GENETIC ANALYSIS OF LYSOSOMAL ACID LIPASE FUNCTION
Richard A Andersen, Professor Of Neuroscience
Internal Medicinewake Forest University
1834 Wake Forest Road
winston-salem, Nc 27106
Grant 1R01HL047864-01A3 from National Heart, Lung, And Blood Institute IRG: PTHA
Abstract: Lysosomal acid lipase/cholesteryl ester hydrolase is crucial for the intracellular hydrolysis of cholesteryl esters and triglycerides that have been taken up via receptor mediated endocytosis of lipoprotein particles. The process is central to the supply of cholesterol to cells for growth and membrane function and in the regulation of processes that are mediated by cellular cholesterol flux. This project will characterize, at the molecular genetic level, the defects that cause a deficiency of this acid lipase activity in two human diseases, Wolman disease (WD) and cholesteryl ester storage disease (CESD), both inherited as Mendelian autosomal recessive traits, with the long term objective of understanding the biochemical and physiological activities of human lysosomal acid lipase (HLAL) in relationship to normal and aberrant states of cholesteryl ester processing and storage. The deficiencies of acid lipase activity in WD and CESD, with their dramatically different biochemical and clinical phenotypes, provide an "experiment of nature" for the testing of hypotheses concerning the control of cholesterol metabolism. The observation that CESD patients exhibit premature atherosclerosis suggests the applicability of this "experiment" to cardiovascular risk in the general population. Despite the recognized importance of HLAL in the regulation of cholesterol metabolism, difficulties with experimental manipulation of the enzyme have limited progress in understanding its control and physiological role. This project will circumvent earlier problems by exploiting the recently isolated HLAL cDNA and genomic DNA clones to test hypotheses concerning the mutations causing WD and CESD l) Defects in expression of the structural gene for acid lipase are responsible for both WD and CESD throughout the spectrum of phenotypes. This will be done by transducing the cDNA coding for functional HLAL into mutant fibroblasts using retroviral vectors to demonstrate that this structural information is sufficient to correct the deficiency. 2) The different phenotypes arise from mutations at the HLAL structural gene locus that differentially inactivate its triglyceride hydrolase and cholesteryl esterase functions. This will involve identifying the mutations that cause WD and CESD at the nucleotide sequence level by a) characterizing the functional status of mutant HLAL genes; b) determining the structure of the coding and control regions of the normal genomic locus for comparison to the structures of the loci from the mutant cells; and c) recreating the mutated sites in vitro and expressing the constructions
Keywords: Wolman`s disease, cholesterol ester, cholesterol ester storage disease, enzyme deficiency, hydrolase, lipase, lysosome autosomal recessive trait, lipid metabolism, molecular genetics, mutation, phenotype, structural gene, transfection northern blotting, polymerase chain reaction, site directed mutagenesis, southern blotting, tissue /cell culture
Project start date: 1994-04-01
Project end date: 1997-03-31
1R01HL047864-01A3 (1994): $173214
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to Richard A Andersen
Richard A Andersen, Professor Of Neuroscience
California Institute Of Technology Office Of Sponsored Research, Mail Code 201-15 Pasadena, Ca 91125
Grant 5R01EY007492-14 from National Eye Institute IRG: VISB
Abstract: Two of the most interesting functions of the visual motion system are the analysis of optic flow for heading perception and the determination of 3D structure-from-motion (SFM). This proposal will examine how these functions are accomplished by visual cortex using single cell recording techniques in behaving monkeys. The first specific aim is to examine the unsolved problem of how flow generated by eye and head movements is subtracted from flow generated by observer translation in order to recover the direction of heading. Pilot experiments for the proposal indicate that eye pursuit signals shift the spatial tuning curves of flow sensitive neurons in the dorsal division of the medial superior temporal area (MSTd). This shift enables MSTd neurons to code heading direction irrespective of whether the eyes are still or moving. Experiments are also proposed to determine whether head movements also lead to spatial tuning shifts, and to examine whether the head movement signals are derived from efference copy, vestibular, and/or proprioceptive sources. It will also be determined whether MSTd neurons code heading in eye-, head-, body-, or world-centered coordinates. The second specific aim is to examine the neural mechanisms for 3D SFM perception. Monkeys will be trained to report the perceived direction of rotation of cylinders defined by disparity and motion cues and cylinders defined only by motion cues. These latter cylinders are perceived as 3D, but the perceived direction of rotation is bistable. Recordings will be made from the middle temporal area (MT) while animals perform this task. Pilot studies indicate that MT activity is correlated with the perceived rotation direction of the bistable stimulus, with cells giving different responses for the same physical stimulus depending on the percept. Experiments are also planned to examine a 3 stage model for SFM processing the first stage measures motions and likely occurs in V1; the second stage segregates and depth orders surfaces and likely occurs in MT; the third stage uses speed gradients to calculate 3D shape and may occur in MT or MST. Recordings will be made in V1, MT and MST using variations of the bistable cylinder paradigm to determine where these three stages are located in the motion pathway. The experiments in this proposal will determine the neural mechanism for heading computation during eye and head movements and whether MSTd is directly involved. They will also determine if monkeys perceive SFM and the role of V1, MT, and MST in this important perceptual process.
