Laminar organization of neurons in cerebral cortex is critical for normal brain function. Two distinct cellular events guarantee the emergence of laminar organization-- coordinated sequence of neuronal migration, and generation of radial glial cells that supports neurogenesis and neuronal migration. Our goal is to understand the cellular and molecular mechanisms underlying neuronal migration and layer formation in the mammalian cerebral cortex. Towards this goal, we are studying the following three related questions:
1. What are the signals that regulate the establishment, development and differentiation of radial glial cells, a key substrate for neuronal migration and a source of new neurons in cerebral cortex?
2. What are the signals for neuronal migration that determine how neurons reach their appropriate positions in the developing cerebral cortex?
3. What are the specific cell-cell adhesion related mechanisms that determine how neurons migrate and coalesce into distinct layers in the developing cerebral cortex?
We study the interface between signal transduction and cell function. Approaches employed include - molecular genetics, protein and lipid biochemistry, confocal and electron microscopy, protein crystallography, and model organisms approaches (e.g. yeast, Arabidopsis, C. elegans, mouse gene knockout technology).
Dr. Belger's research focuses on studies of the cortical circuits underlying attention and executive function in the human brain, as well as the breakdown in these functions in neuropsychiatric and neurodevelopment disorders such as schizophrenia and autism. Her research also examines changes in cortical circuits and their physiological properties in individuals at high risk for psychotic disorders. Dr. Belger combines functional magnetic resonance imaging, electrophysiological scalp recording, experimental psychology and neuropsychological assessment techniques to explore the behavioral and neurophysiological dimensions of higher order executive functions. Her most recent research projects have begun focusing on electrophysiological abnormalities in young autistic children and individuals at high risk for schizophrenia.
My lab uses a cognitive neuroscience approach to understand the neurobiology of drug addiction in humans. The tools we use include fMRI, cognitive testing, physiological monitoring, pharmacology, and genetic testing. We specifically seek to determine 1) how the brain learns new stimulus-response associations and replaces learned associations, 2) the neurobiological mechanisms underlying the tendency to select immediate over delayed rewards, and 3) the neural bases of addiction-related attentional bias.
This multidisciplinary laboratory has 6 interests: 1) Defining regionally specific adaptations responsible for functions altered by chronic ethanol; 2) Characterizing regional CNS biochemical changes induced by stress and CRF after chronic ethanol; 3) Defining the role of central cytokines in behaviors induced by stress; 4) Exploring how a benzodiazepine (BZD) agonist shares actions with a BZD antagonist; 5) Defining TRH receptor subtype(s) responsible for its anti-anxiety and analeptic actions; and 6) Defining the action of galanin on ethanol withdrawal-induced anxiety. To undertake our interests, behavioral, anatomical, pharmacological, electrophysiological, biochemical, and molecular biological approaches are used.
The Brenman lab studies how a universal energy and stress sensor, AMP-activated protein kinase (AMPK) regulates cellular function and signaling. AMPK is proposed to be a therapeutic target for Type 2 diabetes and Metabolic syndrome (obesity, insulin resistance, cardiovascular disease). In addition, AMPK can be activated by LKB1, a known human tumor suppressor. Thus AMPK signaling is not only relevant to diabetes but also cancer. We are interested in molecular genetic and biochemical approaches to understand how AMPK contributes to neurodegeneration, metabolism/cardiac disease and cancer.
Research in the Carelli laboratory is in the area of behavioral neuroscience. Our studies focus on the neurobiological basis of motivated behaviors, including drug addiction. Electrophysiology and electrochemistry procedures are used during behavior to examine the role of the brain 'reward' circuit in natural (e.g., food) versus drug (e.g., cocaine) reward. Studies incorporate classical and operant conditioning procedures to study the role of the nucleus accumbens (and dopamine) and associated brain regions in learning and memory, as they relate to motivated behaviors.
Our research centers on the cell biology and biochemistry of motor proteins and the cytoskeleton and their roles in processes such as cell crawling, phagocytosis, organelle transport.
Research in the lab is focused on four major areas - (1) Genetic, cellular, and genomic analyses of Drosophila CNS development, (2) Brain development and behavior, (3) Molecular genetics of gene regulatory pathways, and (4) Control of cell migration and fusion events.
