- Email: [email protected]
Complex microstructures of sensory cortical connections
545
Complex microstructures
of sensory cortical connections
Kathleen S Rockland The neocortex organization. structure studies
has a distinctive Although
and function
microstructure. are rapidly intracellular designed
remain
a finer scale of synaptic
New findings
emerging
concerning
from approaches
recordings
of cell and synaptic
questions
at this level of organization,
are addressing
network in which
in vitro are combined
morphology,
to label multiple
systems),
laminar and modular
important
regarding recent
and network properties dual or triple
with analyses
as well as from experiments
cell populations.
review lesser
Iowa City, Iowa 52242-l e-mail:
053,
of Iowa, 200
Hawkins
Drive,
USA;
[email protected]
Current
Opinion
0 Current
Biology
in Neurobiology
Publications
1998,
8:545
-551
ISSN 0959-4388
Abbreviations co EM
cytochrome oxidase electron microscopic/microscopy
EPSP GABA
excitatory
on rodent
somatosensory
cortex.
although an important component are not addressed, and modeling
have also been
largely
identification is central
and
The to a
Cortical
of cortical approaches
excluded.
Neuronal types: elements networks types
University
extent,
oscillations, organization,
The Addresses Department of Neurology,
as a commentary on the ‘state-of-the-field’. focuses mainly on the visual cortex and,
of circuits and
characterization
to understanding
of neuronal cortical
sub-
organization,
and considerable progress has been made over the past 20 years. Cortical neurons can be classified into distinct subtypes of interneuron (mostly inhibitory) and projection neuron (i.e. pyramidal neurons). Classification has been easier for interneurons, and a small number of major categories of interneuron has been established on the basis of multiple correlative criteria (e.g. dendritic and axonal morphology, axonal connectivity, peptide co-localization, and firing patterns; see use of single criterion approaches, expected.
finer
[Z] for a recent review). Through [3] and multiple criteria [4”]
classification
of
interneurons
can
be
defined
on
postsynaptic
potential
IPSP
y-aminobutyric acid inhibitory postsynaptic
potential
LM
light microscopic/microscopy
Subcategories
VI v2
primary visual cortex secondary visual cortex
the basis of the correlation between projection targets, the particular dendritic morphology of the efferent neurons, and the branching patterns of their local axon collaterals [5,6]. This approach remains useful, and has been complemented by newer modifications, such as in vitro intracellular fills [7] and single-neuron fills by juxtacellular injections [S]. Immunohistochemical’ markers, either alone [9*] or in combination with other markers, provide another mearis of classifying pyramidal neurons. For example, SMI 32, an antibody against nonphosphorylated neurofilaments, is reported to co-localize in characteristic proportions with connectionally distinct subpopulations [lo].
Introduction Cortical organization is commonly discussed in terms of a columnar or modular architecture. Although there is considerable evidence supporting a columnar organization, the issue is complex-a system as basic as the ocular dominance columns of primates is still not fully understood anatomically and even less so functionally. The problem is compounded by the dynamic and plastic elements of cortical organization, in the sense that structure and function do not necessarily have any direct, immutable relationship. Factors such as synaptic weight and selective interaction among convergent inputs are now known to effect significant contextually related changes in neural architecture [ 11. Papers from the past year fall primarily into three groups. One group deals with the continuing effort to establish a functionally meaningful taxonomy of cell types. A second based largely on physiological recording from group, pairs of identified neurons, is concerned with elucidating connectivity rules, or network ‘syntax’. The third group attempts an even more fine-grained investigation of modular systems, in terms of their substructure and dynamics. Although no unifying framework has yet emerged, this review is organized around these three themes (i.e. cell types, network properties, and modular
of projection
neurons
have been
The prospect of an ever more finely fractionated ‘alphabet soup’ poses serious problems of functional significance and may not be entirely welcome. Systematic correlations of multiple criteria, however, such as firing patterns and biochemical patterns of co-expression [4**], raise the interesting prospect of something resembling a periodic chart of classification, whereby populational characteristics might be linked to different areas and/or functions.