Keywords: motion perception, neural information processing, visual cortex, visual pathway, brain mapping, eye movement, form /pattern perception, head movement, psychophysics, visual stimulus, Macaca mulatta, behavioral /social science research tag, human subject, microelectrode, single cell analysis
Project start date: 1987-09-01
Project end date: 2002-02-28
5R01EY007492-14 (2001): $354489
5R01EY007492-13 (2000): $403795
5R01EY007492-12 (1999): $394212
5R01EY007492-11 (1998): $384909
2R01EY007492-10 (1997): $340150
MOLECULAR, CELLULAR AND SYSTEMS NEUROSCIENCE
Richard A Andersen, Professor Of Neuroscience
California Institute Of Technology Office Of Sponsored Research, Mail Code 201-15 Pasadena, Ca 91125
Grant 5T32NS007251-20 from National Institute Of Neurological Disorders And Stroke IRG: NST
Abstract: This proposal is an application to continue postdoctoral study in the neurosciences at the molecular cellular, and systems levels at the California Institute of Technology. The program involves 22 members of the faculty of the Division of Biology, many of whom are also members of the Computational and Neural Systems (CNS) Program. Due to the tremendous growth in neuroscience research at Caltech, we are requesting an increase in the level of the program to fund six trainees per year rather than the four of the past. The program comprises a wide range of areas in the neurosciences such as (1) sensory systems including the auditory, visual and olfactory systems, (2) sensory-motor integration, (3) the cellular and molecular basis of synaptic transmission, (4) neural mechanisms of learning and plasticity, (5) neural development, cell lineage and differentiation, and (6) theoretical neurobiology and computational modeling of neural systems. Future directions of the program will include (1) application of molecular techniques to neurobiology, (2) basic research with medical relevance, and (3) the analysis of complex neural functions from computational and theoretical perspectives, (4) brain imaging in humans, non-human primates, and rodents, and (5) neurophysiological studies using multicellular recordings. The primary mission is to train scientists for fruitful, successful careers in neurobiological research. Trainees hold Ph.D. or M.D. degrees and have daily contact with the research sponsor. The duration of the training period is usually two years with occasional extensions to three years when warranted. Research-related activities such as seminars, journal clubs, and collaborative research through the CNS Program, the Sloan-Swartz Center, the Silvio Conte Neuroscience Center, and the Beckman Institute afford a rich training experience. Also included in the program will be instruction in responsible conduct of research. Special efforts will be made to attract more minority trainees to the program through several approaches, including the extensive involvement of the faculty. The neuroscience laboratories are well equipped and occupy five buildings on the Caltech campus. There are many special resources available to the postdoctoral trainees which include facilities for monoclonal antibody production, transgenic mice study, MRI and optical imaging, primate behavior and electrophysiology, equipment fabrication, computer modeling, electronic circuit design and manufacture, electron microscopy, synthesis and sequencing of proteins and genes, cell sorting, cell culture, and cell electrophysiology. The Biological Sciences Initiative has just been completed, which includes funds for a new biology building, several neuroscience faculty appointment, and new neuroscience facilities.
Project start date: 1996-09-30
Project end date: 2007-06-30
5T32NS007251-20 (2006): $157995
5T32NS007251-19 (2005): $209912
5T32NS007251-18 (2004): $124959
5T32NS007251-17 (2003): $139915
2T32NS007251-16 (2002): $177072
Sponsored Links Excellgen http://Excellgen.com
VISUAL/SPATIAL PROPERTIES OF POSTERIOR PARIETAL NEURONS
Richard A Andersen
California Institute Of Technology, Office Of Sponsored Research, Mail Code 201-15, Pasadena, Ca 91125
Grant 5R01EY005522-30 from National Eye Institute
Abstract: This application is to study how sensory-motor transformations are accomplished in the cerebral cortex. In particular we will examine how spatial information is represented in cortex (Aim 1) and how coordinate transformations are accomplished between these representations (Aim 2). Previous work on these topics has examined how space is represented for achieving the movement of a single effector, for instance the eyes or the hand. However, movements generally involve multiple effectors and typically include hand-eye and bimanual movements. In Aim 1 we will advance a new finding, made in dorsal premotor cortex (PMd) during the last grant period, of a relative coding of the position of the hand, eyes and goal of a reach. This aim will test several new aspects and implications of relative coding. (1) It will examine the extent of relative coding in other areas of the sensorimotor pathway including area 5 and primary motor cortex. {2) It will determine if the 2 limbs also show a relative coding in cortical areas involved in reaching. Such a result would indicate that relative coding may be general mechanism for movements involving multiple body parts. (3) It will examine if relative coding of the hand is state dependent in PMd, and changes depending on the task, or if it is "hard wired". (4) It will determine if eye movement areas also show a relative coding of the eye and hand for eye movement tasks, which made facilitate eye- hand coordination. (5) It will directly test the hypothesis that relative coding, by its nature, is translation (and perhaps rotation) invariant across the workspace. In Aim 2 we will examine the gain field mechanism that is thought to be responsible for coordinate transformations between representations. (1) This aim will determine if gain fields exist simultaneously with relative position encoding. (2) It will determine whether gain fields in particular areas of cortex are concerned with extrinsic space around the body or intrinsic space within the body. 3) The mathematical mechanism for gain modulation will be determined. We will distinguish whether it is a pure multiplication of inputs or a function which approximates multiplication such as non-linear addition. Since gain fields are believed to be a general mechanism for neural computation, the results of these studies should have broad applicability to understanding neural processing beyond coordinate transformations. The results of the proposed studies can be used to help design therapies for patients suffering from damage to frontal and parietal cortex from strokes and traumatic brain injuries. They will help in understanding deficits that result from neurological diseases that effect cortical functioning, and can guide the diagnoses and treatments for these diseases
