Overview: The institutional postdoctoral training program in neuroscience and epilepsy allows faculty in the Departments of Biological Sciences, Molecular and Cellular Physiology, Comparative Medicine, Neurology and Neurological Sciences, Neurobiology, and Psychiatry at
and Faculty: Training takes place in the laboratories of the faculty within the
Departments of Biological Sciences, Molecular and Cellular Physiology,
Comparative Medicine, Neurobiology, Neurology and Neurological Sciences and
Psychiatry and Behavioral Sciences at
· Ben Barres, M.D. Ph.D. Neurobiology
· Paul Buckmaster, DVM, Ph.D. Comparative Medicine
· Robert Fisher, MD, Ph.D. Neurology & Neurological Sciences
· Craig Garner, Ph.D. Psychiatry and Behavioral Sciences
· Eric I. Knudsen, Ph.D. Professor of Neurobiology
· Liqun Luo, Ph.D. Biological Sciences
· Robert Malenka, M.D., Ph.D. Psychiatry & Behavioral Sciences
· Susan McConnell, Ph.D. Biological Sciences
· Brenda Porter, M.D. Ph.D. Neurology and Neurological Sciences
· David Prince, M.D. Neurology & Neurological Sciences
· Richard Reimer, M.D. Neurology & Neurological Sciences
· Robert Sapolsky, Ph.D. Biological Sciences
· Thomas Südohf, M.D. Molecular and Cellular Physiology
Ben Barres, M.D., PhD., Professor of Neurobiology, Neurology and Neurological Sciences and Developmental Biology: Dr. Barres is interested in the development and function of glial cells in the mammalian central nervous system. To understand the interactions between neurons and glial cells he has developed methods to highly purify and culture retinal ganglion cells (neurons) as well as the glial cell types they interact with, oligodendrocytes and astrocytes, from the rodent optic nerve. Barres and his fellows have used a large variety of methods to address these issues including cell purification by immunopanning, tissue culture, patch clamping, immunohistochemistry and molecular biology. Currently, they are focusing on several questions: (1) What are the cell-cell interactions that control myelination and node of Ranvier formation? (2) Do glial cells play a role in synapse formation and function? (3) What are the signals that promote the survival and growth of retinal ganglion cells; can this knowledge be used to promote their survival and regeneration after injury? (4) How do protoplasmic astrocytes, the main glial cell type in gray matter, develop and what is their function? Dr. Barres has found evidence for several novel glial signals that induce the onset of myelination, the clustering of axonal sodium channels, the survival and growth of retinal ganglion cells, and the formation of synapses. He is characterizing these processes and attempting to identify the glial-derived molecules.
Paul Buckmaster, D.V.M., Ph.D., Professor of Comparative Medicine: Dr. Buckmaster works on problems of hippocampal anatomy, physiology and experimental epilepsy. His major research goal is to understand the basic cellular mechanisms of epileptogenesis. His laboratory uses electrophysiological, molecular, and anatomical methods to examine the neuronal circuitry in rodent models of epilepsy. Current projects are focused on synaptic reorganization in the hippocampal dentate gyrus, changes in GABAergic circuitry in the dentate gyrus and entorhinal cortex, and molecular mechanisms of hyperexcitability in a model of inherited epilepsy. Trainees in Dr. Buckmaster's laboratory will learn a variety of electrophysiological and neuroanatomical techniques including in vivo intracellular recording and labeling, three-dimensional neuron reconstruction, whole-cell voltage-clamp recording, EEG and unit recording, quantitative PCR, in situ hybridization, immunocytochemistry, confocal microscopy, electron microscopy, and stereological methods.
Robert S. Fisher, MD PhD) Dr.
Fisher is Maslah Saul MD Professor of Neurology and Director of the
Craig Garner, Ph.D. Professor of Psychiatry and Behavioral Sciences. Research in the Garner lab is focused on three areas. The first research area is aimed at understanding the molecular mechanisms that guide synapse formation. The second is designed to define the principles that regulate synaptic strength or synaptic plasticity. The third research area aims to understand how changes in synaptic function in individuals with neurodevelopmental disabilities alter their behavior and capacity to learn. In this regard, we are focusing our efforts on Down syndrome and autism spectrum disorders. Experiments designed to address each of these questions have begun to lay the foundation for both an understanding of how specific genetic lesions can cause intellectual disabilities and possible treatment strategies.