Our laboratory has research interests that include developmental neurotoxicity, with an emphasis on the use of mode-of-action models to study the impact of endocrine disruptors and the cumulative risk of thyroid disruptors and pesticides.
The Cyr laboratory studies cellular mechanisms for cystic fibrosis and prion disease. We seek to determine how protein misfolding leads to the lung pathology associated with Cystic Fibrosis and the neurodegeneration associated with prion disease.
We study how mammalian cells activate the programmed cell death pathway and die by apoptosis. We have focused our work on identifying unique mechanisms by which this pathway is regulated in postmitotic cells such as neurons, cardiomyocytes, and myotubes, as well as cancer, senescent, and stem cells. Excessive cell death is seen in many pathological conditions such as after stroke, neurodegeneration or cardiovascular diseases. In contrast, reduced cell death is a hallmark of cancers. Therefore, discovering the mechanism by which mammalian cells regulate cell death has significant therapeutic implications.
The Dokholyan group focuses primarily on understanding protein dynamics, more specifically on how induced changes in protein folding and aggregation lead to diseases, such as cystic fibrosis, many types of cancers, and a number of neurodegenerative diseases. The Dokholyan group focuses on several such diseases, including Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease, and Huntington disease. The Dokholyan group is developing a hierarchy of molecular models, from simplified coarse-grained models to more detailed ones, to create a novel multi-scale simulation methodology. This methodology will enable simulations of large molecular complexes at the biologically-relevant time scales, thereby allowing to directly glance into processes associated with human diseases. Member of the Molecular & Cellular Biophysics Training Program.
The study of opioid analgesics, with particular focus on opioids that are less likely to produce physical dependence and abuse. Research in the laboratory has examined the relationship between the analgesic effects of opioid analgesics and their interaction with specific opioid receptor types. A more recent research interest includes investigations of genetically-altered mice with relevance to drug dependence and the development of models of mouse behavior for examining behavioral phenotypes related to a range of behavioral disorders.
We are characterizing the structural signals that are responsible for moving proteases normally stored intracellularly in lysosomes into the extracellular environment, where they may participate in tumor cell metastasis. One putative mediator of this altered protease targeting is an endosomal integral membrane protein that behaves like a cellular "dirty bomb", undergoing proteolysis which releases fragments that target to various cellular sites where they serve distinct functions. The multiple proteolytic cleavages ultimately release the cytoplasmic tail from the membrane. This tail, which possesses a putative signal for import into the nucleus, can modify other proteins with ubiquitin, which causes them to be degraded rapidly. Proteolysis of the putative receptor is mediated by the same enzymes that cleave the Alzheimer's precursor protein into fragments that can aggregate to form plaques in the brain. When neurite outgrowth is stimulated, expression of this protein is upregulated, suggesting that it also plays a role in development. We are using biochemical characterization of the protein's domain structure to relate its proteolysis, cellular targeting, and signaling to the nucleus to altered targeting of lysosomal enzymes.
The central goal of my research is to understand how immune cells are activated and regulated within the Central Nervous System. Our research looks at the different pathways of activation of the microglia, the role of the microglia in sensory responses, and the role of stress responses in activating and regulating the response of the microglia. We are currently investigating the mechanism of microglia activation and regulation in Parkinson's Disease (PD). We also study the mechanisms by which CD8 T lymphocytes dictate the nature of inflammatory responses to cancer cells. Research in my laboratory seeks to delineate the immunologic mechanisms involved in the generation of protective anti-tumor responses in CD8 cell populations, and in developing therapies for treatment of cancer.
The role of associative learning and memory in cue-induced relapse to drug seeking and the role of the prefrontal cortex in suppression of drug seeking. Studies in my laboratory utilize surgical, behavioral, and histological techniques as well as neuropharmacological manipulations.
Dr. Gilmore’s research group is applying state-of–the-art magnetic resonance imaging and image analysis techniques to study human brain development in 0-6 year olds, with a focus on cortical gray and white matter development. Studies include normally developing children, twins, and children at high risk for schizophrenia and bipolar illness. We are beginning to study the contributions of specific genes of risk to brain development in humans. A collaborative study with the Harlow Primate Lab at the University of Wisconsin is using imaging to study brain development in Rhesus monkeys, and the impact of prenatal exposure to maternal infection on brain development.