Keywords: Accounting; Apoplexy; Area; Articulation; Behavior; Body part; Brain; Brain Stem; Brainstem; Cell Communication and Signaling; Cell Signaling; Cerebral Stroke; Cerebral cortex; Cerebrovascular Apoplexy; Cerebrovascular Stroke; Cerebrovascular accident; Code; Coding System; Complex; Computer Simulation; Computerized Models; Diagnosis; Disease; Disorder; Dorsal; Encephalon; Encephalons; Extremities; Eye; Eye Movements; Eyeball; Figs; Figs - dietary; Goals; Grant; Hand; Intracellular Communication and Signaling; Investigators; Joints; Knowledge; Limb structure; Limbs; Location; Mathematical Model Simulation; Mathematical Models and Simulations; Methods; Models, Computer; Motor; Motor Cortex; Motor output; Movement; Muscle; Muscle Tissue; Nature; Nerve Cells; Nerve Unit; Nervous; Nervous System Diseases; Nervous System, Brain; Neural Cell; Neurocyte; Neurologic Disorders; Neurological Disorders; Neurons; Non-Trunk; Parietal; Parietal Lobe; Parietal Lobe of the Brain; Pathway interactions; Patients; Position; Positioning Attribute; Posture; Process; Programs (PT); Programs [Publication Type]; Property; Property, LOINC Axis 2; Pursuit, Saccadic; Relative; Relative (related person); Reporting; Research; Research Personnel; Researchers; Rotation; Saccades; Saccadic Eye Movements; Sensory; Signal Transduction; Signal Transduction Systems; Signaling; Simulation, Computer based; Staging; Stroke; System; System, LOINC Axis 4; Testing; Translations; Trauma, Brain; Traumatic Brain Injury; Traumatic encephalopathy; Vascular Accident, Brain; Visuospatial; Work; biological signal transduction; body movement; brain attack; cerebral vascular accident; computational modeling; computational models; computational simulation; computational studies; computer based models; computer studies; computerized modeling; computerized simulation; design; designing; disease/disorder; experiment; experimental research; experimental study; eye hand coordination; eye/hand coordination; frontal eye fields; gaze; hand and eye coordination; hand/eye coordination; in silico; innervation; insight; intervention design; lateral intraparietal area; nerve supply; nervous system disorder; neural; neural mechanism; neurological disease; neuromechanism; neuronal; novel; parietal cortex; pathway; programs; relating to nervous system; research study; response; stroke; therapy design; traumatic brain damage; treatment design; virtual simulation; visual motor; visual spatial; visuomotor
Project start date: 1994-03-01
Project end date: 2012-08-31
Budget start date: 1-SEP-2009
Budget end date: 31-AUG-2010
5R01EY005522-30 (2009): $508758
5R01EY005522-29 (2008): $484061
2R01EY005522-28A1 (2007): $479552
MOLECULAR, CELLULAR AND SYSTEMS NEUROSCIENCE
Richard A Andersen
California Institute Of Technology, Office Of Sponsored Research, Mail Code 201-15, Pasadena, Ca 91125
Grant 5T32NS007251-23 from National Institute Of Neurological Disorders And Stroke
Abstract: This application is to continue the Postdoctoral Program in the Neurosciences at the Molecular Cellular, and Systems levels at the California Institute of Technology. This program is in its 20th year and has been highly successful in training a generation of Neuroscientists. The program involves 22 faculty members whose main research area is Neuroscience. Two new Neurobiology faculty members were appointed during the last period of the grant. Due to the tremendous growth in neuroscience research at Caltech, we are requesting an increase in the level of the program to fund six trainees per year rather than the four of the past. Topics of training in the program include 1) sensory systems including the auditory, visual and olfactory systems, 2) sensory-motor integration, 3) the cellular and molecular basis of synaptic transmission, 4) neural mechanisms of learning and plasticity, 5) neural development, cell lineage and differentiation, 6) theoretical neurobiology and computational modeling of neural systems and 7) reward systems. Additional and new directions of the program include 1) application of molecular techniques to understanding behavior, 2) translational research with medical relevance, and 3) theoretical neurobiology, 4) brain imaging across species including humans, non-human primates, and rodents, and 5) neurophysiological studies of neural populations using multicellular recordings. These studies will lead to the understanding and translation of research toward developing cures for a variety of neurological diseases including Alzheimer´s Disease, Parkinsonism, learning disabilities, aging, vision and hearing deficits, paralysis, strokes, and drug and alcohol dependency. The primary mission is to train scientists for fruitful, successful careers in neurobiological research. Trainees hold Ph.D. or M.D. degrees and have daily contact with the research sponsor. The duration of the training period is usually two years with occasional extensions to three years when warranted. Research related activities such as seminars, journal clubs, and collaborative research through the CNS Program, the Sloan-Swartz Center, the Broad Fellows Program, Information Science and Technology, and the Beckman Institute afford a rich training experience. Also included in the program will be instruction in responsible conduct of research. Special efforts will be made to attract more minority trainees to the program through several approaches at all levels of education. These efforts include extensive involvement of the faculty in recruitment. In the current group of eligible postdoctoral fellows associated with the training faculty 13.5% are from underrepresented minorities. The neuroscience laboratories are well equipped and occupy six buildings on the Caltech campus. There are many special resources available to the postdoctoral trainees which include facilities for monoclonal antibody production, transgenic mice study, MRI and optical imaging, primate behavior and electrophysiology, equipment fabrication, computer modeling, electronic circuit design and manufacture, electron microscopy, synthesis and sequencing of proteins and genes, cell sorting, cell culture, and cell electrophysiology
Project start date: 1996-09-30
Project end date: 2012-06-30
Budget start date: 1-JUL-2009
Budget end date: 30-JUN-2010
5T32NS007251-23 (2009): $274897
5T32NS007251-22 (2008): $264321
2T32NS007251-21 (2007): $182669
Smart MEMS Recording Systems For Visual Cortical Studies
Richard A Andersen, Professor Of Neuroscience
California Institute Of Technology Office Of Sponsored Research, Mail Code 201-15 Pasadena, Ca 91125
Grant 5R01EY015545-03 from National Eye Institute IRG: ZRG1
Abstract: The purpose of this proposal is to design and build a smart MEMs device for recording multicellular activity in the visual nervous system. This miniaturized and implantable microelectrode array system will automatically adjust the depths of the electrodes to optimize recording performance. The rationale for this system is to improve long term, chronic recording from populations of neurons in the visual system for scientific and neuroprosthetic applications. Current systems with fixed electrode geometries cannot be adjusted to optimize recordings in terms of yield or cell type. Moreover, these systems cannot "follow" cells over time to overcome loss of signal due to movement of the tissue with respect to the electrodes. Manual systems have the drawback of becoming unmanageable for large arrays in scientific studies, and unacceptable for permanent implants for prosthetics applications. The proposed system overcomes all of these drawbacks by automating the position of each electrode based on recorded signal quality. The first aim of this study is to develop algorithms to automatically search for, and hold, recorded signals from neurons. Preliminary data show that this is possible for cortical neurons recorded from awake, behaving monkeys and anesthetized rats. The second aim is to develop MEMS actuators that have low heat dissipation, are lockable with minimal energy application, and can provide large displacements. Preliminary studies indicate that electrolysis actuators developed by one of the co-investigators are ideal for this application. Aim three will integrate all of the components developed in the earlier aims into a single system. This device will consist of a MEMS-based multielectrode array with independently moveable electrodes, and on-board control, monitoring and communications circuits. Although this is a proposal to develop technology, an underlying hypothesis is that this system will improve multiunit, chronic recordings substantially over what can be achieved with fixed geometry systems. This hypothesis will be tested initially with cortical recordings in anesthetized rats followed by recordings from visual cortical areas in behaving monkeys.
