can lead to an enhancement of the remaining senses. The behavioral enhancements are often accompanied by cortical reorganization, where sensory-deprived auditory regions are recruited for processing visual and tactile stimuli. To date, studies of compensatory plasticity in early deaf individuals have tended to focus on unisensory (either tactile or visual) spatial processing, and the recruitment of deprived auditory areas. Combining behavioral and neuroimaging measurements, the goals of this proposed project are to examine the effects of auditory deprivation on multisensory temporal processing, and to characterize the neural mechanisms underlying these effects. Specifically, we will determine whether early deafness impairs both the precision and the malleability of multisensory temporal integration and whether these impairments are spatially modulated. Furthermore, we will characterize neural correlates and neural dynamics of multisensory temporal processing in deaf individuals focusing on the right superior temporal sulcus (rSTS), a multisensory region that is the likely candidate mediating behavioral alterations in multisensory temporal functions following auditory deprivation. Taken together, this work will provide insights into the brain mechanisms underlying multisensory temporal perception in deaf individuals.
Paul MacNeilage: Role of motor signals for perception during self-motion
Sensing and reconstructing self-motion is necessary to support a number of behaviors that are critical to normal everyday function, including postural control, locomotion and navigation. The current research will advance our understanding of the role of motor signals in self-motion processing, which has the potential to improve diagnosis, treatment, and rehabilitation methods for wide array of spatial orientation disorders.
Dennis Mathew: Functional diversity of olfactory receptor neurons
The ability of an animal to detect, discriminate, and respond to odors depends on the functions of its first-order olfactory receptor neurons (ORNs). The extent to which each ORN, upon activation, contributes to chemotaxis is not well understood. Olfactory behavior in the Drosophila larva is based on the activities of only 21 ORNs. Our preliminary studies suggest that larval ORNs are functionally diverse. The knowledge of how ORN diversity contributes to encode odor information is critical for developing odor coding models that can reliably predict larval behavior. The objectives of this project are to develop methods to account for ORN diversity in computational models and to determine the molecular mechanisms by which ORN diversity impacts olfactory function. Overall, this study represents a substantive departure from the status quo by considering an often overlooked aspect of olfactory information processing - the functional diversity among peripheral sensory neurons. This study is expected to advance understanding of how sensory information is encoded in the activities of a group of functionally diverse ORNs and further propagated down the circuit. It will also identify novel mechanisms by which an insect's physiological state impacts individual ORN function. As a result, new research horizons are expected to become attainable. Translational horizons such as developing solutions for insect control are also likely to become attainable.
Jenny Ouyang: Dark side of night lighting: effects of light spectra on neurosensory function
The nighttime environment has changed dramatically since the invention of electric lighting, in which as much as two-thirds of the world's populated areas are currently above the threshold set for light pollution. However, research on the effects of light pollution has been marked by a lack of connection between biomedical studies in the laboratory and fitness consequences. Moreover, governments and agencies are now replacing fluorescent lighting with LEDs for economic reasons. Full spectra LEDs emit short wavelengths that are known to be disruptive to sleep, health, and hormone balance. The disruptive effects of light pollution may be mitigated by leaving out certain wavelengths, but the impacts of these spectra on physiology and health, especially in relation to sensory neurobiology and stress physiology, are largely unknown. Merging neurobiology, mechanistic and behavioral approaches is a way forward to uncover the proximate as well as ultimate consequences of artificial light at night. We will use zebra finches, Taeniopygia guttata, which serve as ideal, diurnal model organisms to test the effects of nocturnal lighting with adapted spectra on stress physiology, circadian gene expression, and neurosensory function.