Network properties of intrinsic connections Individual neuronal elements interact within networks of interneurons and pyramidal cells, but facts and principles of network organization are relatively scant. Some data on the synaptic organization of connections have been provided by electron microscopic (EM) analyses (see e.g. [ll-131). These pertain to the location and number of synapses between different neurons.
546
Sensory
Most
cortical
systems
neurons
appear
wide variety of postsynaptic proportions [2,13]. However, especially interneurons, of synaptic specificity. interneurons in primate
to form
synapses
elements, albeit some populations
with
a
in different of neurons,
appear to have a high degree For example, calretinin-positive area Vl (but not V2 or frontal
areas) have a laminar-specific synaptology, in that they form symmetric synapses with GABAergic elements in the upper layers, but with pyramidal cells in the deeper layers [ 14’1. An
interesting
new
finding
is that
the
degree
1 mV
of self-
innervation (‘autapses’) may be greater than previously believed for at least two cell types. Tarn& et al. [15*] have recently reported that GABAergic basket cells and dendrite-targeting interneurons have a higher number of autapses neurons.
than either double-bouquet cells or pyramidal They postulate that extensive self-innervation
may modulate integrative properties and/or pattern of these particular neurons in a manner correlated with their own activity.
-62
mV
the firing temporally
As sample sizes in EM studies are necessarily small, there are major gaps in the database. As summarized by Jones et al. [Z], “What is missing.. is knowledge of the relative contributions of individual forms of GABA cells to the inhibitory input to a single pyramidal cell, the degree of convergence of inputs from members of the same (or other) GABAergic cell class, and the variations that occur in these parameters among pyramidal cells of different types.. ”
A more network labeling
recent, powerful approach for characterizing organization is the combination of intracellular and EM analyses with dual or triple intra-
cellular recordings i~r vitro. This combined anatomical/physiological approach provides highly specific structural data regarding the number and location of synapses between interconnected neurons [ 16”, 17**, 18*, 19”,20”]. Using this approach, hlarkram et al. [16”] found tliat pairs of thick, tufted pyramidal neurons in layer 5 make four to eight synapses. Buhl et al. [17**] found that pyramidal-to-interneuron connections also invo!ve small numbers of synapses (i.e. one to two or five to seven, depending on the type of postsynaptic neuron); however, Tam& et al. [ 18*] have reported that the connections from interneurons to pyramidal neurons appear to involve more synapses-up to 17, depending on the cell type. Aside from articulating rules of anatomical interconnectivity, this approach is well suited for investigating functional properties of local synaptic connections, and the relationship between structure and function (see Figure 1). Partly at issue is what parameters determine synaptic efficacy. Recent work reports that these parameters may be tightly correlated with different classes of connections. Thomson and Deuchars [19**] found that higher presynaptic firing rates result in frequency-dependent, incre-
-67
mV
-62
mV
Current Op,n,on ,n Neurobiology
Intracellular interconnected architecture
recordings neurons
from histologically permit
and investigation
identified
quantitative
analysis
of the physiological
pairs of of network properties
of
local synaptic connections [15*,16**,17”,1 El’,1 9**,20**1. This schematic summary (modified slightly from figure 2 of Thomson
and
Deuchars [19*4) represents several local inputs to pyramidal cells (P). Typical synaptic locations (small filled circles) and averaged IPSPs are shown at the left for four types of inhibitory interneurons (CFS, classical fast spiking; LTS, low threshold spiking; RS, regular spiking;
?, unclassified
synaptic locations pyramid-to-pyramid (Pl)
or slow spiking).
Two averaged
EPSPs
and
(small triangles) are shown at the right for two pairs. EPSPs generated by nearer pyramidal cells
arise in the basal dendrites
and have a faster time course
than
more distal apical inputs, arismg from presynaptic pyramldal cells separated by > 100 km (P2). The number of active synapses required to fire a cell varies with different conditions. For example, EPSPs are typically large between closely neighboring pyramidal cells in layer 5, and small in the case of connections from layer 5 to layer 3 pyramidal cells.
mental facilitation of pyramidal-to-interneuron, but not of pyramidal-to-pyramidal connections. Moreover, efficacy may be labile. Synaptic connections between thick, tufted pyramidal neurons are reported to show a ZO-fold range in efficacy, which is attributed, primarily, to differences in
Complex microstructures
transmitter
release
probability
(16”,20”].