Keywords: biomedical equipment development, brain electrical activity, electronic recording system, microelectrode, miniature biomedical equipment, visual cortex, electrophysiology, implant, single cell analysis, Macaca mulatta
Project start date: 2005-02-15
Project end date: 2010-01-31
5R01EY015545-03 (2007): $742414
5R01EY015545-02 (2006): $725066
1R01EY015545-01A1 (2005): $742587
NEURAL PROSTHESIS USING POSTERIOR PARIETAL REACH REGION
Richard A Andersen
California Institute Of Technology, Office Of Sponsored Research, Mail Code 201-15, Pasadena, Ca 91125
Grant 5R01EY013337-09 from National Eye Institute
Abstract: The purpose of this application is to explore how high level planning signals can be used for control of neural prosthetics to assist paralyzed patients. This study has both scientific and engineering components. The scientific investigations entail exploring how cognitive signals related to movement intentions are encoded in the parietal-frontal circuits. The engineering component will be guided by the scientific findings to best design and tailor algorithms for decoding these cognitive signals. Areas of algorithmic development include new signal processing and feature extraction techniques, extensions of Bayesian classification and Kalman filtering algorithms, and new applications of speech recognition and finite state machine techniques. Aim 1 will examine how the goals of reach movements are represented in 3 dimensions in the parietal reach region (PRR) and the dorsal premotor cortex (PMd) and develop decode algorithms to control the location of a cursor using these signals (so-called brain-control task). Goal decoding has the attributes of being very versatile and rapid for prosthetics applications. This aim will also determine if goal locations can be decoded using local field potentials (LFPs) rather than spike activity using advanced signal processing techniques. An advantage of LFPs for prosthetics is their ease and longevity of recording. Aim 2 will examine whether neural activity in PRR and PMd predicts the current location of the limb during trajectory movements, and if this "forward model" can be used to generate trajectories in brain control tasks. Techniques suited for continuously varying dynamic systems will be applied to decoding the trajectories. Aim 3 will study plasticity in PRR and PMd related to context, learning and reward. In this aim we will examine how the ability of the brain to learn and adapt can lead to better performance of brain-machine interfaces. Aim 4 will examine the very challenging situation of decoding movement plans continuously. Studies in this field generally use event markers derived from the trials of a task to assist decoding. However, these markers will not exist for clinical applications of prosthetics and the problem of recognizing and interpreting neural signals becomes much more challenging. We will apply and extend techniques from speech recognition and finite state machines to this problem. In particular, we will examine how eye movement information during natural hand-eye coordination can help decode reach movements from neural activity. This eye movement information will be derived from eye movement recordings and from the recording of neural signals related to eye movements. Knowledge from this work will be applied to brain- control tasks involving the continuous, sequential determination of goals
Keywords: 3-D; 3-Dimensional; Algorithms; Animals; Area; Assistive Technology; Behavioral; Brain; Cell Communication and Signaling; Cell Signaling; Classification; Cognitive; Computers; Control Animal; Development; Dimensions; Dorsal; Encephalon; Encephalons; Engineering; Engineerings; Environment; Event; Extremities; Eye; Eye Movements; Eyeball; Goals; Grant; Implant; Intention; Intracellular Communication and Signaling; Investigation; Knowledge; Lead; Learning; Length of Life; Limb structure; Limbs; Location; Longevity; Maps; Methods; Methods and Techniques; Methods, Other; Modeling; Monitor; Monkeys; Moods; Motivation; Movement; Nature; Nerve Cells; Nerve Unit; Nervous; Nervous System, Brain; Neural Cell; Neurocyte; Neurons; Non-Trunk; Palsy; Paralysed; Parietal; Patient Preferences; Patients; Pattern; Pb element; Performance; Plegia; Position; Positioning Attribute; Process; Prosthesis; Prosthetic device; Prosthetics; Research; Rewards; Robotics; Scanning; Self-Help Devices; Signal Transduction; Signal Transduction Systems; Signaling; System; System, LOINC Axis 4; Systematics; Techniques; Testing; Time; Visual; Work; ing; assistive device; base; biological signal transduction; body movement; brain control; brain machine interface; clinical applicability; clinical application; computerized data processing; data processing; design; designing; expectation; experiment; experimental research; experimental study; eye hand coordination; eye/hand coordination; gaze; hand and eye coordination; hand/eye coordination; heavy metal Pb; heavy metal lead; improved; life span; lifespan; mind control; neural; neural prosthesis; neural prosthetic; neuronal; paralysis; paralytic; parietal-frontal circuits; relating to nervous system; research study; response; signal processing; speech recognition; success
Project start date: 2001-02-01
Project end date: 2011-08-31
Budget start date: 1-SEP-2009
Budget end date: 31-AUG-2010
5R01EY013337-09 (2009): $397063
Sponsored Links Excellgen http://Excellgen.com
5R01EY013337-08 (2008): $377789
5R01EY013337-07 (2007): $374271
2R01EY013337-06A1 (2006): $373912
Richard A Andersen, Professor Of Neuroscience
California Institute Of Technology Office Of Sponsored Research, Mail Code 201-15 Pasadena, Ca 91125
Grant 5R01EY007492-19 from National Eye Institute IRG: VISB
Abstract: The aims of this proposal are to understand high-level perceptions derived from visual motion. Two phenomena that have attracted considerable interest are self-motion perception and structure-from-motion perception. We propose experiments aimed toward understanding the neural circuits responsible for these percepts. Subjects can perceive their direction of self-motion from "optic flow" signals that are produced on their retinas during translation through the environment. An important problem for the visual system is to recover translation based motion cues when smooth gaze movements are made that generate additional, laminar motions on the retinas. During the last grant period we found that extra-retinal and retinal cues produce shifts in the tuning curves of MSTd neurons that are tuned to the direction of heading. In the first aim of the current proposal we plan to extend these findings with three new lines of research, examining translation compensation, the effects of 3D cues, and the coordinate frame used by MSTd to represent heading direction. The second aim is to study the neural networks responsible for SFM perception. Observers can perceive the 3D shape of objects based purely on relative motion cues. Such displays are bistable, and this feature has allowed us to examine the neural correlates of SFM perception. Based on work in the last grant period, we proposed a two-stage model; in the first stage motion signals are measured in Vi and in the second stage surfaces are represented from these motion signals by a circuit within MT. In the current proposal we plan to test this model by examining its temporal dynamics. These studies are designed to gain knowledge of how the brain processes information, and will help to understand neurological deficits that occur with brain diseases.