Marian Berryhill - Understanding the neural basis of working memory to improve WM function
Remembering new acquaintance's names, losing your train of thought, accidentally bumping into a curb you just saw are examples of working memory (WM) failures that become more frequent with age. WM is a fundamental component of almost every cognitive task. Unfortunately, WM is resistant to improvement. WM training studies reveal subtle, temporary, and task-specific improvements. In other words, people get better at a computer game, but this does not extend to WM demands in real life. Our work shows that pairing WM training with transcranial direct current stimulation (tDCS) can produce longer-lasting WM benefits in healthy older adults. Our protocols also demonstrate significant transfer to untrained tasks. This means that WM skills are strengthened in a way that improves WM performance more generally. Importantly, tDCS-based is safe, well-tolerated and affordable. The long-term goal of this work is to combat age-related WM decline in healthy aging populations and to extend these benefits to vulnerable populations such as those with traumatic brain injury (TBI) and mild cognitive impairment (MCI). Ideally, tDCS-linked WM training will be able to improve the quality of life and the safety of older adults. Project 1 is researching the best paradigms and protocols to optimize and extend tDCS-linked WM benefits to a wide range of cognitive skills including attention, episodic memory, and decision-making.
In summary, the project results have the potential to reduce age-related WM decline, improve cognition more generally, and to clarify the underlying neural mechanism enhanced by tDCS.
Gideon Caplovitz: Behavioral and neural investigations of spatiotemporal form integration in healthy, sleep-restricted and brain-injured persons
In order to survive in a world full of potentially life-threatening danger, the movement of objects in the visual scene must be rapidly detected and identified. Characterizing how the visual system constructs our perception of an object's form and motion is essential to understating how the visual system works in general. An understanding of the intact, normally functioning visual system is a fundamental starting place for diagnosing and treating the visual system when it is impaired or damaged.
This project builds on a growing body of evidence that our perception of a moving object is mediated by mutually interacting neural representations of the object's form and motion. It investigates one unifying neural mechanism that may underlie such form-motion interactions: spatiotemporal form integration (SFI). Spatiotemporal form integration is the integration of neural representations of form features (i.e. the corners of a square) over space and time.
The overall aim of the project is to investigate the properties and neural correlates of spatiotemporal form integration in mediating both form and motion perception and the possible application of this knowledge to the detection and identification of impaired neural processing in the visual system arising from sleep deprivation and mild traumatic brain injury.
David Feil-Seifer: Using socially assistive robot assistants to augment neuro-rehabilitation exercise therapy
Stroke and other Traumatic Brain Injuries are major causes of neurological disability. Most of those affected are left with some loss of movement, speech difficulties, and cognitive deficits.
Concerted rehabilitation during the neuroplasticity period following a stroke can help a patient recover some of their lost function. For upper-limb hemiperisis in stroke recovery, through concerted use and training of the affected limb during the critical post-stroke period, such disability can be significantly reduced. The rate and amount of recovery greatly depends on the amount of focused training, along with stroke severity and cognitive availability. Evidence shows that the intensity and frequency of focused therapy can improve functional outcomes. The goal of this project is to develop healthcare and education robots that effect positive long-term behavioral changes. This includes helping children with developmental disorders to socialize in a positive way, encouraging positive user health choices, and assisting in physical rehabilitation.
Since such rehabilitation normally requires supervision of trained professionals, lack of resources (i.e., workforce shortage, insurance shortfalls, patient non-compliance) limits the amount of time available for supervised rehabilitation. As a result, the quality of life of patients with TBI or stroke is dramatically reduced, and medical costs and lost productivity continue to be incurred. In addition, a growing rate of diagnosis, an aging population, and geographic disparities are contributing to inadequate health resources to meet the care needs. Socially Assistive Robotics (SAR) can potentially address these care caps. A critical deficit for the development and adoption of SAR in care scenarios is the lack of performance and study of long-term Human-Robot Interaction in care settings. While there has been an explosion of research into HRI over the last decade, a large majority of this work examines short-term SAR scenarios. Furthermore, studies that have examined long-term HRI scenarios have been very specialized in nature, none of which involves neurorehabilitation care for patients with TBI. This project aims to bridge that gap.
Fang Jiang: Sensory plasticity and aging
Vision undergoes profound deterioration at both optical and neural levels in healthy aging as well as in age-related diseases. Consequently, age-related decline in vision is a major health and quality of life concern for elderly individuals. To maintain relatively constant visual percepts, the visual system must correct or compensate vision for the age-related sensitivity losses. Currently it is not clear whether the mechanisms contributing to this plasticity remain robust across the lifespan or also deteriorate with aging. Using behavioral and neuroimaging measurements, we will assess the effects of aging on the plasticity of the visual system and specifically whether aging effects on short-term plasticity differ in quantitative or qualitative ways between central vision and the visual periphery, two regions of the visual field that carry different visual functions and are processed at separate neural sites.
