Past projects
More than 13,000 people in the US are diagnosed with brain cancer (Glioblastoma multiforme/Glioma, GBM) yearly, with an expected five-year survival rate of less than 22%. The presence of the highly impermeable blood-brain barrier, subject-specific brain heterogeneity, unfaithful animal trials, and the lack of clinical trials are currently impeding the progress of brain cancer research. Infusion-based targeted drug delivery in the brain is a method to directly and accurately administer drugs into the brain tissue through catheters/probes for local treatment of brain cancers (e.g., glioblastoma multiforme/glioma, GBM). Such an infusion-based approach can significantly reduce cognitive impairments, which are the major consequences of radiation or chemotherapy impacting CNS tissues. However, due to the anisotropy and heterogeneity of brain tissues and the brain structure variation from patient to patient, precise knowledge of the infusion-based drug flow and distribution has been difficult to predict and thus limits its applications in clinical settings. In this pilot project, we gather preliminary data for two R01 applications to address the unmet need.
Over 250 million children globally are failing to achieve their full developmental potential as a result of the effects of poverty and chronic malnutrition. Stakeholders everywhere are urged to design and implement public health, education, and environmental policies and programs to advance early childhood development (ECD). Evaluating the impact of these programs on the development of children under 3 years of age is a global challenge. The current reliance on behavioral assessments overlooks possible synergies with state-of-the-art technologies available in cognitive neuroscience that could expand our understanding of “what works” to advance ECD. This research aims to integrate neuroimaging measures of brain function with measures of development obtained during children’s performance on specific behavioral tasks used to evaluate ECD globally. Functional near-infrared spectroscopy (fNIRS) has been used for over 25 years to investigate cortical brain activity by quantifying changes in the amount of oxygenated (HbO) and deoxygenated (HbR) hemoglobin in response to stimuli that are metabolically taxing to the brain. fNIRS is especially suited to studying children because it is non-invasive, safe, silent, and, unlike other imaging techniques, is portable and tolerates bodily movement. These child-friendly attributes have enabled advances in detecting early neural indicators of atypical and compromised development in children and in assessing the need for intervention in neonatal care. Critically, fNIRS allows participants to engage in naturalistic scenarios, such as reaching for an object in studies of infants’ motor skills. We propose to exploit this feature and collect fNIRS data while administering select behavioral tasks that reflect age-driven developmental milestones in ECD. Based on studies in adults, we hypothesize that with children’s increasing age, experience, and ability to complete certain behavioral milestones, we will detect more changes in HbO and HbR concentrations in the brain. Examples of behavioral milestones we plan to test include the pincer grasp (e.g., the ability to pick up a small object between the thumb and finger), scribbling, and recognition of named objects in pictures. We expect to see differential cortical activity as the developmental skill emerges with increasing age. By combining state-of-the-art cognitive neuroscience methods, such as neuroimaging and computational neuroscience, with traditional behavioral assessments at different stages of children’s development, we are better positioned to detect underlying neural mechanisms of change over age as children learn new skills. Further translation of cognitive neuroscience in the use of behavioral assessments will allow for the examination of ways in which early experience and adversity (e.g., preterm birth, neglect, or disease) influence ECD and inform how programs aimed at helping children achieve their developmental potential are evaluated.
Female mosquitoes are vectors for some of the most debilitating infectious diseases of humans. Current chemical management strategies use insecticides that target the neuro-endocrine system almost exclusively. With insecticide resistance on the rise, there is a serious resurgence of mosquito-borne diseases, and therefore an urgent need to develop new targets for new strategies. Female of most mosquito species require vertebrate blood to provide nutrients for egg production and therefore need to locate an appropriate host mainly through their sense of smell. Consequently, mosquitoes have evolved an acute olfactory information processing system that detects and processes odor information to enable localizing the odor source, and finally rapidly inactivates the odor signal so as to maintain high odor sensitivity. Studies in the last several decades have greatly improved our understanding of how odors are detected and processed by the olfactory circuit, the neuroscience underlying odor-signal inactivation is poorly understood. Recent studies have suggested that antennal cytochrome P450s (CYPs) play an important role in odor molecule breakdown. In honeybees, a member of insect-specific CYP subfamily, CYP4G11, has been shown to degrade short-chain alcohols and aldehydes (common volatile odor molecules in plants and animal odor). The yellow fever mosquito, Aedes aegypti, has two functional CYP4G orthologs, CYP4G35 and CYP4G36. Our preliminary data show that CYP4G35 mRNA levels are highest in the head and peripheral olfactory tissues (antennae, maxillary palps, proboscis, and head). CYP4G35 knockdown by RNAi results in vertebrate host avoidance by the adults. Based on the evidence in the literature and our preliminary data, we hypothesize that the CYP4G35 is an odor degrading enzyme, important for odor clearance. We will test this hypothesis through two specific aims: Aim 1) assessing the effects of CYP4G35 knockout on host and mate finding (olfaction and mating), and Aim 2) Functional determination of CYP4G35 as an odor degrading enzyme by determining enzyme substrates and localization in the antennae. We will employ techniques in molecular biology, biochemistry, and neuroscience/behavior to achieve these aims. This work will impact the field by providing 1) a novel target for mosquito control, and 2) an enhanced understanding of the olfactory information processing in mosquitoes.
