Postdoctoral
Involved Departments and Faculty
Postdoctoral trainees: Qualifications, criteria
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
Involved Departments
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
·
John Huguenard, Ph.D. Neurology & Neurological Sciences,
Program Director
·
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
epileptology:
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,
supported by
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