John Huguenard, Ph.D., Professor of Neurology and Neurological Sciences: Current research directions in Dr. Huguenard's laboratory include regulation of excitability in thalamic neurons and the interactions between voltage- and ligand-gated conductances in single neurons within the thalamic and cortical circuits. This approach has led to insights regarding how genetic defects can lead to the hyperexcitability that causes epilepsy. His biophysical studies of low threshold calcium currents and their modulation by selective petit mal anticonvulsants, as well as experiments dealing with effects of benzodiazepines and ethosuximide on thalamic neurons and circuits have important implications for both the mechanisms and potential therapies of epilepsies in which spike-wave discharges are prominent features. Dr. Huguenard has also been involved in studies of development of voltage-dependent conductances in cortical neurons. An in vitro callosal slice preparation has recently been developed as a model of intracortical excitatory connectivity for the purposes of exploring its developmental and neuromodulatory regulation. Mouse knockouts are used to define the roles of specific molecules (ion channels) in complex neuronal functions. Modeling is an important tool in the laboratory, useful in the integration of neurophysiological data and generation of hypotheses. Trainees in his laboratory will learn techniques for studying biophysics of voltage- and ligand-gated currents in neurons utilizing mainly in vitro slice preparations, circuit mapping via UV laser molecular uncaging, dynamic clamp, optogenetics and computer simulation tools (NEURON).
Eric I. Knudsen, Ph.D. Professor of Neurobiology: Research in the Knudsen laboratory explores neural mechanisms of learning and attention. These mechanisms are studied in the brain pathways that underlie gaze-control in barn owls. The instructive effects of experience on biochemical, anatomical and functional mechanisms are studied at the levels of single cells, circuits and behavior. In addition, mechanisms that regulate excitability in these pathways are studied in the context of attention, and the influences of these attentional mechanisms on mechanisms of learning are investigated. Techniques employed in the laboratory include in vivo neurophysiology, pharmacology, microstimulation, anatomical pathway tracing, and behavioral conditioning.
Liqun Luo, Ph.D. Professor of Biological Sciences. Dr. Luo’s uses molecular genetic approaches to address questions of neural circuit formation. He has recently developed a modern genetic analog of Golgi staining, MARCM (for Mosaic Analysis with a Repressible Cell Marker), that has allowed his lab to label small groups or isolated single neurons in the Drosophila brain. With MARCM they can also genetically manipulate only these labeled neurons, for example by deleting a gene of interest to assess its function in the assembly of neural circuits. MARCM has been used to study the morphological development of individual neurons and the formation of specific connections between neurons. His laboratory is currently developing an approach for MARCM in mice, which may allow for fundamental insights into the maladaptive disorganization of mammalian brain circuits during epileptogenesis.
Susan McConnell, Ph.D., Susan B. Ford Professor of Biological Sciences: Dr. McConnell's interests in developmental neurobiology involve studies of neurogenesis and neuronal migration in the developing cerebral cortex, the specification of discrete neuronal phenotypes through cell lineage and cell-cell interactions, the control of axonal growth between developing neocortex and targets, and factors that influence the formation of lamina-specific axonal connections within the neocortex. Trainees in her laboratory learn a variety of investigative approaches including transplantation of neuronal precursor cells, time-lapse imaging using laser scanning confocal microscopy, molecular biological aspects of cell-target identification and migration, cell and tissue culture, in situ hybridization, and intracellular electrophysiology and dye fills in brain slices together with axonal tracing techniques, and genetic manipulations of mouse development. Dr. McConnell has found that multipotent neuronal precursors in the embryonic cerebral cortex make an early commitment to generating young neurons that are destined for specific cortical layers just prior to the precursor cell's final mitotic division.
Robert Malenka, M.D., PhD., Professor of Psychiatry and Behavioral Sciences. Dr. Malenka's primary interest is in the detailed mechanisms by which activity, neurotransmitters and drugs modify synaptic transmission in a variety of brain regions including the hippocampus, somatosensory cortex, nucleus accumbens and ventral tegmental area. A major goal of his laboratory is to elucidate both the specific molecular events that are responsible for the triggering of various forms of synaptic plasticity and the exact modifications in synaptic proteins that are responsible for the observed, long-lasting changes in synaptic efficacy. His work on the mechanisms of long-term potentiation (LTP) and long-term depression (LTD) has led to the novel hypothesis that activity can rapidly and profoundly influence the synaptic distribution of glutamate receptors. Trainees in Dr. Malenka's lab learn a range of cell biological, molecular and electrophysiological techniques that are applied to both brain slices and primary cultured neurons. These techniques include whole cell patch clamp recording, immunocytochemical localization of synaptic proteins, and transfection of cDNAs to express recombinant proteins. Dr. Malenka currently holds the Pritzker Chair of Psychiatry and has received a number of awards for his research including the Young Investigator Award from the Society for Neuroscience and several career development awards from NIH.