We are interested in how complex signaling systems interact to preserve homeostasis, while also optimizing the response of the organism to environmental changes. Two different projects are ongoing in the laboratory: Project 1: Matching renal salt excretion with dietary salt intake is vital for survival. We are integrating whole animal physiological studies and innovative molecular techniques to investigate the role of a new intestinal hormone, uroguanylin, in this process. Project 2: How do target organs communicate with neural circuits? We are investigating feedback regulation of a simple neural circuit that uses a novel form of muscle-to-nerve communication to control the contractions of the heart musculature.
The primary thrust of research in this lab seeks to understand the effects of neurosteroids on development, particularly how neurosteroid levels in the developing cortex affect patterns of migration and neurogenesis in the prefrontal cortex. A secondary interest is the mechanisms by which increases in neurosteroid levels might be relevant to their therapeutic action.
We focus on mechanistic/structural aspects of regulatory proteins (heterotrimeric and Ras family GTPases, RGS proteins, and PLC isozymes) involved in inositol lipid signaling, and on G protein-coupled receptors for extracellular nucleotides.
The Neurotoxicology Group examines the role of microglia interactions with neurons and the associated immune-mediated responses in brain development and aging as they relate to the initiation of brain damage, the progression of cell death, and subsequent repair/regenerative capabilities. We have an interest in the neuroimmune response with regards to neurodegenerative diseases such as, Alzheimer's disease.
One focus of my research has been the investigation of the neural consequences of reflexive, or automatic, shifts of visual attention. I have combined behavioral measures with recordings of event-related brain potentials in humans. A second interest has been to gain a more temporally precise and anatomically specific understanding of human attention systems, through the development of a multi-methodological approach that combines event-related potentials with neuroimaging methods like positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). Finally, I am also investigating mechanisms of top-down attentional control in order to understand the cognitive neural architecture of executive attentional processes.
Effects of drugs of abuse on maternal behavior and aggression and the effects of prenatal exposure to drugs on offspring development and behavior. Approaches range from molecular to behavioral as our work is basic science with a clinically applicable focus.
I study a canine model of Duchenne muscular dystrophy. Both conditions occur due to mutations in the dystrophin gene. Our research has defined clinical and pathologic features to better understand disease pathogenesis and to assess treatment.
Lab research signals and effectors necessary to establish regional and cellular differences in the regions of the forebrain. Human diseases are a starting point for identifying novel genes that may participate in normal forebrain development.
Our lab group is interested in the behavior, sensory ecology, neuroethology, and conservation biology of animals, particularly those that live in the ocean. Research focuses include: (1) physiology and ecology of animals that migrate long distances; (2) navigational mechanisms of sea turtles, spiny lobsters, monarch butterflies, and salmon; (3) neuroethology and behavioral physiology of invertebrate animals; (4) use of the Earth’s magnetic field in animal navigation; (5) technoethology (the use of novel computer and electronic technology to study behavior).
Molecular, cellular and in vivo approaches in intestine to define mechanisms by which hormones and growth factors regulate normal growth and cancer. Uses model cell lines, mutant mice, mouse models of disease, translational approaches to growth factor action and signal transduction, gut immune interactions in obesity.
The Magnuson Lab works in three areas - (i) Novel approaches to allelic series of genomic modifications in mammals, (ii)Mammalian polycomb-group complexes and development, (iii) Mammalian Swi/Snf chromatin remodeling complexes
Dr. Maixner’s research program focuses on identifying the pathophysiological processes that underlie pain perception, persistent pain conditions, and related disorders. His current research focuses on genetic, environmental, biological, and psychological risk factors that contribute to the onset and maintenance of chronic pain conditions. A long term goal of his program is to translate new discoveries into clinical practices that improve the ability to diagnose and treat patients experiencing chronic pain.
Physiology and pharmacology of the basal ganglia; neurobiology of motivation and reward; substance abuse neurobiology; and neurobehavioral teratology.