This
result
has
been interpreted to imply that a single target neuron in the network of layer .5 pyramidal cells can be recruited to ensemble activity by the synchronous activation of as fe\\ as five strongly interconnected neighboring neurons, or of as many as 100 weakly interconnected neurons. similar combined anatomical/ In the hippocampus, physiological experiments have redefined interneuronal subtypes. and have shown that interneuronal netlvorks regulate various aspects of pyramidal cell operations. including cooperati\,e synchrony and plasticity [21,22]. It seems likely that in the ncocortcx, as in the hippocampus, highly constrained inhibitory networks will be found to have prccisc and important ensemble activit)- [ 16*“].
functional
roles
in controlling
more
of sensory cortical connections
fragmentary
than
for
Rockland
thalamocortical
547
connections
(see [28] for a recent review). There is little information concerning postsynaptic distributions of cortico-cortical their interactions with other systems, or connections, anatomical/physiological correlations. At least two major categories of cortical connections occur in the early sensory areas, ‘feedforward’ and ‘feedback’. These systems originate from neurons in different terminal Because
layers. terminate in different layers, and have arbors with different spatial characteristics [28]. feedback connections terminate predominately
in layer dendrites
1, they are thought to target selectively apical of underlying pyramidal neurons. In rodents
[B], although not necessarily in primates [28], feedback connections have an unusually high proportion (97%) of direct excitatory contacts.
Network properties of extrinsic connections liltimatcly, tions with
we nitt need to understand extrinsic connccthe same anatomical/physiological detail as is
emerging for intrinsic net\vorks (described surprisingly, if only because of the spatial these
systems,
this has been
harder
abo\.e). Not dispersion of
to achieve.
The thalamocortical system is the most accessible of the major systems of extrinsic connections. Their axonal featurcs, synaptic targets, and functional propcrtics have been the subject of several combined anatomical/physiological investigations (see e.g. [2,3]). ‘I’hatamocortical connections to primary cortical arcas are known to have driving, as opposed to modulator): effects. This finding, although well documented, is somewhat paradoxical, as thrrc arc fcwcr thalamocortical connections than intrinsic ones [24’], and the mechanisms elucidated.
underlying
these
effects
remain
whisker
varies
with
temporal
investigations to rely
had
mainly
of extrinsic on
cortical
indirect
connections
methods.
There
are modeling ‘experiments’, many closely informed by concrete data (see e.g. [30]) and analytic approaches, that attempt to translate bet\veen anatomical and functional connectivity [31’]. Innocenti et al. [32] describe a model of action potential timing in tvhich they used a computer to ‘inject’ currents into callosal axons with different gcomctric characteristics. In an interesting new approach, used visual stimulation under time intervals to map neuronal by measuring the expression of protein in primary visual cortex
Chaudhuri ft a/. [33**] different conditions and activity at a cellular level ~$268 mRNA and zif268 of primates.
to be
Scl-cral interesting ne\v findings have been reported in rodent barrel cortex. Iising cross-correlation techniques, S\vadlow PI a/. [25*] ha1.e demonstrated that a highly branched subgroup of thalamocortical connections contacts a population of inhibitory neurons and is involved in nctlvorks of synchronous inhibition. (Ising combined optical-imaging-stimLllation approach, Sheth rt a/. [Xi*] have shown that functional mappings in rat barrel cortex are more labile than anatomical mappings, and that the spread of cortical activation following the deflection of a single
Functional have
The connectional strength of extrinsic systems has been estimated by comparing the number of synapses in a target structure derived from different sources [34], or the number of neurons giving rise to different connections (table III in [B]). These are useful interim measures, but they are relatively insensitive. A recent study has reported significant discrepancies between the predicted anatomical strength of a connection (visualized by labeling with jI_I-amino acids) and the effects of cooling deactivation of the injected areas [35].
area on deoxyglucose
uptake
in several
target
frequency.