Brenda Porter, M.D. Ph.D. Associate Professor of Neurology and Neurological Sciences. Dr. Porter interests include difficult to treat epilepsy, with a special focus on children with neuronal developmental disorders leading to epilepsy such as tuberous sclerosis and focal cortical dysplasia. Her clinical research focuses on improving outcomes in epilepsy surgery by better defining the epileptic network using a variety of intracranial EEG features. She enjoys working in her lab studying the molecular and cellular changes that contribute to the development of epilepsy. Her research has shown that suppression of CREB a transcription factor can decrease the severity of epilepsy and is hoping to expand on this finding and someday turn her research findings into a therapeutic strategy for preventing epilepsy.
David Prince, M.D., Professor of Neurology and Neurological Sciences. Dr. Prince is the former director of the Epilepsy Training Program. Current research directions in Dr. Prince's laboratory include 1) developmental studies of neuronal function in normal and epileptogenic rat neocortex, including experiments focused on cellular electrophysiology and anatomy of cortical developmental malformations; 2) anatomic and physiologic properties of neurons in areas of chronic cortical injury and epileptogenesis in a model of post-traumatic epilepsy studied in vitro; alterations of membrane properties and reorganization of receptors and cortical circuits occurring after such injuries are being investigated; 3) actions of transmitters and neuropeptides within intra-thalamic circuits as they relate to rhythmic activities in models of petit mal epilepsy; and 4) electrophysiology and anatomy of cortical interneurons, and their modulation by neurotransmitters. Trainees in his laboratory learn a variety of techniques including use of in vitro neocortical, hippocampal, and thalamic slices; combined physiologic-anatomic analysis of labeled neurons; immunocytochemistry; methods for drug application and assessment of physiological effects of agonists; models of acute epileptogenesis; and production of chronic epileptogenic foci in mammalian brain in vivo. Dr. Prince and his colleagues and fellows have employed patch-clamp techniques to study whole-cell currents and single channel activities from cortical and thalamic neurons in slices, using both “blind” slice-patch methods and infrared video microscopy to record from directly-visualized cells.
Richard Reimer, MD, Associate Professor of Neurology and Neurological Sciences. Dr. Reimer recently joined the Stanford faculty after finishing a residency in neurology at UCSF and post-doctoral fellowship with Dr. Robert Edwards at UCSF. His post-doctoral work focused on identifying transporter proteins involved in neurotransmitter release and metabolism. His laboratory used molecular, biochemical and cell biological approaches to understanding how transporters are involved in the normal physiology of neurons and how their activity is modulated in pathological states including animal models of epilepsy. Trainees in his laboratory will learn techniques for studying expression and function of transporters, metabolism of neurotransmitters and trafficking of proteins.
Robert Sapolsky, Ph.D. Professor of Biological Sciences, Neurology and Neurological Sciences: Dr. Sapolsky's interests are in the cellular and molecular mechanisms underlying necrotic neuronal death, the role of stress and of glucocorticoids in promoting this process, and the use of gene therapy approaches using viral vectors to protect neurons from injury. His trainees gain experience in primary neuronal culturing, use of in vitro and in vivo models of damage to neurons, microdialysis studies of excitatory amino acid trafficking, measurements of calcium concentrations in cytoplasm, detection of reactive oxygen species and quantification of oxidative damage, and molecular biological techniques for construction and delivery of viral vectors. The Sapolsky laboratory was among the first to document that sustained stress can damage the hippocampus and that glucocorticoids are critical to such neurotoxicity. These agents also impair the capacity of hippocampal neurons to survive after insults including seizures. Cellular and molecular events leading to hippocampal neuronal death are being examined, and in addition, approaches are being designed to confer resistance to such events through overexpression of potentially protective genes. Dr. Sapolsky's contributions have been recognized by receipt of several awards including the Lindsley Prize and a Young Investigator of the Year Award from the Society for Neuroscience.
Thomas Südhof, M.D. Professor of Molecular & Cellular Physiology, Neurology & Neurological Sciences, Psychiatry & Behavioral Science and Molecular Genetics,
Investigator of the Howard Hughes Medical Institute Dr. Südhof's interests are protein chemistry and molecular biology with mouse genetics and cell biology, biophysical studies, physiological and behavioral analyses of mutant mice. In addition, electrophysiology on slices and cultured neurons (patch clamping and extracellular recordings); knockin/knockout mice; behavior; molecular biology; biochemistry; biophysics; imaging using fluorescent proteins and dyes; histo-/immunocytochemistry; viral expression of shRNAs and/or proteins in vitro and in vivo. Synaptic transmission, in particular how synapses are formed, how synaptic neurotransmitter release is effected, and how synaptic transmission becomes dysfunctional in neurological disease.