My laboratory studies the function of neural circuitry involved in the perception of reward and the reinforcement of motivated behaviors in several mouse models of neurodevelopmental disorders, including early developmental exposure to drugs of abuse, such as alcohol or cocaine; and genetic models relevant to the study of autism, such as inactivation of the Fmr1 (Fragile-X Mental Retardation) or MeCP2 (Methyl-CpG Binding Protein) genes. My laboratory employs techniques in behavioral pharmacology, including intracranial self-stimulation (ICSS); in vitro patch-clamp electrophysiology in acute brain slices; and immunohistochemistry with unbiased stereological microscopy.
My research focuses on molecular mechanisms of mammalian nervous system development. We investigate mechanisms by which developing neurons migrate to the neocortex and form connections.
Our laboratory studies the mechanisms of sensory information processing in the nervous system, with an emphasis on processing in the auditory pathways. We study the role of ion channels in integration at the single cell level, short and long-term synaptic plasticity, synaptic function, and ion channel dynamics in the auditory brainstem and auditory cortex. We are also studying how different kinds of hearing loss affect central auditory function. Experimentally, we use patch clamp (current, voltage and dynamic clamp) methods in brain slices, live optical imaging of activity, a variety of biochemical and molecular methods, mice with genetic hearing loss, noise-induced hearing loss, auditory brainstem evoked response, and acoustic startle response to evaluate hearing function in animal models. The laboratory extensively utilizes quantitative experimental techniques, complemented with detailed computational modeling at the single cell and network levels to further understand the normal information processing capacity of auditory neurons, and the consequences of changes in ion channel and synaptic function after hearing loss.
Research in our laboratory falls at the interface between Genetics and Cell Biology and is concentrated on understanding the molecular details of how small nuclear ribonucleoprotein (snRNP) complexes are assembled and transported to their proper subcellular compartments. Interestingly, defects in the machinery required for assembly of snRNPs are associated with a neurogenetic disease called Spinal Muscular Atrophy (SMA). Mutations in the human survival of motor neurons 1 (SMN1) gene cause SMA. A variety of projects in the lab are focused on SMN's role in the biogenesis of small RNPs as well as in neuromuscular development and function. Other projects focus on nucleocytoplasmic trafficking and the functional organization of the nucleus. We use a combination of approaches, from in vitro biochemistry and cell culture, to in vivo mouse and Drosophila model systems.
Our laboratory is interested primarily in the responses of macrophages during injury to the central nervous system and during inflammation after insult by bacterial pathogens. We use molecular, cellular and biochemical approaches both in vitro and in vivo to identify the function of key mediators during pathogenesis.
Dr. Meeker’s research is focused on the mechanisms of HIV neuropathogenesis. Inflammatory changes within the brain caused by the viral infection initiate a toxic cascade that disrupts normal neural function and can eventually lead to neuronal death. To explore the mechanisms responsible for this damage, we investigate changes in calcium homeostasis, glutamate receptor function and inflammatory responses in primary neuronal, microglial and macrophage cultures. New therapeutic approaches targeted to signal transduction pathways and calcium regulation that protect the neurons and reduce inflammation are under investigation.
My laboratory studies diffuse gliomas, devastating primary tumors of the central nervous system for which few effective drugs are currently available. We utilize model systems (genetically engineered mice, cultured cells, and human tumor specimens) to explore the molecular pathogenesis of
and develop drugs and diagnostic markers for individualized therapy of gliomas. Rotating students gain experience with techniques that include genomics (expression microarrays and array CGH), fluorescence microscopy, computer-enhanced image analysis, and tissue microarrays.
Function, expression and trafficking GABA-A receptors in the CNS; effects of chronic ethanol exposure that leads to ethanol tolerance and dependence; role of endogenous neurosteroids on ethanol action and adaptations; etiology of essential tremor.
We study the cells, the chemical mediators and the functional organization of peripheral and spinal systems associated with normal and pathological pain, itch, and temperature sense using electrophysiological, molecular and histochemical techniques.
The main focus of our research is to examine the molecular and cellular mechanisms that are involved in conferring neural identity to stem cells during embryogenesis and the adult.
