Topobiology; An Introduction to Molecular Embryology
Neural Darwinism; The Theory of Neuronal Group Selection
The Remembered Present: A Biological Theory of Consciousness
Bright Air, Brilliant Fire: On the Matter of the Mind
Edelman has asked the question: should we attempt to construct
models of functioning minds or should we attempt to construct models of
brains which through interactions with their surroundings can develop minds?
Edelman's answer is that we should make model brains and I think Edelman
is on the right track. Unfortunately, most folks who are trying to figure
out the brain can't seem to figure out Edelman. That's too bad. So, I must
start with my spin on the Study of Edelman: Dealing
with Edelman's writing.
My comments on Edelman can be found at the links listed below,
Edelman contents:
Neural
Edelmanism: his approach to Theoretical Neurobiology
Artificial
Intelligence Research vs. Theoretical Neurobiology
Molecular
Memory Mechanism in Neural Network Models
Selectionism
vs. Constructionism in Brain Function
Similarities between Edelman and Wittgenstein
Edelman's books can be taken as motivation for attempting a certain type
theoretical neurobiology, in which known mechanisms of synaptic plasticity
are put into brain network models. An example
of current work using molecular mechanisms of synapse plasticity in neural
network models:
In "MODELS
OF THE CEREBELLUM AND MOTOR LEARNING" by James
C. Houk, Jay T. Buckingham and Andrew G. Barto, they
describe attempts to use experimentally based cerebellar synapse modification
rules in models of motor learning. "Models of motor learning need to adopt
a rule for modifiying synaptic efficacy, hereafter referred to as a learning
rule. Preferably the learning rule should conform to, or at least be motivated
by, the cellular mechanisms that underlie neuronal plasticity in the region
(or regions) of brain that is (are) being modeled." The two learning rules
they have used are: rule #1, a rule based on the observed long-term depression
(LTD) that is observed in response to appropriate combinations of climbing
and parallel fiber activity in the cerebellum combined with rule #2, a
rule for long-term potentiation (LTP) in response to activity of parallel
fibers in the absense of climbing fiber activity. This group claims that
"Most cerebellar modeling studies have not attempted to conform to the
mechanisms of synaptic plasticity to this degree." They fault models that
use other less biologically motivated learning rules for not "addressing
the basic neurobiology of motor learning". They found that for their model
"The model's learning process was not robust enough to learn arbitrary
movements". They seem to suggest that the failure of their model might
be corrected by modifying the learning rule for purkinje cell synapses
so as to allow delayed feedback from climbing fibers (CFs) to correctly
modify the function of those purkinje cell synapses that were active initially,
before each wave of climbing fiber activity.
They put this cryptically as: "the cerebellar learning rule needs to
modify synaptic actions that occurred prior to a CF's discharge." In other
words, there seems to be a need for slow molecular mechanisms that would
mark synapses as having been in certain activation states at certain (fairly
long) specific times in the past. They fault synaptic physiologists for
not having adequately addressed this problem, that is, not yet having found
the type of slow synaptic modification mechanism that seems to be needed
according to the model. "The important point here is that climbing fiber
firing, in trials when it occurs, arrives several hundred msec after the
purkinje cell response that needs to be evaluated." They suggest that models
incorporating such a synaptic memory mechanism work better (Buckingham,
J.T., Houk, J.C., Barto, J.G. (1994) Controlling a nonlinear spring-mass
system with a cerebellar model. In: Proceedings of the Eighth Yale Workshop
on Adaptive and Learning Systems). They suggest the kind of experiment
that needs to be done to look for such a mechanism in the cerebellum. The
last paragraph in section 3.1 of their article extends this idea of involvement
of synaptic modification rules with different time-courses of action to
even longer-term responses that might convert synaptic function changes
into synaptic structural changes. The article also goes some distance into
the issue of interactions of cerebellar cortex with other brain regions.
It seems that Edelman was ahead of his time and not very good at communicating
with his target audience. Individual researchers struggle to achieve the
kind of bredth in scope displayed by Edelman, since they are more concerned
with the details. It seems like more cooperation
between research groups and a central collection site for information would
help everyone. It might even give us mortals a chance to catch up with
Edelman.
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Book Page.