Examples of general areas of research training available:
Developmental studies: Fellows interested in cortical development might get their primary laboratory experience with Dr. McConnell learning techniques of developmental neurobiology applied to studies of neurogenesis and neuronal migration in the developing cerebral cortex, or with Dr. Barres, working on glial influences on neuronal development and synapse formation. Investigative approaches would include those of molecular biology, in situ hybridization, tissue culture and transplantation as well as electrophysiological and anatomic methods in use in these laboratories. Such a trainee might spend time in Dr. Prince's laboratory learning methods for producing and studying epileptogenic cortical malformations, and applying neuroanatomic and slice-patch electrophysiological techniques to examine disorders of development in such models. Suggested courses: Comparative Medicine 207, (Comparative Neuroanatomy, Buckmaster); Biology 258 (Neural Development, McConnell).
Use-dependent changes in excitability: Another general area of trainee research might be long-term changes in neuronal and synaptic properties associated with use of circuits (e.g. the long-term potentiation or kindling models). Such experiments could be pursued in hippocampal slices using current clamp and patch-clamp techniques. Trainees in Dr. Malenka’s and Dr. Südhof's laboratories would study cellular and circuit synaptic physiology and its modulation by activity, neurotransmitters and intracellular signaling, and would have opportunities to apply these techniques to models of neurological disease. Suggested courses: Neurobiology 254 (Molecular and Cellular Neurobiology,); Neurobiology 216 (Genetic Analysis of Behavior, Clandinin & Goodman).
Cellular neurophysiology-neuropharmacology: In the laboratories of Drs. Buckmaster, FHuguenard, Malenka , Prince or Südhof, a trainee whose interests focus on cellular neurophysiology might initially learn to apply the techniques of sharp and whole cell recordings to neurons of slices using either the "blind" slice-patch approach, or infra-red video microscopy to visualize neurons. Methods for analysis of spontaneous and evoked whole cell synaptic currents, and effects of drugs and neurotransmitters on these might be employed. Experiments might focus on areas such as regulation of normal cell and circuit excitability; electrophysiology, structure and pharmacology of interneurons and pyramidal cells; and biophysical properties of voltage-and agonist-activated currents or single channel properties in subclasses of neurons. Experience would also be gained in methods for intracellularly labeling, reconstructing and analyzing recorded neurons. A collaborative project with Dr. Luo’s or Dr. Reimer’s laboratory would acquaint the trainee with methods for assessment of genetic regulation of circuits, or neurotransmitter recycling, as appropriate to his/her primary project. Suggested courses: Molecular and Cellular Physiology 215 (Synaptic Transmission, Smith, Madison); Molecular and Cellular Physiology 256 (Molecular Physiology of Cells, Aldrich & Maduke), Neurology 220 (Computational Neuroscience, Huguenard).
Molecular neurobiology: Molecular neurobiological techniques are being employed in the laboratories of Drs. Barres, Huguenard,Luo, Malenka, McConnell, Reimer, Sapolsky, or Südhof,to examine aspects of cortical development, mechanisms of neurosecretion, second messengers, and regulation of gene expression and factors in hippocampal cell death, as described in Section B-2 above. A trainee involved in such experiments might learn to use a range of methods including in situ hybridization, site directed mutagenesis, gene transfer using viral vectors, cloning techniques, polymerase chain reaction applied to single neurons, Southern blots, etc. Depending upon the nature of the problem under investigation, it might be possible for the trainee to learn to apply other complementary techniques. For example, a combined molecular-electrophysiological approach could be used to investigate the molecular basis for functional differences in agonist-activated synaptic currents in different cell types, or in a given type of neuron in control versus injured or epileptogenic cortex, using single cell PCR together with patch clamp methods. Suggested courses: Neurobiology 254 (Molecular and Cellular Neurobiology, Luo & Stryer); Neurobiology 216 (Genetic Analysis of Behavior, Clandinin & Goodman); Molecular and Cellular Physiology 256 (Molecular Physiology of Cells, Aldrich & Maduke)
Experimental epileptology: Mechanisms underlying abnormal activities during chronic epileptogenesis might be studied in models of post-traumatic epilepsy or cortical malformations in Dr. Prince’s laboratory, using combinations of anatomical, electrophysiological and pharmacological techniques applied to epileptogenic slices. The fellow might elect to work in Dr. Fisher’s or Dr. Buckmaster’s laboratory and examine models of temporal lobe or acquired absence epilepsy by combining both in vivo and in vitro cellular recording and labeling techniques and immunocytochemical approaches. A project in Dr. Sapolsky’s laboratory might involve acquisition of techniques for gene therapy of epileptogenic lesions in hippocampus or neocortex, and studies of approaches to neuroprotection in epilepsy. Trainees might elect to study models of abnormal intrathalamic rhythms and their modulation by neurotransmitters and peptides, or callosally mediated excitation in epileptogenic neocortical lesions in Dr. Huguenard’s laboratory. Joint training in cortical development or molecular mechanisms of synaptic processes in epileptogenesis might be obtained in collaboration with Drs. Barres, McConnell, Luo, Reimer or Malenka, as appropriate. Trainees interested in the role of trophic factors in post-injury epileptogenesis might design projects in collaboration with Dr. Mobley’s laboratory. Suggested courses: Neurology 205 (Clinical Neuroscience, Reimer, Yang);
Training in clinical
Occasionally, a postdoctoral fellow who has completed a residency in clinical
neurology may want to gain experience in clinical epileptology, as well as
obtain basic research training. This program does not support training in
clinical epileptology per se, however there is opportunity for such M.D.
