[Comp-neuro] Discussion - cerebellum not philosophy

james bower bower at uthscsa.edu
Fri Aug 22 20:03:12 CEST 2008


>>

While I have left the more general discussion behind -- am happy to  
answer questions about the details of the systems I work on (which of  
course, I would claim reinforces my arguments on the larger issues -  
or another way to put it -- where my concerns have come from. )

>>
>
> Let me get this straight--granule cell axons first synapse strongly  
> on a single Purkinje cell and then split into parallel fibres,  
> synapsing weakly (both directly and indirectly via interneurons)

Granule cell axons make multiple synapses on overlying Purkinje cells  
as they course vertically into the molecular, although we don't yet  
know if a single granule cell makes those multiple synapses on a  
single Purkinje cell).  Once parallel fibers bifurcate, they make only  
one synapse.  This was first described to the cerebellar world 25  
years ago, but has largely been ignored since -- a good example of -  
'the tyranny of ideas'.  The synapse of the parallel fibers is not  
weaker in any biophysical sense (this has been demonstrated  
experimentally), instead the network appears to be organized so that  
local parallel fiber excitation is counterbalanced by local molecular  
layer inhibition - we have suggested, in effect, producing a voltage  
clamp control of the local dendrite.

(most recent paper, and see references for earlier experimental work:  
Santamaria, F., Tripp, P., and Bower, J.M. 2007  Feed-forward  
inhibition controls the spread of granule cell induced Purkinje cell  
activity in the cerebellar cortex. J. Neurophysiol. 97: 248-263.)

> on a large number of other Purkinje cells. So the output of a  
> Purkinje cell is dominated by a few granule cell axons and is tuned  
> by a large population of parallel fibres.

we have used the more nebulous (and undefined) 'modulated by"  but  
don't yet know the nature of the modulation.  We are working on that  
both experimentally and computationally.

What does the climbing fiber do?

Calcium conductances (and associated potasium conductances) are the  
dominate form of ionic conductances in the Purkinje cell dendrite

(Jaeger, D., and Bower, J.M.  (1999)  Synaptic control of spiking in  
cerebellar Purkinje cells:  Dynamic current clamp based on model  
conductances.  J. Neuroscience. 19:6090-6101.)


-- larger in sum by a factor of 5 over the synaptic conductances.   
Numerous of our modeling and experimental papers suggest that it is  
the state of activation of these conductances that influences somatic  
spiking - Given the relatively long time constants of the Ca related  
conductances, the influence of the pf/mli voltage clamp is likely to  
be 'felt' in the dendrite for 10s of milliseconds.  I have suspected  
for a long time that the climbing fiber does exactly what it looks  
like it does - floods the cell with Ca.  Our guess at the moment (also  
subject to experimental study), is that the climbing fiber resets the  
dynamics of the dendrite, wiping out the previous 100's of miliseconds  
of pf influence.  Our previous experimental work has suggested that  
the timing of the cf, at least in the parts of the cerebellum we  
study, is under control of the cerebral cortex, which therefore  
appears to influence, if not control, this dendritic resetting.  

(Brown, I.E., and Bower, J.M. (2002)  The influence of somatosensory  
cortex on climbing fiber responses in the rat cerebellum following  
peripheral tactile stimulation.  J Neurosci. 22(15): 6819-6829.)

We have spent the last 5 years reconstructing using serial electron  
microscopy (very hard) 5 - 8 micron lengths of the purkinje cell  
dendrite and identifying the location and type of every synapse  
(excitatory and inhibitory) along those lengths.  We ware now using  
this data to build realistic simulations to test the voltage clamp  
idea.  With respect to nested multi-scale simulations -- with GENESIS  
3.0, we will be able to nest these high resolution models of what are  
in effect single compartments in our compartment models, into the  
compartmental model of the Purkinje cell - this will be, to my  
knowledge, the first ever simultaneous simulation within a single  
model of two fundamentally different levels of realistic scale and is  
a technical feat.  So comments made earlier that this kind of thing  
hasn't yet happened, is true, suggestions that it is not possible, are  
not true -- it is possible, simply requires a development of new  
tools, which we are doing - driven by the scientific questions we now  
need to answer using realistic models.

