93
Bioscience Reports 4, 93-98 (1984)
Printed in Great Britain
N e w concepts on the structure o f the neuronal networks:
The miniaturization and hierarchical organization
of the central nervous system*
Hypothesis
Luigi F. AGNATI and Kjell FUXE
Department of Human Physiology, University of Modena,
Modena, Italy; and Department of Histology,
Karolinska Institutet, Stockholm, Sweden
(Received 5 January 1984)
The h y p o t h e s i s is i n t r o d u c e d that miniaturization of
neuronal circuits in the central nervous system and the
h i e r a r c h i c a l organization of the various levels, where
information handling can take place, may be the key to
understand the enormous capability of the human brain
to store engrams as well as its astonishing capacity to
reconstruct and organize engrams and thus to perform
highly sophisticated integrations.
The concept is also
proposed that in order to understand the relationship
between the structural and functional plasticity of the
central nervous system it is necessary to postulate the
existence of memory storage at the network level, at
the local c i r c u i t level, at the synaptic level, at the
membrane l e v e l , and finally at the moIecular level.
Thus, memory organization is similar to the hierarchical
o r g a n i z a t i o n of the various levels, where information
handling takes place in the nervous system. In addition,
each higher level plays a role in the reconstruction and
o r g a n i z a t i o n of the engrams stored at lower levels.
Thus, the trace of the functionally stored memory (i.e.
its reconstruction and organization at various levels of
storage) will depend not only on the chemicophysical
changes in the membranes of the local c i r c u i t s but also
on the organization of the local circuits themselves and
their associated neuronal networks.
Introduction
In previous papers ( l , # ) we have focused our attention on the
possible functional meaning of local circuits. Local circuits, according
to Rakic (IG,18), are defined as any portion of neurons that under
given conditions function as an independent integrative unit.
In this
f r a m e we have introduced the heuristic hypothesis that islands of
receptors located on pre- and postsynaptic membranes of local circuits
can be formed by means of receptor-receptor interactions, favoring
certain types of electrotonic sequences in the local circuits. We have
*Dedicated to Prof. R. Luft for his outstanding achievements in
endocrinology and his provocative and inspiring discussions in
biology.
01984
The Biochemical Society
9#
AGNATI
& FUXE
called this hypothesis the receptor-mosaic hypothesis of the engram.
This hypothesis underlines the role of the local cirucits for learning
and memory and is in line with the view of Ramon y Cajal (17) (see
also 7), who emphasized the importance of local c i r c u i t neurons for
complex and integrated behaviors, suggesting that these local c i r c u i t
neurons may represent the basis for human intelligence.
It has also
been reported (16) that a relationship exists between the number of
local c i r c u i t neurons per unit area of certain brain regions and the
degree of phylogenetic development. It remains to be shown, however,
whether the local circuits are found in higher concentrations in the
most phylogeneticaIIy r e c e n t regions of the central nervous system
(CNS), that is, within the neocortex.
When discussing the functional
role of local circuits i t should be mentioned that in the vertebrates all
sensory pathways at a certain level of the neuroaxis have at least one
region, or more often several regions, where local circuits are highly
concentrated. Thus, it is in those areas where complex integrations of
sensory inputs may take place.
In the present paper we will introduce the concept that local
c i r c u i t neurons represent a step in the 'miniaturization' of the neural
networks and that this event can be an i m p o r t a n t feature for the
e m e r g e n c e of the h i g h e r b r a i n f u n c t i o n s under the pressure of
evolutionary forces.
Present Hypothesis
In the past decade i t has become evident that the synapses had a
set of homeostatic mechanisms which tend to maintain the constancy
of the synaptic transmission despite disturbances. In this context it is
enough to quote the phenomenon of up and down regulation of the
postsynaptic receptors, which can be shown by chronically decreasing
or increasing the presynaptic release of the transmitter (19).
We
have suggested, however, that there are also 'heterostatic mechanisms',
i.e., mechanisms capable of displacing the synaptic transmission from
its set-point. Furthermore, the existence of more transmitters at the
presynaptic level, of more than one receptor for one transmitter at
the postsynaptic level, and of the possible receptor-receptor interactions (9) has led us to propose the view of the synapse as a device
endowed with multiple transmission lines interacting with each other
(2).
We have also considered that the discovery of receptor-receptor
interactions at various levels of the central nervous system may be
i m p o r t a n t in e x p l a i n i n g in a logical frame the putative role of
co-transmitters in the synaptic function o r more generally the role of
local circuits in the high integrative functions of the brain (9). Thus,
we consider the receptor-receptor interactions as an example of the
many p e c u l i a r b i o c h e m i c a l mechanisms w h i c h can increase the
heterostatic regulation of the synapses, and hence can be an important
phenomenon in evaluating the function of local circuits, which are in
regions where synaptic cont act s are highly c o n c e n t r a t e d .
