The past year (2003-04) represents a special milestone
for the Volen National Center for Complex Systems-its
10th anniversary. Almost from the beginning, the M.R.
Bauer Foundation has supported the Bauer Colloquium Series
and Retreat, later joined by the Bauer Distinguished Guest
Lecturer Series, which have served to enrich the educational
and research missions of the Center, raise its visibility
in the neuroscience community, and strengthen connections
between host and visitors. In light of this anniversary,
I am especially pleased to present the proceedings of
the 2003-04 M.R. Bauer Foundation Colloquium Series, Distinguished
Guest Lecturer Series, and Symposium (Retreat) on Autism
and Behavioral Genomics. My colleagues and I owe a special
debt of gratitude to the M.R. Bauer Foundation for its
continuous support that has enabled the Volen Center to
mount these outstanding programs and advance the efforts
of neuroscientists to understand the complex system constituted
by the brain.
The M.R. Bauer Colloquium Series hosted seven
speakers in 2003-04. The speakers focused on advances
in understanding cellular and system changes that underlie
learning and other behaviors, underscoring the link that
is now commonly made by neuroscientists between physiological
changes and behavior. Denis Pare,
Ph.D., from Rutgers University talked about the
physiological properties of certain neurons in the amygdala,
which is thought to play a critical role in the expression
and learning of fear responses. Disturbances in the amygdala
are thought to be responsible for some human anxiety disorders,
such as post-traumatic stress. Certain inhibitory neurons
in this part of the brain are essential in reconciling
the opposite requirements of plasticity and stability
in brain networks. As these neurons are excited or depressed,
there is an opposite change in the strength of inputs
at other dendrites, leading to no net change in total
synaptic weight despite a change in the relative strength
of inputs.
Ann Graybiel, Ph.D.,
from MIT's McGovern Institute for Brain Research, reported
on recordings made from the cortex of macaque monkeys
as they executed a sequence of eye movements. Her surprising
finding was that electrical activity in neurons peaked
at the end of these movements, suggesting that this activity
does not depend on sensory input but rather was an explicit
signal inherent to the neuron marking the completion of
learned behaviors.
Jonathan Cohen, Ph.D.,
from Princeton University spoke about one of the fundamental
mysteries of neuroscience-how our capacity for purposeful
behavior arises from the distributed activity of billions
of neurons in the brain. Although we have a poor understanding
of how systems in the brain lead to cognitive control
(the ability to guide attention, thought, and action in
accord with our intentions), he is using computational
modeling to develop explanations for the function of particular
brain systems. His work has led to novel hypotheses about
how systems work in the brain as well as the discovery
of new anatomic relationships.
Jeff Lichtman, Ph.D.,
from Washington University School of Medicine is taking
advantage of new techniques to demonstrate the dramatic
remodeling that occurs in brain circuits soon after birth.
Using newly available techniques of genome manipulation
and the fluorescent imaging of neurons that together permit
scientists to label neurons with different colors so that
synaptic circuitry can be untangled, he is showing how
young mammals use experience to mold their nervous systems
to conform to the world they inhabit.
Nelson Spruston, Ph.D.,
from Northwestern University described how sensory information
is integrated in the hippocampus to provide a map of experience
with a spatial component. He identified dendritic excitability,
the spike in electrical activity at the connections between
neurons, as the central factor in the process that leads
to the formation of memories.
Todd Holmes, Ph.D.,
from New York University spoke about the interaction between
biochemical signaling and electrical signaling as they
influence neural circuits and animal behavior. He has
engineered ion channels that have novel properties in
order to determine how systematic changes in cellular
electrical activity affect circadian rhythms, the physiology
of neurons, and development.
Michael Ehlers, Ph.D.,
from Duke University spoke about his work on the formation
of receptors in the brain responsible for information
storage. External stimuli trigger the strengthening of
connections between neurons, growth in the number of receptors,
and recycling of the materials used to create these receptors.
Now completing its sixth year, the M.R. Bauer Distinguished
Guest Lecturer Series brought two outstanding neuroscientists
to campus in 2004. David McCormick,
Ph.D., serves as a professor of neurobiology at Yale University
School of Medicine. He is best known for his work on the
visual system, which has advanced our understanding of
the forebrain (cortex) to a level that had previously
been possible only with invertebrate systems. His public
lecture, "The Possible Role of Recurrent Cortical Networks
in Memory and Attention," emphasized that the brain is
constantly active. During long periods of sleep and conscious
attention, when there isn't any physical movement, cortical
networks in the front of the brain generate persistent
electrical activity through a balance of recurring excitation
and inhibition. When this system is "unbalanced," with
electrical activity that is random or chaotic, the result
is brain activity typical of epilepsy. With a stable network,
changes in the excitability of neurons allow us to shift
attention or remember something in a specific time and
space.
