Download Fridtjof Nansen Science Symposium 2011

The anatomy of synapses – structural basis of long-term potentiation
and synaptic scaling
Kristen M. Harris
Center for Learning and Memory, Section of Neurobiology, University of Texas at
Austin, USA
[email protected]
This talk will emphasize work dedicated to understanding the role of dendritic spines and
synapse structure in learning and memory. Long-term potentiation (LTP) of synaptic
efficacy is a model of learning and memory that is well-suited to investigate this process.
A clear understanding requires the nanometer resolution of three-dimensional (3D)
reconstruction from serial section electron microscopy (ssEM). In this talk, I will review
our work with ssEM to discover structural synaptic scaling, where synaptic input
redistributes from many small to fewer enlarged spines with enlarged synapses by 2 hr
after the induction of LTP. These enlarged spines sequester more core structures,
including polyribosomes (involved in local protein synthesis), endosomes (a local source
of plasma membrane, channels, and other signaling molecules), and smooth endoplasmic
reticulum (an organelle that regulates calcium and receptor trafficking). Remarkably, the
summed synaptic surface area per unit length of dendrite remains constant across control
and LTP conditions. These findings support the hypothesis that competition for intrinsic
dendritic resources regulates the number and size of synapses that a mature dendrite can
support. I will also present new findings that show several presynaptic changes occur by
2 hr after the induction of LTP including a parallel loss of small axonal boutons and small
dendritic spines; a homogeneous redistribution of presynaptic vesicles among the
enlarged synapses; and a decrease in the number of presynaptic vesicles per synapse,
suggesting either more presynaptic release or less recycling accompanies the expression
of LTP. These findings support a synchrony between pre and postsynaptic elements that
coordinates and refines synaptic circuitry to express LTP.
Short biography
Kristen M. Harris, PhD was born in Fargo, ND, and raised in the twin city of Moorhead, MN – her father,
while born American, was of 100% Norwegian heritage from the Bergen area. She earned her BS, summa
cum laude in Biology, Chemistry and Math, from the Minnesota State University Moorhead, her MS in
Neurobiology at the University of Illinois with William Greenough, and her PhD at Northeastern Ohio
Universities College of Medicine with Timothy Teyler – himself a postdoctoral graduate from Per
Andersen’s laboratory at the University of Oslo. Harris had the great honor to be a member of an
International Committee to examine 6 Ph.D. candidates from Prof. Per Andersen’s laboratory in 1995 (not
the least of whom were the Mosers now at Trondheim). Hence, her Norwegian roots are strong. She went
on to postdoctoral research at Harvard Medical School and remained there on the faculty for 15 years
before moving to Boston University where she co-directed a Program in Neuroscience with Howard
Eichenbaum. After 4 years at BU, she was recruited as a Georgia Research Alliance Eminent Scholar to the
Medical College of Georgia where she built and directed the Synapses and Cognitive Neuroscience Center
for 4 years, before moving to the University of Texas-Austin where she is now Professor and Fellow in the
new Center for Learning and Memory. She served on the search committee to recruit Laura Colgin (a
postdoctoral fellow from the Moser’s laboratory) to UT. She is the recipient of many awards including the
National Institutes of Health Javits Merit Award. Her research is at the forefront of the systematic study of
synapse structure, especially as it relates to the maturation of synaptic function and long-term potentiation.
Spinal motor networks – excitation moving us forward
Ole Kiehn
Mammalian Locomotor Laboratory, Department of Neuroscience, Karolinska Institutet,
Stockholm, Sweden
[email protected]
Brain functions are generated by activity in dedicated neural circuits. A major challenge
to modern neuroscientist is to understand the function and mode of operation of such
circuits in the complex mammalian brain. For locomotor behaviors, like walking, motor
circuits in the spinal cord itself generate the actual timing and coordination of the
rhythmic muscle activity. Excitatory neurotransmission is known to play a critical role in
the generation of the locomotor rhythm and the drive in these spinal motor networks.
Here, I will present data on the identification of excitatory networks in the mammalian
spinal cord and brainstem locomotor networks. Among several classes of excitatory
interneurons in the spinal cord, V2a interneurons are marked selectively by the
expression of the transcription factor Chx10. Using combined physiological and
molecular approaches we have determined the role of V2a interneurons in the locomotor
network and shown that the V2a interneurons play little or no role in rhythm-generation
but drive commissural interneurons to insure left-right alternation during locomotion. The
V2a network is organized in a modular fashion along the cord and using genetic tracing
and ablation and we show that the V2a interneurons together with other excitatory
neurons control specific molecularly defined groups of commissural interneurons
involved in left-right alternation. Using a transgenic mouse line that selectively drive
light-sensitive channels in glutamatergic excitatory neurons in the spinal cord and
brainstem we show that such neurons in the cord are directly responsible for rhythmgeneration and that glutamatergic neurons in the lower hindbrain serve as command
neurons for initiating locomotor activity. Surprisingly motor neurons may also - in
addition to their classical transmitter acetylcholine - release glutamate from central
synapses and activate locomotor networks. Together our experiments provide insights to
the principal mode of operation of a large-scale mammalian motor circuit.