Keywords: motion perception, neural information processing, visual cortex, visual pathway, brain mapping, eye movement, form /pattern perception, head movement, psychophysics, visual stimulus, visual tracking, Macaca mulatta, behavioral /social science research tag, human subject, microelectrode, single cell analysis, statistics /biometry
Project start date: 1987-09-01
Project end date: 2008-02-28
5R01EY007492-19 (2006): $385718
5R01EY007492-18 (2005): $400000
5R01EY007492-17 (2004): $400000
5R01EY007492-16 (2003): $400000
2R01EY007492-15 (2002): $382000
5R01EY007492-08 (1995): $290309
7R01EY007492-07 (1994): $292553
Sponsored Links Excellgen http://Excellgen.com
2R01EY007492-06A1 (1993): $268069
GENETIC ANALYSIS OF LYSOSOMAL ACID LIPASE FUNCTION
Richard A Andersen, Professor Of Neuroscience
Wake Forest University 1834 Wake Forest Road Winston-salem, Nc 27106
Grant 5R01HL047864-02 from National Heart, Lung, And Blood Institute IRG: PTHA
Abstract: Lysosomal acid lipase/cholesteryl ester hydrolase is crucial for the intracellular hydrolysis of cholesteryl esters and triglycerides that have been taken up via receptor mediated endocytosis of lipoprotein particles. The process is central to the supply of cholesterol to cells for growth and membrane function and in the regulation of processes that are mediated by cellular cholesterol flux. This project will characterize, at the molecular genetic level, the defects that cause a deficiency of this acid lipase activity in two human diseases, Wolman disease (WD) and cholesteryl ester storage disease (CESD), both inherited as Mendelian autosomal recessive traits, with the long term objective of understanding the biochemical and physiological activities of human lysosomal acid lipase (HLAL) in relationship to normal and aberrant states of cholesteryl ester processing and storage. The deficiencies of acid lipase activity in WD and CESD, with their dramatically different biochemical and clinical phenotypes, provide an "experiment of nature" for the testing of hypotheses concerning the control of cholesterol metabolism. The observation that CESD patients exhibit premature atherosclerosis suggests the applicability of this "experiment" to cardiovascular risk in the general population. Despite the recognized importance of HLAL in the regulation of cholesterol metabolism, difficulties with experimental manipulation of the enzyme have limited progress in understanding its control and physiological role. This project will circumvent earlier problems by exploiting the recently isolated HLAL cDNA and genomic DNA clones to test hypotheses concerning the mutations causing WD and CESD l) Defects in expression of the structural gene for acid lipase are responsible for both WD and CESD throughout the spectrum of phenotypes. This will be done by transducing the cDNA coding for functional HLAL into mutant fibroblasts using retroviral vectors to demonstrate that this structural information is sufficient to correct the deficiency. 2) The different phenotypes arise from mutations at the HLAL structural gene locus that differentially inactivate its triglyceride hydrolase and cholesteryl esterase functions. This will involve identifying the mutations that cause WD and CESD at the nucleotide sequence level by a) characterizing the functional status of mutant HLAL genes; b) determining the structure of the coding and control regions of the normal genomic locus for comparison to the structures of the loci from the mutant cells; and c) recreating the mutated sites in vitro and expressing the constructions.
Keywords: Wolman s disease, cholesterol ester, cholesterol ester storage disease, enzyme deficiency, hydrolase, lipase, lysosome, autosomal recessive trait, lipid metabolism, molecular genetics, mutation, phenotype, structural gene, transfection, northern blotting, polymerase chain reaction, site directed mutagenesis, southern blotting, tissue /cell culture
Project start date: 1994-04-01
Project end date: 1997-03-31
5R01HL047864-02 (1995): $179140
VISUAL-SPATIAL PROPERTIES OF AREA NEURONS
Richard A Andersen, Professor Of Neuroscience
California Institute Of Technology Office Of Sponsored Research, Mail Code 201-15 Pasadena, Ca 91125
Grant 5R01EY005522-16 from National Eye Institute IRG: VISB
Abstract: Lesions to the inferior parietal lobule (IPL) in humans from stroke, cerebral trauma, or tumors, produce deficits in complex cortical functions including spatial perception and visuomotor integration. Similar deficits are found with lesions to IPL (also known as area 7) in monkeys, indicating that monkeys provide an appropriate model for beginning to understand the function of this area in humans. In the experiments in this proposal we will examine the role of IPL in visuomotor and spatial functions by recording from and microstimulating this area in awake, behaving monkeys. These experiments will investigate the role of this area in the processing of spatial information, with special emphasis on its role in coordinate transformations. Previous experiments in this area indicated that eye position and retinal position information converged onto single cells and may produce a representation of visual space in head-centered coordinates. One set of experiments will examine the possibility that activity related to head position is also found for these same cells, and is integrated in a similar way to the eye position signals, consistent with an encoding of locations in body-centered coordinates. We will also examine if the saccade-related activity in the lateral intraparietal area (LIP) is coding gaze shifts, which can include combined eye and head movements, rather than simply eye movements. In a second set of experiments related to coordinate transformations, we will examine if a newly found auditory-related activity in area IPL is coded in head or retinal coordinates, and if this activity is modulated by eye position in a similar way to the modulation for visual signals by eye position. These experiments may find that more than one modality uses the same coordinate transformation machinery in this area and would represent one of the first examples of how modalities are associated in the cortex. In another group of experiments we will examine the functional organization of IPL using cortical microstimulation techniques. These experiments will provide new data on the role of area LIP in eye movement functions. We will also examine the topographic organization of evoked responses in the different cortical areas in IPL to see if they contain orderly retinotopic or spatiotopic representations. In a final group of experiments we will examine the role of IPL in the formation of motor plans. We will be interested in a memory-linked activity that is prevalent in this area, and we will test the hypothesis that this activity is a neural correlate of the intention to make movements. These experiments will help us to understand the fundamental problem of how coordinates are transformed in proceeding from sensory input to motor output. They will also help us to understand how high level cortical functions such as motor plans are processed in this visuomotor pathway.