Cortical modules Ilow thalamocortical and cortico-cortical connections interact in the primary cortices is another important issue, but one which has barely been addressed. A recent study, using combined physiological recording and pharmacological manipulation in a thalamocortical slice preparation, reports specific and differential suppression/enhancement effects consequent to neuromodulators and activity [27*]. For extrinsic cortico-cortical from light microscopic (Lhl)
connections, investigations
most data arc and are even
hlodular organization at the scale of 0.1-0.5 mm is a robust feature of cortical sensory architectures. One of the most dramatic examples is the cytochrome oxidase (CO) compartmentation in areas Vl and V2, but new instances of modularity are still being discovered. There is, for example, a recent report of patches in the lateral suprasylvian cortex of cats that are preferentially dominated by thatamic inputs from lamina A or from the medial interlaminar nucleus (MIN) [36”]. There is another recent report of two systems in L’l concerned with
548
Sensory systems
Figure 2
The visual cortex crystalline
fashion.
has multiple Optical
and spatial frequency. as contour
modular
imaging
systems
of intrinsic
(a) Spatial frequency
lines): iso-orientation
that interrelate signals
yields
(gray regions
in complex
patterns.
high-resolution
correspond
lines tend to cross the borders
to modules
between
(dark gray) tend to avoid the borders
of ODCs.
Anatomical
color selectivity, blobs [37]. A reasonable and current systems will interdigitation. is evidence
neither
of which
studies
indicate
to the CO
hypothesis that has motivated much previous research is that different patchy or modular be tightly organized in a pattern of overlap or Although this possibility is attractive, there that it may not hold in all situations. Variable
are arranged
features low spatial
domains
in a nonrandom,
such as ocular frequency)
at right angles,
but not rigidly
dominance,
and orientation and ‘pinwheel’
orientation, maps (shown centers
favor
(ODCs) and orientation maps: iso-orientation lines tend to cross are in the middle of the ODCs. (c) Low spatial frequency domalns that horizontal
patterns may differ for excitatory et al. [43-l.
may be related
preferring
spatial frequency
the center of the spatial frequency modules. (b) Ocular dominance columns the borders between ODCs (shaded) at right angles, and ‘pinwheel’ centers functional characteristics, although the connectivity was modified from figures 4, 9 and 12 of Hijbener
The modules
maps for stimulus
intrinsic
and inhibitory
connections networks
tend to link zones with similar
(Kisvarday
et a/. [48”]).
This figure
visual cortex, there are many instances of only partial correspondence [43’]. Of the interlaminar connections in Vl from layer 6 to 4, some arc restricted to an overlying ocular dominance column, but others are not [44]. Intrinsic connections interlink ocular dominance columns, but only a subset of about 70% of the connections are confined to like-eye columns or to borders between columns [45,46].
patterns can occur as a function of species differences. In squirrel monkeys, unlike macaques, CO blobs do not
Horizontal intrinsic connections between orientation domains have been taken as a strong instance of like-to-like
align with Variability
connectivity. This has been strikingly confirmed by recent studies in the tree shrew. In this species, the horizontal connections between orientation domains exhibit sprcificity both for neuronal modules of similar orientation preference and for an axis in visual space that corresponds to the preferred orientation of the injection site [47”]. Even in this case, however, the pattern of connections within a radius of 0.5 mm from the injection site is less specific, with boutons found along every axis and thus contacting sites with a wide range of preferred orientations.
the centers of ocular dominance columns [38]. also occurs in different projection systems.
Patches of extrinsically projecting neurons from layer 3 of area Vl have been reported to match closely with CO compartments [39], but the groups of neurons in layer 4B projecting to llIT/VS do not seem to match with the overlying CO compartments [40]. Neurons in V2 projecting to V4 have a patchy distribution, but, again, this may not match exactly with the pattern of CO stripes [41]. In the cerebellum, various connectional or molecular markers reveal some kind of modular organization, but only some of the systems are co-registered by clear overlap or interdigitation [42]. Continuing investigations of cortical modularity similarly reveal instances of complex relationships between different feature mappings (see e.g. [43*] and Figure 2). In point of fact, it may be that of the several modular systems identified in the primate
In a recent high-resolution analysis of the relation between horizontal connections and orientation domains in areas 17 and 18 of the cat, Kisvarday et al. [48”] report that excitatory connections have only a moderate preference for iso-orientation, and inhibitory connections have an even weaker preference. In another study, hlalach rl al. [49] reported that there is only an approximate specificity in
Complex
the relationship and intrinsic
between horizontal
orientation connections
domains,
CO stripes,
in area \‘2 of squirrel
monkeys.
microstructures
of sensory
cortical
connections
Rockland
549
On a positive note, we have gained substantial insight into aspects of cortical workings. This is not the same as knowring how the cortex works, but is a significant step in that direction.