Short biography
Ole Kiehn is Professor at the Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. He
obtained a medical degree in 1985 from University of Copenhagen where he also gained his doctoral
degree in neurophysiology in 1990. Kiehn trained as a post-dotoctoral fellow at Cornell University in 198990 where after he returned to University of Copenhagen to established his lab. In 2001 he was recruited to
Karolinska Institutet. Kiehn’s work on motor neurons has provided new insights to the role of intrinsic
membrane properties to normal motor function as well as their contribution to dysfunctional motor
symptoms after spinal cord injury. His work on spinal locomotor circuitries controlling walking in
mammals has defined some of the fundamental building blocks of the network, including interneuron
circuitries controlling left-right coordination and inhibitory and excitatory interneuron networks engaged in
pattern formation. In his work he has combined genetic manipulation with electrophysiological and
anatomical techniques needed to understand complex network function in the mammalian brain. Kiehn is
on the editorial board for Current Opinion of Neurobiology, Journal of Neurophysiology, and Neural
Development among others. His is a member of the Nobel Assembly and his work has been acknowledged
by the Schellenberg Prize and an endowed Söderberg’s professorship.
Worms reveal how the brain works – functional genomics in C. elegans
Cori Bargmann
Howard Hughes Medical Institute, The Rockefeller University, New York, USA
[email protected]
All animals and even unicellular organisms recognize other members of their species and
interact with them, suggesting that ancient biological systems are involved in these
recognition processes. Innate social behaviors emerge from neuronal circuits that
interpret sensory information based on an individual’s own genotype, sex, and
experience. Our work centers on genes that regulate social behaviors of C. elegans, a
nematode worm with a simple and well-characterized nervous system. A specific
neuropeptide receptor has different activity levels in wild-type social strains and solitary
strains of C. elegans. Neuropeptides like vasopressin and oxytocin and their receptors
are also implicated in mammalian social behaviors, suggesting a common genetic
vocabulary for sociality.
How do genes and the enviroment interact to generate behavior? In C. elegans, a
specialized “social brain” integrates the genetic regulation of social preference with
environmental context. The genetic and anatomical hub of the social brain is a neuron
called RMG, which connects to many other neurons through gap junction synapses.
Sensory input into RMG determines whether the environment is appropriate or
inappropriate for aggregation. If the environmental context is correct, RMG alters the
animal’s behavioral preferences so that it approaches pheromones released by its
companions. Regulation of RMG by the neuropeptide receptor switches animals between
social and solitary behavioral modes.
Short biography
Cornelia Isabella Bargmann is Investigator, Howard Hughes Medical Institute, and Torsten N. Wiesel
Professor and Head, Laboratory of Neural Circuits and Behavior, The Rockefeller University, New York.
Education and Training. 1977-1981: B.S. with a major in Biochemistry, The University of Georgia,
Athens, GA. Undergraduate research with Sidney Kushner. 1981-1987: Ph.D., Massachusetts Institute of
Technology, Department of Biology. Doctoral research with Robert A. Weinberg at the MIT Cancer Center
and the Whitehead Institute for Biomedical Research. Field of study: Cancer biology. 1987-1991:
Postdoctoral research with H. Robert Horvitz at the Howard Hughes Medical Institute, Massachusetts
Institute of Technology. Field of study: Genetics.
Positions. 1991-2004: Assistant/Associate/Full Professor, The University of California, San Francisco,
Department of Anatomy and Department of Biochemistry and Biophysics 1995-present: Investigator,
Howard Hughes Medical Institute. 2004-present: Torsten N. Wiesel Professor and Head of Laboratory,
The Rockefeller University
Honors. 1981: Phi Beta Kappa, First Honor Graduate (Valedictorian). 1981: National Science Foundation
Predoctoral Fellow. 1987: Helen Hay Whitney Postdoctoral Fellow. 1990: Lucille P. Markey
Scholar. 1992: Searle Scholar. 1997: Takasago Award for Research in Olfaction. 1997: W. Alden
Spencer Award for Neuroscience Research, Columbia University. 2000: Faculty Mentorship Award,
UCSF Graduate Student Association. 2000: Charles J. Herrick Award, The American Association of
Anatomists. 2001: Elected Associate of the Neurosciences Research Program. 2002: Elected Fellow of the
American Academy of Arts and Sciences. 2003: Elected to the National Academy of Sciences. 2004:
Prize of the Dargut and Milena Kemali Foundation for Basic and Clinical Neuroscience. 2006: Elected
Fellow of the American Association for the Advancement of Science. 2009: Richard Lounsbery Award in
Biology and Medicine, National Academy of Sciences.