trainees to maintain their exposure to clinical medicine by spending ½ day/week
in some clinically related area (see Section B-3d above). It is thus
possible for such individuals to attend an epilepsy clinic and read EEGs with
one of the attendings on a regularly scheduled basis, and become more familiar
with clinical epilepsy in this way. For those who want more substantial
clinical exposure, with the assistance of the head of the clinical epilepsy
program, it has been possible to arrange a block rotation in clinical epilepsy,
Courses, seminars and conferences: Postdoctoral fellows will have the opportunity to supplement their laboratory training with a wide variety of graduate courses in the major areas of the neurosciences. Those fellows who have not had extensive background in neuroscience will be encouraged by their sponsor to take at least one course per year in areas relevant to their research training program. These include lecture courses, seminars, and classes in specialized laboratory techniques. Examples are provided above in Section B-3e, with the summary of general areas of research training. Appendix B lists selected courses for predoctoral students in the neurosciences which might be audited by postdoctoral fellows. All fellows are required to attend a course on Responsible Conduct of Research (Med 255) described in Section D below and are also encouraged to attend Neurobiology 300, a course on Professional Development and Ethics.
Seminar series: The fellows of the training program will attend an Epilepsy Seminar Series. A speaker from the Stanford neuroscience community or another institution is invited to give a seminar once a quarter and spend time informally discussing ongoing research and new experimental approaches to problems of epilepsy-related research with trainees. In addition, fellows and faculty attend the Frontiers in Neuroscience, Fundamental Themes in Neuroscience, and Neurobiology of Disease series, each of which runs for one quarter; neuroscience seminars of interest sponsored by the Neuroscience Ph.D. Program and Department of Neurology and Neurological Sciences; as well as selected others arranged by Neurobiology, Biology, Molecular and Cellular Physiology, and Pharmacology. Appendix A contains a partial list of recent research seminars.
Epilepsy Program Conference: Dr. Prince has organized an Epilepsy Conference, held 2 to 4 times per year, which is attended by fellows supported by the Epilepsy Training Program, neurology residents and others, together with Program faculty. The purpose is to give trainees an opportunity to interact and review selected problems in epilepsy from both clinical and basic perspectives. Typically one clinical and one basic research fellow review a selected subject. Topics that have been covered are listed in Appendix C.
Clinical Epilepsy Conferences: Trainees with interests in clinical epileptology may occasionally attend other conferences including a weekly epilepsy EEG conference at which video EEG records of hospitalized patients in the Epilepsy Unit are reviewed, and a case conference. All trainees are encouraged to familiarize themselves with the phenomenology of human epilepsy. During their fellowship, trainees visit the inpatient Epilepsy Monitor Unit where one of the clinical epileptologists discusses with them the techniques used to diagnose and classify epilepsy and reviews tapes of various types of epilepsy.
Postdoctoral trainees: Qualifications, criteria, procedures: Research training is
provided in areas relevant to basic science aspects of epilepsy for 1)
candidates with M.D., M.D./Ph.D. or other medical degrees, and 2) individuals
who have Ph.D degrees. From past experience, most M.D. or M.D./Ph.D. candidates
interested in epilepsy research training will have completed a residency in
clinical neurology, however, well-qualified candidates from other clinical
neuroscience backgrounds (Neurosurgery, Psychiatry), or those who have chosen
not to enter postdoctoral medical specialty training, will be considered.
Candidates must have interests in developing academic careers that will be
relevant to epilepsy-related research and must be