McCormick indicated that there are two explanatory models
for what is happening in the brain: (1) activity is generated
through ion channel function in the membrane of neurons,
or (2) activity is generated by the networks of neurons.
It is more likely that networks are more important than
membrane channels in controlling electrical activity that
underlies our working memory, although membranes are clearly
also involved in this process. He has discovered, for
example, that H-channels, which serve as a pacemaker setting
the heart rate, are also a major controlling factor in
how much information gets to the central part of the neuron,
and they may modulate neurons' ability to communicate.
The brain is inundated with background activity. How does
this recurrent electrical activity affect the connections
between cells? This question may shed light on how we
learn. Networks in the cortex are highly interconnected
and highly plastic (i.e., they adapt to changes rapidly).
McCormick's hypothesis is that attentional command may
select a subnetwork that enters into the "up" state, thereby
biasing the processing of information. These mechanisms
underlie our conscious focus on particular stimuli in
the external world and permit our brain to filter the
massive sensory and background information it receives.
The stability of the neural network, balanced between
electrical excitation and inhibition, allows the brain
to shift focus rapidly, as needed.
The other M.R. Bauer Distinguished Guest Lecturer was
Charles Zuker, Ph.D.,
professor of biology and neurosciences at the University
of California, San Diego, School of Medicine, as well
as an Investigator of the Howard Hughes Medical Institute.
Zuker was also the keynote speaker at the Volen National
Center's 10th Anniversary Symposium on Autism and Behavioral
Genomics, which served as this year's scientific retreat.
Zuker addressed "Signaling and Coding in the Mammalian
Taste System: Sweet, Bitter, and Umami." For the past
five years, he has been working to understand how the
brain encodes and decodes sensory stimulations, particularly
chemosensation in mammals. Before we can figure out how
the brain does this, however, it is necessary to understand
the process at the periphery, in other words, how taste
cells work in the tongue.
The ability to discriminate tastes has important evolutionary
implications for humans. For example, all toxins taste
bitter to us, and lead to an aversion. Zuker concentrates
on a family of genes that appear to be responsible for
mediating the sweet and umami (amino acid) tastes. His
genetic experiments are a striking example of how the
selectivity for taste can be altered. Zuker validated
in vivo that certain genes play an essential role in sensing
sweetness. Humans like MSG 100 times more than any other
amino acid, while mice like all amino acids equally. Unlike
humans, mice do not like the taste of aspartame, an artificial
sweetener, at all. These differences reflect the different
ecological niches that humans and rodents occupy.
When the human receptor for sweetness is placed in a
transgenic mouse, the mouse likes aspartame. There is
a paradoxical complexity, however, underlying this simple
sense. Zuker showed that we do not have broadly tuned
cells but rather cells dedicated to each taste. Every
taste cell expresses all 30 receptors (making them fundamentally
different from olfaction cells). There is only one kind
of "bitter" cell, however, that senses the full range
of bitter tastes. "We need to know that something is bad,"
Zuker said, "but we don't need to know what kind of bad
it is." He demonstrated through these experiments that
we have a good grasp of how taste operates at the periphery
(on the tongue).
But how is this information transferred to the brain?
There do not appear to be broadly tuned areas across modalities
in the brain. Taste is a property of the cell, not of
the receptor. By elucidating the molecular genetics of
taste, Zuker is working to demonstrate how the senses
interact with the environment and how sensory information
is processed in the brain. For animals, the attraction/
aversion response to each taste is a life-and-death issue.
For humans, the inability to respond to certain features
of the external environment appears to be at the heart
of disorders such as autism.
The 2004 Volen Center retreat, the Symposium on Autism
and Behavioral Genomics, sponsored in part by the
M.R. Bauer Foundation, took place on the Brandeis campus
on March 22. Seven speakers, including Zuker, helped to
define, sometimes controversially, the progress that we
have made in understanding one of the most elusive and
troubling disorders of the brain. The Symposium was also
one of the best-attended events in the Volen Center's
history, with some 300 scientists, students, and interested
laypeople attending.