Editorial Boards. Neuron (1995-), Genes and Development (1998-), Cell (1999-), Current Biology (1999-),
Current Opinion in Neurobiology (2010-)
Optogenetics: unlocking mysteries of the brain in health and disease
Karl Deisseroth
Departments of Bioengineering and Psychiatry, Stanford University, Stanford CA, USA
[email protected]
The technology of optogenetics has allowed millisecond-precision optical control over
activity in defined cell types within freely moving mammals. The approach introduced by
Karl Deisseroth in August of 2005 has now been adopted by thousands of scientists
around the world. In 2010 optogenetics was named Method-of-the-Year across all fields
of science and engineering by the Nature journals, and headlined the Breakthroughs-ofthe-Decade piece in Science. Beyond initial tool discovery, Deisseroth’s team has also
developed the enabling in vivo methods (molecular targeting, fibreoptics and solid-state
optics), and led the application of optogenetics to obtain fundamental insights into neural
circuit dynamics in health and disease states such as anxiety and Parkinsonism.
Deisseroth’s talk will briefly review this history and also focus in detail on new
optogenetic technologies including the third-generation halorhodopsin (Nature 446, 6339, 2007; Cell:141, 1–12, 2010), which has enabled the first optogenetic loss-of-function
behavioral results in freely-moving mammals (complementing their earlier gain-offunction work). This recent set of papers has resulted in identifying a causal role for
nucleus accumbens cholinergic neurons in cocaine conditioning (Science 330:1677-81,
2010), and allowed Deisseroth’s team to map out a specific amygdala projection causally
involved in anxiety (Nature, in press 2011), the most common of the psychiatric diseases.
www.stanford.edu/group/dlab/papers/breakthroughscience2010.pdf
www.stanford.edu/group/dlab/papers/deisserothnature2010.pdf
www.stanford.edu/group/dlab/papers/moynature2010.pdf
Short biography
Karl Deisseroth received his bachelor's degree summa cum laude from Harvard in 1992, his PhD from
Stanford in 1998, and his MD from Stanford in 2000. He completed postdoctoral training, medical
internship, and adult psychiatry residency at Stanford, and he was board-certified by the American Board of
Psychiatry and Neurology in 2006. He is a faculty member in the Bioengineering and Psychiatry
Departments at Stanford, and in the medical school continues as a practicing psychiatrist, employing
medications as well as high-speed (action potential-based) brain stimulation treatments (VNS, TMS and
others) in patients. Deisseroth’s development of optogenetics in his bioengineering laboratory has allowed
millisecond-precision optical control over activity in defined cell types within freely moving mammals, and
his team. He has received numerous prestigious and international awards for this work, including the
Lawrence C. Katz Prize from Duke University, the Schuetze Prize from Columbia University, the Society
for Neuroscience YIA Award, the Koetser Prize, and the Nakasone Prize from the international HFSP, all
for optogenetics.
www.stanford.edu/group/dlab/optogenetics/sciam.html
www.forbes.com/forbes/2010/0719/opinions-lasers-algae-bioengineering-ideas-opinions.html
Brain network activity and cognition – grid cells, sense of space and
memory
Edvard I. Moser
Kavli Institute for Systems Neuroscience, NTNU, Trondheim, Norway;
[email protected]
This talk will focus on the neural substrate of spatial representation in the entorhinal
cortex and hippocampus. A key element of the mammalian spatial map is the entorhinal
grid cell. Grid cells fire selectively at regularly spaced positions in the environment such
that, for each cell, activity is observed only when the animal is at places that together
define a repeating triangular pattern tiling the entire environment covered by the animal.
The pattern is reminiscent of an abstract coordinate system defining places by distances
and directions independently of the particular features of the environment. The scale of
the grid map is topographically organized in that the spacing of the grid increases from
the dorsal to the ventral end of medial entorhinal cortex. I will show that the organization
of the grid map is likely to be modular and that HCN channels contribute to the
determination of grid scale. I will follow up by showing that, at each dorsal-ventral level,
grid cells co-localize with head-direction cells and border cells, which also contribute to a
dynamically updated metric representation of current location. Based on studies using a
virus-mediated approach to selectively express photoresponsive channel proteins in
entorhinal cells with projections to the hippocampus, I shall finally present preliminary
data suggesting that grid cells, head direction cells and border cells may all provide direct
input to environment-specific place-cell maps downstream in memory networks of the
hippocampus.