Alexander van der Linden: Temperature control of the C. elegans circadian clock
Daily (circadian) rhythms control multiple aspects of human behavior and physiology (e.g. sleep, body temperature) and disruption of these rhythms can either cause or affect the severity of most neurological diseases, such as stroke and sleep disorders. These circadian rhythms are driven by clocks in our brain and body that can be entrained by daily light and/or temperature cycles. Molecular mechanisms comprising these light-entrained clocks in humans and most model organisms studied are well known, but how temperature information controls these clocks is unclear.
Our previous research has established the nematode Caenorhabditis elegans as a powerful new model system to study temperature control of the circadian clock. C. elegans is a well-established system to study temperature responses; it has a well-mapped brain circuitry that senses small changes in temperature, and exhibits circadian behavior induced by temperature cycles.
This project uses genetic, molecular and imaging approaches in C. elegans to investigate the mechanisms underlying temperature control of the circadian clock. We are developing and using imaging systems for long-term recording and quantification of circadian gene expression and behavior in C. elegans.
Findings from this project will aid in understanding the neural pathways that process and integrate temperature signals to the clock. Understanding the inner workings of the circadian clock in great depth and the impacts on circadian time keeping should provide us with new avenues of treatment or prevention of consequences of disrupted circadian timing in neurological diseases.
Pedro Miura: Mechanisms of 3' UTR lengthening and its function in axon guidance
Regulation of gene expression in the nervous system occurs at multiple stages, including at the post-transcriptional level. The 3' Untranslated Region (3' UTR) of mRNAs can regulate localization and translation of mRNAs in neurons. Brain tissues in Drosophila, mice and human all tend to preferentially express alternative mRNA isoforms that have extended 3' UTRs. We are using Drosophila Melanogaster to investigate the mechanism by which this occurs, and the functional roles of extended 3' UTR mRNA isoforms in the nervous system. We are focusing our efforts on a subset of genes that control a fundamental event in nervous system development- axon guidance.
Jacqueline Snow: Comparing cognition, behavior, and neural responses to real objects versus images
The long term goal of this research is to investigate how the human brain processes and represents real world 3-dimensional (3D) objects compared to 2-dimensional (2D) pictures of objects, and whether real objects have unique and measurable effects on cognition and behavior. In the past few decades of research in psychology and neuroscience there has been a rapid rise in the number of behavioral and imaging studies that have examined the structure and function of the visual and motor systems. The stimuli employed in these studies are diverse, ranging from basic elements to more complex stimuli such as objects, faces, and scenes. The overwhelming majority of research to date, however, have utilized 2D images as proxies for real tangible objects. The reliance on images is especially pervasive in functional magnetic resonance imaging (fMRI), mostly for practical reasons: the scanner is a constrained environment in which control over stimulus parameters, and their speed, visibility, and timing is critical-but difficult to realize using real objects. In the real world, however, we predominantly interact with real 3D objects, not 2D images, and the human brain has largely evolved to perceive and interact with real objects and environments (Gibson, 1979). Real objects differ from pictures in many respects, from the presence of additional stereo shape information, to the fact that they afford grasping and interaction - factors known to influence brain-based responses. By focusing on images alone we may compromise ecological validity and impose unnecessary limits in what science can contribute to the development of new and possibly more valid scientific procedures, technologies, diagnostic tools, and patient-based treatments. This research program examines how, and why, the format in which objects are displayed influences fundamental aspects of human cognition and action. The program is comprised of three broad aims that examine the nature of real-object effects on decision-making, attention and eye-movements, and the perception of size. The studies utilize novel and innovative paradigms and equipment designed to present real objects rapidly and efficiently, and includes convergent behavioral studies in healthy observers, neuropsychological patient-based studies, and functional neuroimaging (fMRI).