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.
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.
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.
Electrostimulation (ES) is a versatile and efficient tool to manipulate biological functions, but achieving deep-penetrating, targeted, non-invasive ES remains a major challenge. Current ES methods encompass both invasive and non-invasive technologies. While invasive technologies target a specific area deep inside the brain, the tissue damage, pain, and risks of bleeding and infection associated with electrode placement limit its use. Non-invasive technologies are available; however, they are inefficient due to their limited penetration depth and spatiotemporal resolution. Recent studies of bipolar pulse cancellation, a phenomenon unique to ES mediated by nanosecond-duration electric pulses (nsEPs), suggest that this form of ES may overcome these inefficiencies. Bipolar cancellation refers to the suppression of a stimulatory effect induced by a unipolar nsEP by the application of a second pulse of opposite polarity. This negative effect can itself be cancelled by modulating the parameters of the bipolar pulses, leading to a more spatiotemporally refined excitation than that achieved by the standard delivery of unipolar nsEPs. This manipulation of bipolar cancellation is referred to as stimulation by “cancellation of cancellation” or CANCAN-ES. Due to the high-frequency content of nsEPs relative to longer-duration electric pulses such as those used in deep brain stimulation, CANCAN-ES offers an opportunity to drive the transfer of electrical energy to focused areas deep within biological tissues remotely, without the need for implanted electrodes. While most studies of bipolar nsEPs have focused on identifying bipolar pulse parameters responsible for a cancelling effect using isolated cells in culture, no studies so far have examined the use of bipolar nsEPs to stimulate an excitable cell subtype in an ex vivo or in vivo model. The goal of this project is to determine the biological effects of bipolar nsEPs on peripheral nerve motor axons in an ex vivo neuromuscular tissue preparation. In Aim 1, we will test whether this form of ES is capable of activating the nerve. In Aim 2, we will evaluate whether this form of ES causes any adverse effects. We will use transgenic mice expressing the genetically-encoded Ca2+ indicator GCaMP3 expressed in diaphragm muscle cells to measure intracellular electrical potentials and Ca2+ transients in these cells to achieve our goal.
This project investigates the potential for bipolar nsEPs to be used as a novel technology to achieve deep and focused electric stimulation non-invasively. By elucidating how bipolar nsEPs modulate peripheral nerve excitability, this research will provide fundamental information to guide future in vivo investigations aimed at developing practical applications of nsEPs for neuromodulation.
Individuals with migraine experience sensory sensitivities, such as discomfort to light and sound, that are known to fluctuate during the migraine cycle. The current project will investigate the change in sensory sensitivities over the migraine cycle to ascertain if sensory symptoms can be used as biomarker for approaching migraine-onset. Having biomarkers for approaching migraine-onset allows for prophylactic treatments to be administered before the pain occurs, reducing the frequency and severity of migraine.
Two sensory modalities have been heavily implicated in migraine: vision and audition, to the degree that photophobia (sensitivity to light) and phonophobia (sensitivity to sound) are included in the diagnosis of migraine. Visual auras (disturbances in the visual field) are also frequently reported before and during a migraine, however, auditory auras are not. Very little is formally known about sensitivity to odor, touch, and motion. Therefore, we will focus our investigation on tracking changes in sensitivity in multiple sensory modalities to ascertain if all modalities are equally impacted in migraine or if they offer different but complementary information on migraine-onset, together generating a stronger biomarker.
Aim 1 will investigate sensory sensitivities over the migraine cycle using a migraine diary. Participants (migraine-only) will complete a daily diary on their sensory symptoms and any headaches experienced for one-month. We predict that sensory symptoms will be more severe within 24-hours of migraine-onset.
Aim 2 will focus on a more in-depth investigation into visual and auditory sensitivity in migraine compared to headache-free controls. During the one-month migraine diary duration, participants with migraine will complete a single lab session where electroencephalography (EEG) measures of visual and auditory processing will be collected alongside behavioral measures of discomfort. We will also recruit age- and gender-matched headache-free controls as a comparison group. We predict that migraine will show lower discomfort thresholds (greater sensitivity), and greater responses in the EEG (reflecting greater neural sensitivity) than headache-free controls. When these findings are integrated with the information on migraine cycle from the diary, we predict that the effects will be elevated within 24-hours prior to migraine-onset. Further analyses will ascertain if the visual and auditory responses are predictive of migraine-onset.