With respect to the tyranny of ideas,

In my view, the fact that the climbing fiber results in large calcium  
influx has been "borrowed" by those who believed, a priori, in the  
Marr/Albus cerebellar learning theory as a mechanism to provide  
calcium.  In fact, the parallel fibers all by themselves can provide  
the calcium.  Similarly, LTD has been "borrowed" as well -- but is  
much more likely to be a homeostatic mechanism to regulate the balance  
between pf excitation and molecular layer inhibition -- a balance we  
have suggested is essential for the ongoing modulation of the  
dynamical state of purkinje cell dendrites.  The fact that LTD is not  
specific to active synapses, but spreads to all nearby synapses  
clearly suggests this kind of homeostatic regulation, not associative  
learning (again ignored by high level models).  Two concrete examples  
(and perhaps eventually classical examples if I have anything to do  
with it) of the tyranny of ideas, and the risk of seeking experimental  
support for an otherwise abstract but alluring idea built from a  
cartoon-level understanding of brain structure.  BTW, Marr himself  
recanted the theory later, recognizing it as being exactly that (he  
was a smart guy), but that didn't keep and doesn't keep  
neurobiologists from endlessly trying to prove him right anyway.

More on all this:

(see  Bower, J.M. (2002) The functional organization of cerebellar  
circuitry reconsidered.   In:  Highstein, Stephen M, and Thach, Tomas.  
W. eds), The Cerebellum: Recent Developments in Cerebellar Research.   
Annals of the New York Academy of Sciences. Vol. 978  pp. 135-155. )


>
>
> I understand that a major part of the cerebellum is used to  
> propagate motor plans forward (and backwards). How does the  
> cerebellar architecture support that function?

In short, it doesn't -- this may be the ultimate example of the  
tyranny of ideas - as this particular idea, the cerebellum is a motor  
control device, has more than a 150 year history, and has actually  
destroyed the careers of naysayers (I am stubborn however).  And a nod  
here to my cognitive friends -- human brain imaging has finally blown  
the lid off this 150 year history, demonstrating, among other things,  
that the cerebellum is not active when it is supposed to be (given the  
classical theory) and is active when it isn't supposed to be

see Gao, J-H., Parsons, L.M. ,  Bower, J.M., Xiong, J.,  Li, J., and  
Fox, P.T.  (1996) Cerebellum implicated in sensory acquisition and  
discrimination rather than motor control.  Science , 272: 545-547.)


  -- however, sadly, having made a giant leap forward, our cognitive  
friends  have now made a giant leap sideways, or upwards, or  
something, with all kinds of structure independent conjectures about  
the "cognitive function of the cerebellum" whatever that is.

a paper with easy access on this issue:  Bower, J.M. and Parsons, L.  
(2003)  Rethinking the Lesser Brain,  Scientific American 289: 50-57.

For those who want a more in depth  reconsideration of the function of  
the cerebellum - you will have to wait for the second book I am writing:

"Is the cerebellum sensory for motors sake, or motor for sensory sake?"

However, as I said, the cerebellum is an excellent and very practical  
and totally obvious example of many of the ills in neuroscience and  
modeling in neuroscience that I have referred to in the general  
discussion.

Jim Bower






>
>
> --
> "If academic research is not devoted to finding the truth, it is a  
> form of propaganda, and not necessarily to be preferred to other  
> forms, much cheaper and perhaps more persuasive." (Russell 1993)
>
> Harry Erwin
>
>
>
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==================================

Dr. James M. Bower Ph.D.

Professor of Computational Neuroscience

Research Imaging Center
University of Texas Health Science Center -
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