The reason
for the profound importance of local circuits, e.g. in learning and
memory, does not only r e l a t e to the increase in their numbers but to
the 'miniaturization' of the neuronal circuits which they make possible.
In line with the development of computers from very large machines
to the miniaturized but very powerful ones now available, the brain
has increased its integrative capacity by using local circuits; by means
BRAIN
ORGANIZATION
95
o f e l e c t r o t o n i c and biochemical handling of the information~ these
circuits allow the p e r f o r m a n c e of integrative functions in small areas
of the nerve-cell membranes.
In this way instead of dramatically
increasing the nerve-cell population in order to increase the number
and capabilities of the neuronal networks in the brain, a phenomenon
that would have led to a vast increase of brain size, miniaturization
has taken place.
By means of the local circuits and of synapses
w o r k i n g along m u l t i p l e t r a n s m i s s i o n lines with r e c e p t o r - r e c e p t o r
inl:eractions the development of an e x t r e m e l y advanced central nervous
system in man has occurred without an inappropriate increase of brain
size.
In other words a dr a m at i c development of the logic power of the
cen tr al nervous system may take place by means of miniaturization.
C o m p l e x integrations may now occur without occupying the highly
divergent neuronal networks of the brain, which are free to analyze all
thiLs information. So our hypothesis is t hat the miniaturization process
induced by the formation of local circuits and of multiple transmission
lines at the synaptic level leads to the development of an advanced
cen tr al nervous system capable~ by means of its local circuits or part
of them, to perform integrative actions, which in a simple nervous
system can be per f or m ed only by an entire neuronal network (see Fig.
i).
In t h e advanced central nervous system the highly divergent
neuronal networks have functions other than just performing various
simple tasks: they are controllers of populations of locat circuits. The
profound miniaturization p r o c e s s and the hierarchical organization of
the various levels in the CNS have freed networks to respond or not
to respond to local circuit act i vi t y in various brain areas.
Thus, it
may be considered (Fig. l) t hat neuronal networks can be hierarchically organized. Neuronal networks of a high hierarchical level may be
the overall decision neurons of the brain, considering the rel evance of
the information obtained. In other words these neuronal networks may
represent the substrate for the so-called 'consciousness' found in the
most advanced brain (for a discussion on the definition of consciousness, see ( 6 ) ) .
Engram Storage and Elaboration
We suggest that the engram is stored not only at the level of the
local circuit (3,4)~ but also at the molecular, membrane, synapti%
l o c a l c i r c u i t , and n e u r o n a l network levels.
So in principle, the
possibility should be considered that engrams can be organized and
read out at these various levels. F u r t h e r m o r e , since both a t synaptic9
local circuit, and network level the possibility exists of structural and
functional plasticity changes, it should be emphasized that some types
of l e a r n i n g o c c u r r i n g in e a r l y life, such as the development of
perception or social behavior (11), may depend mainly on structural
changes in neuronal networks while other forms of learning, however9
like the ability to record a telephone number~ may depend upon the
functional plasticity of the neuron systems and can take place at the
membrane, molecular, synaptic, and local circuit level. This opens the
way to p o s t u l a t e m echani s m s by which changes in the structural
plasticity of the CNS could be integrated with the changes found in
t h e f u n c t i o n a l p l a s t i c i t y o c c u r r i n g at the local circuit, synaptic,
membrane, and molecular level. The engrams stored at the membrane
96
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Fig. i. Schematic illustration of our hypothesis on
the structural organization and levels of handling
information in the nervous system.
level could be organized and elaborated upon at the level of the
synapse.
In turn, the engrams stored at the synaptic level could be
organized
and e l a b o r a t e d
a t t h e l e v e l of t h e l o c a l c i r c u i t .
F u r t h e r m o r e , the engrams present at the local circuit level could be
organized and elaborated upon at the network level (see Fig. I ) . This
hypothesis on the organization of memory is supported by observations
of P i a g e t et al. (15).
In these experiments it was shown t hat
children who at an early age do not c o r r e c t l y perform ranking of signs
of various length may do so six months later without again being
exposed to the test.
This change is probably due to the development
of a new level of engram organization and elaboration. The explanation could be that the children may have originally stored the single
pieces of information but needed another level of the organization of
the engram to be able to rank in a proper way the bits of information
obtained.