Lars Strother: Word recognition and the visual cortical processing of two-dimensional shape information
Normal sighted reading relies heavily on human visual system. Despite immense progress in understanding human vision, the visual processing of letters and words during reading is not well understood. The ultimate goal of this research is to understand the role of visual cortex in word recognition, a fundamental component of reading. Specifically, this project seeks to understand how our visual system allows us to use two-dimensional (2D) shape information to quickly and effortlessly recognize familiar letters and words. Although word recognition relies on mechanisms that process 2D shape information during the visual perception and recognition of non-word objects and scenes, preliminary and published (e.g. Strother et al., 2016) research strongly suggests that the visual system processes 2D shape information comprising letters and words differently than it does 2D information in non-word objects. My lab uses functional neuroimaging (fMRI, NIRS and EEG) to study the visual cortical basis of word recognition. We are currently focusing on the neural integration of individual letters into words, which relies on interhemispheric transfer of visual information split between the right and left visual hemifields, and also the neural basis of invariant visual representations of letters and words with respect to retinal location. The proposed research will considerably expand our knowledge of the sensory basis of reading and its foundation in both general purpose mechanisms, some of which become developmentally specialized for word recognition, and sometimes fail in impaired readers.
Yong Zhang: The role of DOMINO in regulation of circadian rhythms in Drosophila
Most organisms on earth use circadian clocks to modulate their bodily functions, thus adapting their metabolism, physiology and behavior to these daily environmental cycles. Malfunctions of circadian clocks are correlated with many human diseases. For example, disrupted circadian rhythms in shift workers are thought to increase the prevalence of cancers, cardiovascular diseases, diabetes and other metabolic diseases. Circadian clocks control rhythmic expression of around 10-15% of mammalian transcripts. The fruit fly Drosophila melanogaster is an excellent model to study circadian clock because of its well-characterized genome, powerful genetics tools, and high throughput automated behavioral assays. In addition, the core of the circadian pacemaker is highly conserved among species, and the molecular mechanisms of circadian clocks were, in great part, discovered in Drosophila. Studying circadian rhythms in Drosophila has profound significance in basic biology and for human health. I have uncovered a novel regulator of Drosophila circadian function for maintaining the locomotor rhythms. This gene is called domino (dom), an important chromatin remodeling protein. DOM plays a critical role in transcriptional regulation by replacing the histone H2A with the H2A.V variant (6). An exchanges of the H2A variant with the H2A affects nucleosome mobility and positioning, thus regulating transcription. We will: 1) define the role of DOM in the control of Drosophila circadian rhythms and sleep. 2) elucidate the mechanism of DOM in the control of circadian rhythms; and 3) identify the protein partners and targets of DOM in circadian neurons. These studies will reveal a novel mechanism of the circadian clock by chromatin remodeling and will advance our understanding of circadian clocks. Chromatin remodeling mechanisms are involved in many metabolic diseases and cancer, which are known to be associated with disruption of circadian clocks. These studies will ultimately lead to improvement of therapeutic methods for circadian clock related diseases.
Xiaoshan Zhu: Engineering magnetofluorescent nanoparticles for neurological disease diagnosis
Engineered nanoparticles with large surface-to-volume ratios, versatile surface functionalization capabilities, and unique physical or chemical characteristics, have attracted significant attention in biomedical research. These versatile nanoparticles can stimulate, respond to, and interact with target proteins, cells, or tissues in controlled ways. Combined with non-invasive molecular imaging techniques such as magnetic resonance imaging (MRI) and fluorescence imaging, the use of nanoparticle probes as exogenous contrast for molecular imaging in neuroscience is bringing the detection and treatment assessment of neurological diseases to a new stage.
In this work, we will devise new, hybrid dual-imaging magnetofluorescent nanoparticles (MFNPs) integrating both iron oxide and an inorganic fluorophore, modify their surface to achieve bio-functionality while minimizing toxicity to cells or tissues, and apply them in a brain tumor model. The hybrid nanostructure ensure a small diameter for nanoparticles thus increasing bioavailability, and the inorganic fluorophore has a high quantum yield and an excellent stability against photobleaching to ensure higher signal to noise in imaging. We will test the hypothesis that the hybrid MFNPs can be surface-modified to specifically target glioma brain tumors and imaged with both MR and optical fluorescence imaging, and explore additional applications of engineered nanoparticles.
Center for Integrative Neuroscience publications
Publications resulting from research supported by the Center