Keywords: brain electrical activity, eye movement, neural information processing, parietal lobe /cortex, space perception, auditory stimulus, brain mapping, head movement, memory, neuroanatomy, neurophysiology, visual pathway, visual stimulus, Macaca mulatta, behavior test, histology, single cell analysis, vision test
Project start date: 1994-03-01
Project end date: 1996-08-31
5R01EY005522-16 (1994): $262078
VISUAL-SPATIAL PROPERTIES OF AREA 7 NEURONS
Richard A Andersen, Professor Of Neuroscience
Massachusetts Institute Of Technology 77 Massachusetts Ave Cambridge, Ma 02139
Grant 5R01EY005522-14 from National Eye Institute IRG: VISB
Abstract: Lesions to the inferior parietal lobule (IPL) in humans from stroke, cerebral trauma, or tumors, produce deficits in complex cortical functions including spatial perception and visuomotor integration. Similar deficits are found with lesions to IPL (also known as area 7) in monkeys, indicating that monkeys provide an appropriate model for beginning to understand the function of this area in humans. In the experiments in this proposal we will examine the role of IPL in visuomotor and spatial functions by recording from and microstimulating this area in awake, behaving monkeys. These experiments will investigate the role of this area in the processing of spatial information, with special emphasis on its role in coordinate transformations. Previous experiments in this area indicated that eye position and retinal position information converged onto single cells and may produce a representation of visual space in head-centered coordinates. One set of experiments will examine the possibility that activity related to head position is also found for these same cells, and is integrated in a similar way to the eye position signals, consistent with an encoding of locations in body-centered coordinates. We will also examine if the saccade-related activity in the lateral intraparietal area (LIP) is coding gaze shifts, which can include combined eye and head movements, rather than simply eye movements. In a second set of experiments related to coordinate transformations, we will examine if a newly found auditory-related activity in area IPL is coded in head or retinal coordinates, and if this activity is modulated by eye position in a similar way to the modulation for visual signals by eye position. These experiments may find that more than one modality uses the same coordinate transformation machinery in this area and would represent one of the first examples of how modalities are associated in the cortex. In another group of experiments we will examine the functional organization of IPL using cortical microstimulation techniques. These experiments will provide new data on the role of area LIP in eye movement functions. We will also examine the topographic organization of evoked responses in the different cortical areas in IPL to see if they contain orderly retinotopic or spatiotopic representations. In a final group of experiments we will examine the role of IPL in the formation of motor plans. We will be interested in a memory-linked activity that is prevalent in this area, and we will test the hypothesis that this activity is a neural correlate of the intention to make movements. These experiments will help us to understand the fundamental problem of how coordinates are transformed in proceeding from sensory input to motor output. They will also help us to understand how high level cortical functions such as motor plans are processed in this visuomotor pathway.
Keywords: brain electrical activity, eye movement, neural information processing, parietal lobe /cortex, visual space perception, auditory stimulus, brain mapping, head movement, memory, neuroanatomy, neurophysiology, visual pathway, visual stimulus, Macaca mulatta, behavior test, histology, single cell analysis, vision test
Project start date: 1981-09-01
Project end date: 1994-02-28
5R01EY005522-14 (1993): $261468
VISUAL-SPATIAL PROPERTIES OF AREA SEVEN NEURONS
Richard A Andersen, Professor Of Neuroscience
Massachusetts Institute Of Technology 77 Massachusetts Ave Cambridge, Ma 02139
Grant 2R01EY005522-13 from National Eye Institute IRG: VISB
Abstract: Lesions to the inferior parietal lobule (IPL) in humans from stroke, cerebral trauma, or tumors, produce deficits in complex cortical functions including spatial perception and visuomotor integration. Similar deficits are found with lesions to IPL (also known as area 7) in monkeys, indicating that monkeys provide an appropriate model for beginning to understand the function of this area in humans. In the experiments in this proposal we will examine the role of IPL in visuomotor and spatial functions by recording from and microstimulating this area in awake, behaving monkeys. These experiments will investigate the role of this area in the processing of spatial information, with special emphasis on its role in coordinate transformations. Previous experiments in this area indicated that eye position and retinal position information converged onto single cells and may produce a representation of visual space in head-centered coordinates. One set of experiments will examine the possibility that activity related to head position is also found for these same cells, and is integrated in a similar way to the eye position signals, consistent with an encoding of locations in body-centered coordinates. We will also examine if the saccade-related activity in the lateral intraparietal area (LIP) is coding gaze shifts, which can include combined eye and head movements, rather than simply eye movements. In a second set of experiments related to coordinate transformations, we will examine if a newly found auditory-related activity in area IPL is coded in head or retinal coordinates, and if this activity is modulated by eye position in a similar way to the modulation for visual signals by eye position. These experiments may find that more than one modality uses the same coordinate transformation machinery in this area and would represent one of the first examples of how modalities are associated in the cortex. In another group of experiments we will examine the functional organization of IPL using cortical microstimulation techniques. These experiments will provide new data on the role of area LIP in eye movement functions. We will also examine the topographic organization of evoked responses in the different cortical areas in IPL to see if they contain orderly retinotopic or spatiotopic representations. In a final group of experiments we will examine the role of IPL in the formation of motor plans. We will be interested in a memory-linked activity that is prevalent in this area, and we will test the hypothesis that this activity is a neural correlate of the intention to make movements. These experiments will help us to understand the fundamental problem of how coordinates are transformed in proceeding from sensory input to motor output. They will also help us to understand how high level cortical functions such as motor plans are processed in this visuomotor pathway.