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Home Page.
send email to:
John William Schmidt
Notes
Proceedings of the National Academy
of Sciences Volume 93, Number 05; Pages: 1892-1896 Neurobiology
Embryonic expression patterns of the neural cell adhesion
molecule gene are regulated by homeodomain binding sites
Yibin Wang, Frederick S. Jones, Leslie A. Krushel, Gerald
M. Edelman
ABSTRACT During development of the vertebrate nervous
system, the neural cell adhesion molecule (N-CAM) is expressed in a defined
spatiotemporal pattern. We have proposed that the expression of N-CAM is
controlled, in part, by proteins encoded by homeobox genes. This hypothesis
has been supported by previous in vitro experiments showing that products
of homeobox genes can both bind to and transactivate the N-CAM promoter
via two homeodomain binding sites, HBS-I and HBS-II. We have now tested
the hypothesis that the N-CAM gene is a target of homeodomain proteins
in vivo by using transgenic mice containing native and mutated N-CAM promoter
constructs linked to a beta-galactosidase reporter gene. Segments of the
5' flanking region of the mouse N-CAM gene were sufficient to direct expression
of the reporter gene in the central nervous system in a pattern consistent
with that of the endogenous N-CAM gene. For example, at embryonic day (E)
11, beta-galactosidase staining was found in postmitotic neurons in dorsolateral
and ventrolateral regions of the spinal cord; at E14.5, staining was seen
in these neurons throughout the spinal cord. In contrast, mice carrying
an N-CAM promoter-reporter construct with mutations in both homeodomain
binding sites (HBS-I and HBS-II) showed altered expression patterns in
the spinal cord. At E11, beta-galactosidase expression was seen in the
ventrolateral spinal cord, but was absent in the dorsolateral areas, and
at E14.5, beta-galactosidase expression was no longer detected in any cells
of the cord. Homeodomain binding sites found in the N-CAM promoter thus
appear to be important in determining specific expression patterns of N-CAM
along the dorsoventral axis in the developing spinal cord. These experiments
suggest that the N-CAM gene is an in vivo target of homeobox gene products
in vertebrates. Go
Back.
Silencer Elements Modulate the
Expression of the Gene for the Neuron-Glia Cell Adhesion Molecule, Ng-CAM
Volume 270, Number 36, Issue of September 08, pp. 21291-21298,
1995
Pekka Kallunki , Stephen Jenkinson, Gerald
M. Edelman , Frederick S. Jones
ABSTRACT The combined factors that regulate the expression
of cell adhesion molecules (CAMs) during development of the nervous system
are largely unknown. To identify such factors for Ng-CAM, the neuron-glia
CAM, constructs containing portions of the 5` end of the Ng-CAM gene were
examined for activity after transfection into N2A neuroblastoma and NIH3T3
cells. Positive regulatory elements active in both cell types included
an Ng-CAM proximal promoter with SP1 and cAMP response element motifs extending
447 base pairs upstream of a single RNA start site and a region within
the first exon corresponding to 5`-untranslated sequences. Negative regulatory
elements included five neuron-restrictive silencer elements (NRSEs) and
a binding site for Pax gene products in a 305-base pair segment of the
first intron. Constructs containing the promoter together with the entire
first intron were active in N2A cells but were silenced in NIH3T3 cells.
This silencer activity was mapped to the NRSEs. In contrast, the Pax motif
inhibited activity of Ng-CAM constructs in both cell types. The DNA elements
defined in these transfection experiments were examined for their ability
to bind nuclear factors. The region within the first exon formed a DNA-protein
complex after exposure to nuclear extracts prepared from both NIH3T3 and
N2A cells. The NRSE region formed a more prominent complex with proteins
prepared from NIH3T3 cells than it did with extracts from N2A cells. A
member of the Pax protein family, Pax-3 bound to the Pax motif. Mutations
introduced within the Pax motif in its ATTA sequence eliminated this binding
whereas mutations in its GTTCC sequence did not, suggesting that paired
homeodomain interactions are important for the recognition of Pax-3 by
this DNA target sequence. The combined data suggest that negative regulation
by NRSEs and Pax proteins may play a key role in the place-dependent expression
patterns of Ng-CAM during development. Go
Back.
Neoteny.
See: Neotony
in Human Evolution by Dr. D. R. Johnson
See some recent
work from Ralph-Axel Mueller where he refers to S.J. Gould:
"Gould's (Stephen J. Gould, 1977. Ontogeny
and Phylogeny. Cambridge {Mass.}: MIT Press.) hypothesis that the
vast phenotypic changes during hominization were due to limited changes
in regulatory genes leading to heterochrony, i.e. alterations in developmental
schedules and an extension of the period of juvenile plasticity (neoteny)."
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Back.
Go to John's
Book Page.
Go to John's
Home Page.
send email to:
John William Schmidt