Short biography
Edvard Moser (born 1962) is the Director of the Kavli Institute for Systems Neuroscience and the Centre
for the Biology of Memory at the Norwegian University of Science and Technology (NTNU) in
Trondheim. A Professor of Neuroscience at NTNU since 1998, Moser studied mathematics, statistics,
psychology and neurobiology at the University of Oslo, where he obtained his PhD with Per Andersen.
Moser trained as Postdoc at the University of Edinburgh and at the University College London 1994-6.
Together with May-Britt Moser, he has since their group was established at NTNU in 1996 studied how
spatial location and spatial memory are computed in the brain. Their most noteworthy contribution is
probably the discovery of grid cells in the entorhinal cortex, which points to the entorhinal cortex as a hub
for the brain network that makes us find our way. They have shown how a variety of functional cell types
in the entorhinal microcircuit contribute to representation of self-location, how the outputs of the circuit are
used by memory networks in the hippocampus, and how episodic memories are separated from each other
in the early stages of the hippocampal memory storage. Edvard Moser is a member of the Board of
Reviewing Editors in Science and co-editor of Current Opinion in Neurobiology. He has won several
international prizes (including the Spencer, Koetser, Bettencourt, Fernström, and Louis-Jeantet).
Nansen as a scientist
Roland Huntford
Wolfson College, University of Cambridge
[email protected]
When Fridtjof Nansen presented his doctoral dissertation on the 28th April 1888, he laid
the foundations of modern neuroscience. Nonetheless he has never had his due as a
neuroscientist.
The explanation lies in the sequel. The same year, Nansen made the first crossing of
Greenland, revolutionising modern polar exploration by the use of skis. He did so, or so
he said, to relieve "fatigue of the brain" after his scientific research. Be that as it may, he
became much more famous for his Greenland exploit. He suffered the fate of the
polymath. His trailblazing discoveries in neuroscience were overshadowed by his
achievements in other spheres, notably exploring the Arctic, oceanography and, yes, even
ski jumping.
His contemporaries in neuroscience at least understood his worth. In 1891, When W.
Waldeyer coined the term 'Neuron' to express the physiological independence of the
nerve unit, he quoted Nansen as one of his authorities. So Nansen, as it were, lies at the
heart of a celebrated medical term.
In his dissertation, Nansen proposed the independence of the neuron, and made a
prediscovery of the synapse. In other words he propounded what came to be called the
neuron theory. In 1886, he published an abstract of what was to be his dissertation in an
English journal, and then the following year in a German paper. Unknown to Nansen,
others were working along the same lines, notably the two Swiss doctors, Wilhelm His
and August Forel. Nansen, however, got into print first. Irrespective of publishing
priority, he was the first explicitly to formulate the doctrine of the neuron theory, and
therefore the foundation of modern neuroscience.
The development of microscopy also had a hand in Nansen's breakthrough. He was
working just as Zeiss put the first apochromatic microscope on the market. The
coincidence played a part in Nansen's priority.
Personally, I think that Nansen ought to have received the first Nobel Prize for
medicine - but that's another story. In an ironical twist, Ramon y Cajal shared the Nobel
Prize for 1906 as the impresario of the neuron theory, although sheer publishing
chronology suggests that he may well have borrowed the idea of the neuron from Nansen.
I propose to put Nansen's work into the context of the intellectual turbulence of
nineteenth century Norway, created by the forces of nationalism and the drive to
independence. He worked as an individual and, for historical reasons, free from the
domination of academies, bureaucrats, official research councils and other corporate
forces. In this connection, I propose to trace the genesis of Nansen's ideas. He owed
much to foreign guests at the Bergen Museum, where he was doing his research
Unlike the world today Nansen was, as someone once put it, no prisoner of deductive
reasoning. As a result, or otherwise, he showed the leap of imagination from which
discoveries spring. This is the leitmotiv of what I propose to say. That, and the fact that
Nansen was a zoologist, specialising in primitive marine creatures, in the belief that study
of simple mechanisms give an insight into complex ones. He was almost certainly the
first to apply the Golgi reazione nero method of staining microscopic sections to
invertebrates. All this goes to show that Nansen proved that sciences should crossfertilize each other, and that the distinction between zoology and medicine is selfdefeating.
Finally, I want to offer my explanation of why a small, sparsely populated country on
the outskirts of Europe, produced someone of Nansen's calibre. He was not alone. This
still has lessons for us today, in the laboratory and outside.
Short biography
Read physics (disastrously) at university, but it would be best to draw a discreet veil over my
undergraduate career. Subsequently worked for the United Nations in Geneva, Nordic correspondent for
The Observer, based in Helsinki and Stockholm, 1960-74. Since then, author by profession, living in
Cambridge. I am a senior member of Wolfson College, University of Cambridge, with a special interest in
Scandinavian history and literature. I held the Alistair Horne Fellowship at St. Antony's College, Oxford
University while doing some of the research for my biography of Nansen.
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