Some of the inexactness may be apparent only, and result from, problems in achieving matches between systems that are themselves complex. That is, horizonral intracorcical connections are a mix of inhibitory and excitatory connections [48”]. CO blobs in VI, CO compartments in \‘2 (50,51], and orientation pinwheels (i.e. singularity points where linear zones of iso-orientation converge) in Vl [SZ”] are all known to have that the many examples
substructure. Assuming, of weak or approximate
ho\i,ever, matching
are not artefactual, there are several interpretations. One interpretation is that the overall cortical organization is much more complex than we yet realize, even if all the components do fit into the machinery of a larger unit (or hypercolumn). A high degree of complexity is suggested by recent physiological mapping experiments that report correlated inhomogeneities in orientation and retinotop); [53**]. ‘I‘hese inhomogeneitics may, in turn, be subserved by intrinsic modules with a wide range of functional relations
[53”].
tween connectional systems. Some systems have terminal fields that are spatially delimited; others, that are spatial]) divergent (cortical feedforward and feedback populations, respectively [28]; or, in the somatosensory cortex, parvalbumin and calbindin thalamocortical populations [%I). at the
very
small
scale
of dendritic
and
axonal
bundles (
‘l‘hc authoris
\upportcd by I ISA fcdcrutf’undinp through the Nationst Scicncc t~wndmon (IUN Y421970) md the Nutionat Inatitutcs of Health (KIti i.35YX md NS lOh32).
References
and recommended
Papers of particular interest, published have been highlighted as: . l
.
reading
within the annual period of review,
of special interest of outstanding Interest
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Caull B, Audinat E, Lambolez B, Angulo MC, Ropert N, Tsuzuki K, Hestnn S, Rossier J: Molecular and physiological diversity of cortical nonpyramidal cells. J Neurosci 1997, 17:3894-3906. This multidisciplinary investigation combined electrophyslological whole-cell recordings in slices of rat sensory-motor cortex with the simultaneous detection of mRNA encoding for three calcium-binding proteins (i.e. calbindin, parvalbumin and calretlnm) and four neuropeptides (i.e. neuropeptlde Y, vasoactive intestinal polypeptide, somatostatin, and cholecystokinin) using singlecell reverse transcription PCR. Three broad subpopulations of cortical cells were identified on the basis of correlations between firing properties (i.e. fast spiking, regular spiking, and irregular spiking) and biochemical co-expression patterns; however, within two of these (fast and regular spiking), the pattern of expression of the biochemical markers itself was complex. The expression of neuropeptides did not seem to be tightly correlated with either the firing pattern or a particular calcium-binding protein. The authors conclude that the full charactenration of the elements comprising a homogeneous network may require additional parameters. 4. ..
Another interpretation is that cortical structure is fundamentally mixed, similar to the caudate nucleus, which has both patch and matrix compartments. There is some indication, for example, of a basic geometric dichotomy be-
Finally,
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Conclusions We are still far from understanding even the basic cortical machinery, let alone its modes of operation. In part, this is simply because we do not know enough. hlany questions remain. At the cellular level, what are the fundamental classes of pyramidal and nonpyramidal cells? At the network level, what are the operational rules and dynamics! How do network subsystems interact? At the modular level, how many systems are there in a given area? Do they interrelate in a regular or approximate manner? In addition, however, there are important basic, even philosophical issues. Mappings from structure to function are not necessarily linear. It is known that high functional specificity can result from apparently low anatomical specificity [48”], but how this comes about is less apparent.
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Tam& G, Buhl EH, Somogyi P: Massive autaptic self-innervation of GABAergic neurons in cat visual cortex. J Neurosci 1997, 17:6352-6364.