Our sensory experiences leave indelible marks on the brain, and the Philpot Lab seeks to understand how this occurs at the level of the synapse. Our research examines the experience-dependent mechanisms that allow functional cortical circuits to emerge and for memories to be stored. We use electrophysiology, biochemistry, and genetic manipulations to study fundamental mechanisms of synaptic plasticity relevant to disease models and other neuropathologies (e.g. amblyopia, mental retardation, and schizophrenia). Through our studies in the visual cortex and hippocampus, we aim to provide insights into preventing common neuropathologies and to discover mechanisms for promoting neural regeneration in the mature brain.
Dr. Piven’s research focus is on the pathogenesis of autism including neural mechanisms, genetic basis and neuropsychological and behavioral phenotype.
Using a combination of in vivo and in vitro approaches, our lab studies the extracellular cues and intracellular signaling pathways regulating neuronal migration, axon guidance and dendritic differentiation during early aspects of brain development.
The nucleus accumbens is a limbic-motor integrator, assimilating memory and drive input and coordinating responsive behavioral output. Anatomical and pharmacological evidence indicates that the core and shell subregions of the nucleus accumbens perform overlapping but distinct roles in motivated behavior. My experiments examine nucleus accumbens core and shell function during ethanol drinking behavior in rats, with particular focus on how dopamine input modulates accumbal activity on the millisecond timescale. I use two approaches: electrophysiological firing patterns of neurons in the nucleus accumbens core and shell are evaluated using multi-electrode arrays, and phasic (subsecond) dopamine activity is evaluated using fast-scan cyclic voltammetry. I am also interested in exploring the pharmacological manipulation of neuronal transmission in the nucleus accumbens, focusing on drugs that have clinical therapeutic value in treating alcoholism.
Ion channels and ionotropic receptors. Molecular mechanisms of ligand binding, channel activation, ion selectivity, and allosteric modulation. Techniques used: Molecular modeling, site directed mutagenesis, heterologous expression in Xenopus oocytes and other cells, chemical modification, and voltage clamp electrophysiology.
Bioinformatics, Cancer Biology, Cell Biology, Chemical Biology, Computational Biology, Genomics, Molecular Medicine, Neurobiology, Pharmacology, Systems Biology, Toxicology, Translational Medicine
Movement control and neuroplasticity in able-bodied humans and humans with neurological dysfunction are the focus of research program. More specifically, would like to understand the basic interaction of spinal circuits and supraspinal systems and adaptability of these interactions during upper limb movements and locomotion. Studies to understand this interaction include anatomical (dissection and MRI), electrophysiological (EMG and reflex) and biomechanical studies to identify the neuromuscular elements that interact with spinal circuits, and what principles govern their coordination. Studies are also underway to understand plasticity of spinal circuits, including those underlying stretch reflexes in both able-bodied humans and humans with spinal cord injury. These studies utilize operant conditioning of reflexes that may be useful for the functional training of newly formed connections in spinal cord injured patients if regeneration can be induced. The operant conditioning studies will also be useful in determining the relationship of spinal circuits and voluntary movement.
Our lab examines cytoskeletal dynamics, the molecules that regulate it and the biological processes it is involved in using live cell imaging, in vitro reconstitution and x-ray crystallography. Of particular interest are the microtubule +TIP proteins that dynamically localize to microtubule plus ends, communicate with the actin network, regulate microtubule dynamics, capture kinetochores and engage the cell cortex under polarity-based cues.
Work in my laboratory is directed at the role of neuronal growth factors in the development and regeneration of axons. We employ sensory neurons of the DRG as a model system. Sensory neurons are unique in elaborating a peripheral axon that regenerates readily after injury and a central axon projecting in the spinal cord that does not. This work is directly relevant to a major NINDS goal of achieving spinal cord repair.
I study the ultimate and proximate factors controlling flexibility in reproductive behavior. Using songbirds as a system, I use field and laboratory studies to investigate the ecological cues regulating reproductive flexibility, the neural integration of these cues, and the neural mechanisms precipitating adaptive behavioral outcomes. Of particular interest is the study of courtship and mate-choice behavior and how the songbird brain integrates ecological and social information. I am also interested in how the timing of reproduction, reproductive effort, and family planning are controlled. I use high performance liquid chromatography for the measurement of central catecholamines and immunocytochemistry and microscopy for quantifying neuropeptides and the expression of immediate early genes as markers of neural activity.