Keywords: brain electrical activity, eye movement, neural information processing, parietal lobe /cortex, visual space perception, auditory stimulus, brain mapping, head movement, memory, neuroanatomy, neurophysiology, visual pathway, visual stimulus, Macaca mulatta, behavior test, histology, single cell analysis, vision test
Project start date: 1981-09-01
Project end date: 1996-08-31
2R01EY005522-13 (1992): $226921
VISUAL/SPATIAL PROPERTIES OF AREA 7 NEURONS
Richard A Andersen, Professor Of Neuroscience
California Institute Of Technology Office Of Sponsored Research, Mail Code 201-15 Pasadena, Ca 91125
Grant 5R01EY005522-22 from National Eye Institute IRG: VISB
Abstract: Lesions of the posterior parietal cortex (PPC) in humans and monkeys produce deficits in visual attention, spatial perception, and the ability to make accurate movements. These deficits are the result of losing the cortical pathway which enables visual information to be transformed into action. This proposal will examine how this transformation is accomplished by recording the activity of neurons in the PPC of monkeys while they perform various visual-motor tasks. The proposal will focus on whether a component in PPC is already coding movement intentions, whether these intentions are coded in the motor coordinates of the movement being planned, and how the different sensory signals that converge on PPC are transformed into various spatial coordinate frames. The role of gain fields (the modulations of sensory signals by eye, head and limb position) in transforming between coordinate frames will be examined. The first specific aim will examine movement intention and will determine if cells in area LIP are specifically engaged in saccade tasks, and if cortical areas around LIP are specifically engaged in reach tasks. The second specific aim will determine if reach-related areas are coding visually derived signals in limb coordinates. Such a finding would indicate that visual signals have been transformed into motor coordinates for the purpose of moving the limbs. The third specific aim will examine how head position signals are combined with eye position and visual (retinal position) signals to code the spatial locations of objects. It will be determined if vestibular signals, which convey information about the location of the head in the world, affect the visual response of PPC neurons; these vestibular gain fields could potentially encode locations in world-centered coordinates. Likewise it will be determined if neck proprioceptive or efference copy signals, conveying the orientation of the head on the body, modulate visual responsiveness and potentially encode locations in body-centered coordinates. Finally the role of optical flow and visual landmark cues in coding the locations of visual stimuli in world-centered coordinates will be examined. The fourth specific aim will be to determine how visual and auditory signals are combined in PPC to code spatial locations independent of the modality of the stimulus. These experiments, particularly the third and fourth aims, are designed to answer the long standing question of how different modalities are combined into a common framework in parietal association cortex. Overall these experiments will significantly further our understanding of how perceptions are transformed into actions.
Keywords: bacterial polysaccharide, brain electrical activity, eye movement, head movement, neural information processing, neuron, parietal lobe /cortex, space perception, brain mapping, neuroanatomy, neurophysiology, visual pathway, visual stimulus, Macaca mulatta, behavior test, behavioral /social science research tag, histology, single cell analysis, vision test
Project start date: 1994-03-01
Project end date: 2001-11-30
5R01EY005522-22 (2001): $260632
5R01EY005522-21 (2000): $280068
5R01EY005522-20 (1999): $274086
5R01EY005522-19 (1998): $331884
2R01EY005522-18 (1997): $343503
Sponsored Links Excellgen http://Excellgen.com
Visual/Spatial Properties Of Posterior Parietal Neurons
Richard A Andersen, Professor Of Neuroscience
California Institute Of Technology Office Of Sponsored Research, Mail Code 201-15 Pasadena, Ca 91125
Grant 5R01EY005522-27 from National Eye Institute IRG: ZRG1
Abstract: From s ) Although the posterior parietal cortex (PPC) has long been appreciated to be an area for association of different sensory modalities for spatial awareness and for spatial attention, recent studies have pointed to an additional, and very major, role of this area in movement planning. One important advance has been the fmding that there is an anatomical map of intentions within the PPC, with different areas specialized for different behaviors. In Aim 1 we will determine the inter-relationship between some of these areas in movement planning. In particular, we will examine whether area LIP has an executive role in decision making for both eye and limb movements, or if LIP is primarily involved in the former, and areas MIP and 5 in the latter. Another important advance has been the elucidation of the spatial representations in some PPC cortical areas. These results have led to a general proposal that the early stages of movement planning are performed in eye-centered coordinates in primates, regardless of the sensory input or eventual motor output. However, the activity of many PPC neurons is gain modulated by eye, head and limb position. Aim 2 will examine whether these PPC "gain fields" may effect the decisions to make eye and hand movements. Classically it has been believed that the coordinate transformation for reaching results from the transformation of the traget object from retinal to body coordinates, and then the subtraction of the object location in body-coordinates from the location of the hand in body coordinates to generate the motor error in limb coordinates. Our finding that early movement planning occurs in eye-coordinates in PPC suggests an alternative scheme, in which the hand is represented in eye coordinates and is subtracted from the location of the target in eye coordinates to produce the motor error signal. We will test this new idea in aim 3. Lastly, in aim 4 we will examine the spatial representation of sound location in an auditory area, Tpt, that provides input to the PPC. These experiments are designed to determine the stage in auditory processing pathway where head-centered auditory fields are converted into eye-centered auditory fields similar to those encountered in the PPC.