Edward Jones, Ph.D.,
director of the Center for Neuroscience at the University
of California, Davis, describes a loss of connections
in the brain as one of the underlying factors in schizophrenia.
In the past two years, following the sequencing of the
human genome, the search for susceptibility genes for
schizophrenia has dominated the field. However, schizophrenia,
like autism, is emerging as a complex disease whose origin
is not a single process. These disorders share certain
characteristics, including susceptibility genes and pre-
and post-natal events that lead to circuitry in certain
areas of the brain that, when faced with stresses in life,
begin to decompensate, demonstrating a kind of maladaptive
plasticity.
Leslie Griffith, Ph.D.,
from Brandeis University's Volen Center uses the biochemistry
of fruit fly courtship behavior to illustrate how the
brain forms memories and learns from the external environment
in order to understand an important area of deficit in
autism. Through a series of careful experiments, Griffith
showed that associative courtship learning is mediated
by a change in sensitivity to pheromones. The molecular
basis of this change is a calcium-dependent protein that
serves as the molecular switch for memory.
Thomas Insel, Ph.D.,
director of the National Institute of Mental Health, addressed
the neurobiological basis of love and social affiliation.
Using the prairie vole, a biparental species that forms
pair bonds for life, he showed that some areas of the
brain respond only to social information, and there are
specific receptors and pathways in the brain for social
attachments. Social behavior is a complex molecular system.
Comparative studies of species of voles are beginning
to shed light on the underlying mechanisms of social attachment,
which in turn may offer potential ways to understand and
treat autism.
Catherine Dulac, Ph.D.,
professor of molecular and cellular biology at Harvard
University and a Howard Hughes Medical Institute Investigator,
talked about the sensory coding of pheromone signals in
the olfactory system. In rodents, pheromones are essential
in parent-infant interactions. Because parent-infant interactions
are also a key issue in autism, understanding the molecular
basis of pheromone detection and processing may provide
important insights in autism.
Rudolph Jaenisch,
Ph.D., from MIT's Whitehead Institute considered how cells
are programmed for their roles and whether this programming
was reversible. While cloning may possibly offer an intriguing
way to re-program cancer cells to reverse the disease,
the process is too complicated at present to be successful
or effective. He suggested that cloning might eventually
provide clues both for understanding autism and treating
it.
David Skuse, M.D., director
of the Behavioral and Brain Sciences Unit of the Institute
of Child Health at University College, London, spoke about
the neurobiological basis of autism. Evidence suggests
that autism is not a distinct condition but a spectrum
of disorders that share certain features varying considerably
in severity. Does mental retardation lower the threshold
for trait manifestation in autism? Skuse believes it does,
but he also points out that 75 percent or more of persons
with autism have normal range IQs, a reversal of the current
orthodoxy. With the need to redefine autism along a broader
spectrum, Skuse also believes that the incidence of autism
is more widespread than previously known. Autism is heritable,
and it is probably related to less than 20 genes, with
a distinctive neurobiological substrate. He has recently
identified candidate genes that may be potentially associated
with the development of social intelligence. Neuroscientists
are close to piecing together, for the first time, a plausible
explanation of how genetic variation affects social intelligence,
which in turn would substantiate the biological origins
of autism.
In the past decade, the M.R. Bauer Foundation Colloquium
and Scientific Retreat have served to facilitate the exchange
of new knowledge, ideas, and techniques that together
have advanced the study of the brain, memory, and learning.
In the past six years, the M.R. Bauer Distinguished Guest
Lecturer Series has brought an impressive list of some
of the most outstanding neuroscientists in the world to
the University. Both programs have greatly benefited our
faculty and students through their contacts with the Bauer
Colloquium speakers and Distinguished Guest Lecturers.
These visitors, in turn, have encountered the exciting
research and learning environments at the Volen Center
and strengthened the web of collegiality that draws neuroscientists
together in a common enterprise. This booklet represents
an important part of the Volen Center's effort to reach
out to neuroscientists in the international community
in order to make this work more widely known and to continue
these scientific discussions and collaborations. With
sincere gratitude, I am pleased to recognize the support
of the M.R. Bauer Foundation for making these programs
possible through its foresight and generosity.
Arthur Wingfield, D.Phil.
Nancy Lurie Marks Professor of Neuroscience and
Director, Volen National Center for Complex Systems