Research in my laboratory is directed toward achieving a better understanding of the mechanisms and pathogenesis associated with a variety of environmentally induced or genetically based birth defects. This information is then applied to development of preventative/ameliorative measures relative to these defects. Our interest in modeling human genetic malformation syndromes and opportunities for collaborative efforts with molecular geneticists who have produced transgenic mice and mice with targeted gene modification have proven productive in our attempt to better understand the developmental basis for a variety of malformations of the brain including anencephaly, holoprosencephaly, and hydrocephaly. Regarding teratogen-induced birth defects, our major emphasis is on Fetal Alcohol Spectrum Disorders (FASD). Currently, high resolution magnetic resonance imaging (MRI) is being utilized to identify, characterize, and correlate the craniofacial, ocular, otic and CNS dysmorphology that results from prenatal ethanol exposure at specific stages of embryogenesis. These studies are designed to inform human clinical research and to expand the diagnostic criteria for prenatal alcohol exposure.
My primary research interests are directed at the neurobiology of alcoholism. To study the central mechanisms involved with neurobiological responses to ethanol, I use both genetic and pharmacological manipulations. There are many factors that may cause an individual to progress from a moderate or social drinker to an alcoholic. In addition to environmental influences, there is growing evidence in both the human and animal literature that genetic factors contribute to alcohol abuse. Furthermore, the risk for developing alcoholism is likely not associated with a single gene, but rather with multiple genes that interact with environmental factors to determine susceptibility for uncontrolled drinking. Some of the questions that my laboratory is currently addressing are: 1) Does central neuropeptide Y (NPY) signaling modulate neurobiological responses to ethanol and ethanol consumption, 2) Do melanocortin peptides modulate ethanol intake? and 3) Does cAMP-dependent kinase (PKA) play a role in voluntary ethanol consumption and/or other effects produced by ethanol?
Biophysics of cortical information processing, selective attention in the mammalian visual pathway and evidence for spike patterns in cortical spike trains
Topics include gene discovery, genomics/proteomics, gene transcription, signal transduction, molecular immunology. Disease relevant issues include infectious diseases, autoimmune and demyelinating disorders, cancer chemotherapy, gene linkage.
My primary research interest is in elucidating the role of vanilloid receptors (TRPV) in the mediation of pain perception in the dorsal horn of mammals. Recently, this line of research has expanded to include the study of nociception in animal models of cystitis and arthritis. Other interests include amino acid neurotransmitters, their receptors and associated proteins in the postsynaptic densities in the brain and spinal cord, nitric oxide, and the functional role of the protein palladin in reactive astrocytes and glial scar formation after injury to the central nervous system.
I’m a neurobiologist who uses immunocytochemistry and electron microscopy to address functional questions. I am trying to elucidate the molecular organization of postsynaptic signaling in the rat cortex and hippocampus. I'm also interested in the actin cytoskeleton of dendritic spines, and how spines may remodel during LTP.
The laboratory is interested in the role of G proteins and G protein-coupled receptors in the regulation of mammalian cell metabolism, growth control and differentiation. Specific questions addressed by the lab include (1) What are the structural determinants of G-protein-coupled receptors that regulate their interactions with G proteins and with proteins such as kinases and arrestins that are involved in receptor desensitization? and (2) What roles exist for G protein-coupled pathways in the growth and differentiation of mammalian cells? Rhodopsin, the photoreceptor of the mammalian retinal rod, is used as a molecular model for defining the domains of G protein-coupled receptors responsible for the binding and activation of their specific G proteins. Experiments also focus on the mechanism of desensitization of this receptor by phosphorylation and arrestin binding.
We recently found that nociceptive (pain-sensing) circuits in mammals are highly organized at molecular and neuroanatomical levels. In our laboratory, we are using molecular, genetic, electrophysiological and behavioral approaches to study these pain circuits in mice. Our ultimate goal is to identify new analgesics so that debilitating chronic pain conditions can be more effectively treated.
Techniques used in our lab include: Molecular biology and cell culture; In situ hybridization and immunofluorescence staining; Construction and characterization of knock-in and transgenic mice; Mouse behavioral experiments; Bioinformatics; FACS of neurons; Expression profiling with
Affymetrix GeneChip arrays; Calcium imaging; Patch Clamp Electrophysiology.