Keywords: brain electrical activity, eye movement, head movement, limb movement, motor neuron, neural information processing, parietal lobe /cortex, psychomotor function, space perception, auditory feedback, brain mapping, decision making, mind control, neurophysiology, visual pathway, visual stimulus, Macaca mulatta, behavior test, behavioral /social science research tag, neuropsychological test, single cell analysis, statistics /biometry, vision test
Project start date: 1994-03-01
Project end date: 2007-08-31
5R01EY005522-27 (2006): $374467
5R01EY005522-26 (2005): $383960
5R01EY005522-25 (2004): $384426
5R01EY005522-24 (2003): $384715
2R01EY005522-23 (2002): $384880
VISUAL-SPATIAL PROPERTIES OF AREA 7 NEURONS
Richard A Andersen, Professor Of Neuroscience
Salk Institute For Biological Studies La Jolla, Ca 920371099
Grant 5R01EY005522-06 from National Eye Institute IRG: VISB
Abstract: Clinical, electrophysiological, and anatomical studies indicate that the posterior parietal cortex of man and monkeys is important for visual-spatial perception. This proposal is a combined neurophysiological and neuroanatomical study which is designed to investigate how aspects of visuospatial perception might be encoded by the light-sensitive cell class of this region. This proposal has three specific aims 1) to study the spatial interactions of visual stimuli in the large receptive fields of the light-sensitive neurons, 2) to study the effect of position of the eyes and head on light sensitivity, and 3) to study the functional anatomy of Area 7 with particular emphasis on the organization of visuospatial properties. These aims will be achieved by recording the activity of single neurons from the posterior parietal cortex of behaving monkeys. The experimental animals will be trained to perform tasks designed to elucidate visuospatial properties of the light sensitive cells. Microelectrode mapping experiments will be combined with neuroanatomical tracing experiments to define functional subdivisions within this region and the local callosal and ipsilateral cortico-cortical inputs and outputs of these subdivisions. Data analysis will include the reconstruction of the population response of this region. Using the posterior parietal lobe as an example, inferences will be made of the role of homotypic cortex in higher functions.
Keywords: BRAIN, TELENCEPHALON, CEREBRUM, PARIETAL LOBE, EYE, VISION, PHOTOSENSITIVITY, EYE, VISUAL FEEDBACK, EYE, VISUAL PERCEPTION, SPATIAL PERCEPTION VISUAL, NEUROLOGY B STUDY SECTION, SENSORY-PERCEPTUAL PROCESSES, PROPRIOCEPTION, BRAIN, NEURAL PATHWAYS AND TRACTS, VISUAL PATHWAYS, EYE, VISION, VISUAL FIELDS, EYE, VISUAL STIMULUS, MAMMALS, PRIMATES, MONKEYS AND APES, OLD WORLD MONKEYS, MACACA SP., M. MULATTA, NEUROPHYSIOLOGY (GENERAL), neuroanatomy, BIOMEDICAL SYSTEMS AUTOMATED, COMPUTER PROCESSING OF LABORATORY DATA (GENERAL), HISTOLOGY (GENERAL)
Project start date: 1981-09-01
Project end date: 1987-02-28
VISUAL-SPATIAL PROPERTIES OF AREA SEVEN NEURONS
Richard A Andersen, Professor Of Neuroscience
Massachusetts Institute Of Technology 77 Massachusetts Ave Cambridge, Ma 02139
Grant 5R01EY005522-12 from National Eye Institute IRG: VISB
Abstract: Clinical and animal experiments have indicated that the posterior parietal cortex of humans and monkeys is important for visual-motor integration including the coordinate transformations required for these functions. In these experiments the role of this brain region in visual-motor and spatial functions will be examined with primarily neurophysiological techniques, but will also include psychophysical, anatomical and computational approaches. The proposal has two specific aims. 1) To examine in detail the lateral intraparietal area (LIP), a cortical field located in the lateral bank of the intraparietal sulcus which we have found to be involved in the processing of saccadic eye movements. We will examine in detail our recent finding of an eye-position dependent tuning of these neurons for saccades made to locations in head-centered coordinate space. We will also examine a newly discovered class of neurons in this area that hold in short-term memory intended eye movements and thus appear to be involved in motor planning. We will examine the functional and anatomical organization of this area using electrophysiological mapping, micro-stimulation and neuroanatomical tracing techniques. We will examine the effects of ibotenic acid induced lesions of area LIP on saccadic eye movements. Preliminary experiments show a deficit in saccades to remembered locations but not to constantly present visual targets. This deficit has an orbital position dependence and is transient lasting only a few days. In conjunction with these experiments, we will study the metrics of saccades made to remembered spatial locations in monkeys and humans. Initial experiments indicated that the neural representation of remembered locations in visual space used for saccades is highly distorted with hypermetric saccades occurring for upward targets and hypometric saccades occurring for downward targets. 2) In a second series of experiments we will continue to examine the coding of visual targets in head-centered coordinate space by light-sensitive neurons in area 7a of the posterior parietal cortex. We will examine the possible role of proprioception in this spatial tuning by sectioning the ophthalmic branch of the trigeminal nerve which is the sole source of proprioceptive inputs from the eye muscles. We will also examine the role of head position in the spatial tuning of these neurons; i.e., we will determine if the cells are actually coding target locations in a body-centered spatial frame. Finally, we will study the time- course of the integration of eye position and visual signals by these cells and compare it to the time-course for perceptual recalibration for spatial position in humans.
Keywords: eye movement, neural information processing, oculomotor nuclei, parietal lobe /cortex, proprioception /kinesthesia, psychophysics, visual feedback, visual photosensitivity, visual space perception, Macaca mulatta, head movement, ibotenate, neuroanatomy, neurophysiology, saccade, trigeminal nerve (V), visual field, visual fixation, visual pathway, visual stimulus, computer processing of laboratory data, electrophysiology, histology
Project start date: 1981-09-01
Project end date: 1992-08-31
Sponsored Links Excellgen http://Excellgen.com