F u r th er support for our view may also be obtained from m em ory
organization if we assume that t here is a gradient of the density of
local circuits along the neuroaxis with the lowest value at the spinal
cord level (the most ancient part of the central nervous system) and
the highest value at the level of the cortical mantle (the most r e c e n t
part of the central nervous system) (16). It is known that the spinal
cord can perform basic operations but these are not as sophisticated
as tho~e p e r f o r m e d at higher levels, and t here is no 'subjective'
e v a l u a t i o n of t h e o p e r a t i o n p e r f o r m e d .
Such evaluations may,
however, c o m m e n c e at the thalamic level (7) where the information
has already passed through networks possessing local circuits.
The
BRAIN
ORGANIZATION
97
spinal cord can learn simple tasks and so store information, but it
s e e m s u n a b l e to d e v e l o p t h e s a m e complex organization of the
e n g r a m s as is found at higher levels.
This may be because the
functional requirements of the spinal cord are such that a limited
c a p a b i l i t y of elaboration is sufficient for the p e r f o r m a n c e of the
r e f l e x e s and f or t h e i r integration with the descending influences.
Alternatively, it may be conceived that in the cerebral c o r t e x the
functional requirements for engram storage are much more sophisticated, and the d i f f e r e n c e in its abilities from those of the spinal cord
is due to a d r a m a t i c increase in the hierarchical organization of
various levels and the increased capabilities of storage of engrams. It
seems reasonable that the various local circuit populations can be
organized by the well-known functional unit of the cortex, the columns
([0,14).
T he n e u r o n a l n e t w o r k s o p e r a t i n g at various levels of
integration then allow communication between and organization of the
l o c a l c i r c u i t p o p u l a t i o n s , m a k i n g possi bl e highly s o p h i s t i c a t e d
integrative processes.
With e v o l u t i o n (see Fig. 2) the functional organization of the
nervous system moves from the network level to the local circuit
leve% from the local circuit level to the synaptic level, from the
synaptic level to the membrane level, and from the membrane level to
the molecular level.
Developing in parallel are more and more
overlying integrative networks, which do not perform basic elaborations
but can evaluate them.
Thus, these networks, which have a higher
hierarchical level, can 'see' from above the input/output operations of
the organism. Each higher level can play a role in the reconstruction
and reading out of the engrams stored at the lower levels.
So this
view may also e x p l a i n why a limited lesion can never eliminate
specific m em or y traces.
Instead, lesions can only disturb learning or
memory recall (12,13,20).
During the physiological process of aging there is, from a structural
standpoint, a reduction in the number of local circuits available, due
to degeneration of nerve terminals and dendritic r e t r a c t i o n even before
any major failure of networks has taken place (5). From a functional
standpoint, higher integrative brain functions tend to decline with age
and, as does memory, especially r e c e n t memory (g). F u r t h e r m o r e , we
h a v e d e m o n s t r a t e d that during aging, r e c e p t o r - r e c e p t o r interactions
may disappear. Thus one of the mechanisms involved in the functional
plasticity no longer works e f f i c i e n t l y (1). These observations may be
~nterpreted in the f r a m e of the present hypothesis, since the structural
changes mentioned above lead to a loss of local circuits.
This will
[ EVOI,.UTION
/~-'r
~31~I OF
INTfQlltATION
NIW8
THE NERVOdUSIrfWTEM
Fig. 2.
Schematic illustration of our hypothesis
the evolution of the nervous system.
on
9g
AGNATI
& FUXE
l e a d to a d e c r e a s e in the m i n i a t u r i z a t i o n and in the h i e r a r c h i c a l
o r g a n i z a t i o n of the CNS and h e n c e to a d e c r e a s e in its p e r f o r m a n c e
of higher i n t e g r a t i v e functions as well as in its c a p a b i l i t y to r e t r i e v e
and elaborate
the memory
traces.
T h e r e d u c t i o n in f u n c t i o n a l
p l a s t i c i t y m a y also, a t l e a s t in p a r t , explain the r e d u c e d c a p a b i l i t y of
the aging brain to s t o r e new i n f o r m a t i o n .
Acknowledgements
T h i s w o r k h a s been s u p p o r t e d by a g r a n t ( 0 4 X - 7 1 5 ) i r o m the
Swedish Medical R e s e a r c h Council, by a g r a n t f r o m L. O s t e r m a n ' s
Foundation and by a C N R I n t e r n a t i o n a l g r a n t .
We a r e g r a t e f u l to Drs.
M. Zoli and E. Merlopich for useful discussions and to Mrs. L e n a
Sunnas for e x c e l l e n t s e c r e t a r i a l a s s i s t a n c e .
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