We will investigate changes in sensory sensitivity over the course of the migraine cycle to ascertain if sensory sensitivity is a useful biomarker for approaching migraine-onset. Finding a biomarker for migraine-onset will be useful for knowing when to administer prophylactic treatment to reduce the frequency and severity of migraine attacks.
The enteric nervous system (ENS) is an autonomous network of millions of cells embedded in the gastrointestinal wall that monitor and modulate nearly every aspect of bowel activity. Defects in the ENS cause debilitating diseases with complicated etiology and limited treatment options. The complexity and inaccessibility of the mammalian ENS make it challenging to investigate enteric neuron function in the context of the functioning gut. There is a critical need for a simplified model for manipulating and understanding how the ENS operates. To address this problem, the long-term goal of this project is to develop the Mexican tetra, Astyanax mexicanus, as a model to investigate enteric nervous system structure and function. This species of small fish exists as river-dwelling (surface) forms and eyeless cave-dwelling forms (cavefish) that are easy to breed and compare in the laboratory. Cavefish have evolved altered gastrointestinal motility to delay the transit of digesta and maximize nutrient extraction from the unique sources of food in the cave environment. The fish are transparent at early life stages permitting visualization of the ENS in the active gut of live animals. There are less than 700 enteric neurons in the larvae providing a highly simplified system to investigate neuron function. In addition, the gut contains a stomach and pyloric sphincter similar to humans. The central hypothesis of this proposal is that changes in the structure or function of the enteric nervous system underlie evolution of gastrointestinal motility in cavefish. Our objective is to compare enteric neuron connectivity, cell types, and activity between surface fish and cavefish to reveal how nature modifies the ENS to achieve altered gut motility. Completion of the aims will establish cavefish as an innovative and simplified “natural mutant” model to investigate the structure and function of the ENS.
An estimated 30 million Americans meet the diagnostic criteria for irritable bowel disease (IBS) which is associated with debilitating abdominal pain, constipation and diarrhea. The cause of IBS not completely understood, and the treatment options are limited. The enteric nervous system (ENS) controls gut motility which is disrupted in disorders such as IBS. A better understanding of how the ENS controls motility could lead to more sophisticated treatment options for patients with IBS and other enteric neuropathies.
Early life experience induces the remodeling of the nascent synaptic network and enables learning, acquisition of new behavior, and adaptation to new environments. A large body of work has been done to unravel the experience-dependent mechanisms that regulate the addition and elimination of synapses and refine the maturing circuits. While this structural plasticity remodels both the excitatory and inhibitory synaptic network, the diversity of the inhibitory cell population has prevented a detailed understanding of the plasticity mechanisms controlling the remodeling of their synapses. It has long been assumed that the number of inhibitory synapses is homogeneously scaled up or down in response to change in brain activity. However, recently published works and the PI’s strong pilot data challenge this model. We hypothesize that the cellular identity, as well as the level of activity of the postsynaptic neuron, instruct the recruitment of synapses from cholecystokinin-expressing basket cells (CCK-BC). The proposed project will use an integrative approach that includes raising mice in an enriched environment and the use of synthetic receptors to manipulate neural activity. We will combine cutting-edge imaging and electrophysiology techniques to quantify inhibitory synapses in the hippocampus from well-defined inhibitory cell-types. We will determine how early life experience refines these connections and unravel new principles of developmental inhibitory plasticity.
Aim 1 - Determine functional change in the DG of mice raised in an EE. Using electrophysiology and calcium imaging, we will determine the extent to which CCK-BC plasticity transform the filtering capacity in the DG and affect network activity.
Aim 2 - Determine the specificity of experience-dependent remodeling of CCK synapses at the cellular level. Taking advantage of our imaging techniques, we will determine whether the change in inhibitory CCK-BC synapse induced by EE is dependent on neurons identity and their activity. Characterization of CCK-BC plasticity that is induced by experience will be critical will increase our understanding about how synaptic connections are adjusted in response to the changes in neural activity and shed a new light into how genetically wired circuits are remodeled by experience.
The diversity of the inhibitory cell types provides a complex intertwined network of synapses that compute excitatory cells activity. This computation enables information processing and complex cognitive functions. Not surprisingly, many neurodevelopmental disorders are associated with a discrete deficit in the inhibitory network and defect in CCK-BC network affect memory formation and is observed in epilepsy model. The proposed research will improve our understanding about the maturation and plasticity of this important GABAergic cell types.
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 is perturbed in both neurodevelopmental disorders such as autism as well as neurological disorders resulting from traumatic experiences such as PTSD. Thus, the 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 a 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 the 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.
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 the 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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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).
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.
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.
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