The authors determined the numbers and subcellular position of autapses on different smooth dendritic and spiny (pyramidal and nonpyramidal cell types, at the LM level, for 58 intracellularly filled neurons in cat visual cortex (areas 17 and 18). Subsequent EM analysis revealed that the degree of self-innervation (i.e. the number of autapses) is cell specific. Autapses were found to be abundant for GABAergic basket and dendrite-targeting interneurons (respectively, 12 ?7 and 22 *I 2 - mean *SD), but relatively sparse for double bouquet and pyramidal cells. 16. ..
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This and the following group of four papers [I 7”,18’,19”,20**] report on technically demanding experiments that have elucidated principles of functlonal connectivity between pairs or triplets of identified neurons (in vitro). These studies have provided exquisitely precise data about the location, number, and efficacy of the synaptic contacts, and should permit further development and testing of predictions about network properties. In this study, the authors used dual-voltage recordings to demonstrate first-order reciprocal feedback, and then filled pre- and postsynaptic neurons in layer 5 of rat somatosensory cortex with biocytin and analyzed by correlated LM and EM. Among other results, the authors report a 20.fold range in efficacy of the synaptic contacts. The continuum in synaptic efficacy implies that layer 5 pyramidal neurons can be recruited to ensemble activity by as few as five strongly connected neighbors or by as many as 100 weakly connected pyramidal neighbors. I 7. ..
Buhl EH, Tamas G, Szilagyi T, Stricker C, Paulsen 0, Somogyi P: Effect number, and location of synapses made by single pyramidal cells onto aspiny interneurones of cat visual cortex. J Physiol 1997, 500:689-713. Five synaptically coupled pyramidal-to-interneuron pairs in slices of cat visual cortex were physiologically characterized, labeled with biocytin, and analyzed by correlated LM and EM. Among other results, the authors report a lack of correlation for the interneurons between synapse efficacy and location (perhaps because of the electrotonic compactness of the interneurons), and a small degree of paired-pulse depression (this is in variance with the results reported in [19”] and the authors discuss possible reasons for the discrepancy). Because of a rapid decay of EPSPs, the authors postulate a requirement for a high degree of temporal synchrony among the input population, and infer that the three classes of interneurons examined may be predisposed to act as coincidence detectors. See also annotation (16”l.
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Swadlow HA, Beloozerova IN, Sirota MG: Sharp, local synchrony among putative feed-forward inhibitory interneurons of rabbit somatosensory cortex. J Neurophysiol 1998, 79:567-582. A subgroup of highly branched thalamocortical axons is postulated to contact monosynaptically a population of barrel-specific inhibitory neurons. Cross-correlation techniques were used to substantiate the existence of such a highly interconnected thalamocortical network by actually demonstrating the predicted patterns of intra- or cross-barrel sharp synchrony. This network of synchronous inhibition may be viewed as a ‘complete transmission line’, and may be especially effective in suppressing excitatory dnve to target cells that is weak and asynchronous. 25. .
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Gil Z, Connors BW, Amitai Y: Differential regulation of neocortical synapses by neuromodulators and activity. Neuron 1997, 19:679-686. The authors used various experimental manipulations in slice preparations of rodent somatosensory cortex and ventrobasal thalamus in order to test the specificity of regulation in the excitatory thalamocortical (TC) and intracorhcal (IC) pathways. They report differential suppression/enhancement effects: only IC synapses were suppressed by activation of GABAs receptors; only TC synapses were enhanced by nicotinic acetylcholine receptors; and both were suppressed by muscarinic acetylcholine receptors. 27.
.
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Johnson RR, Burkhalter A: A polysynaptic feedback visual cortex. J Neurosci 1997, 17:7129-7140.
30.
Lumer ED, Edelman GM, Tononi G: Neural dynamics in a model of the thalamocortical system. I. Layers, loops and the emergence of fast synchronous rhythms. Cereb Cotiex 1997, 7:207-227.
18.
Tam& G, Buhl EH, Somogyi P: Fast IPSPs elicited via multiple synaptic release sites by different types of GABAergic neurons in the cat visual cortex. J Physiol 1997, 500:715-738. This paper applies similar techniques to [I 7”] to investigate interneuron-topyramidal cell interactions and further discusses network properties. Three classes GABAergic neurons are identified and shown to have distinctive synaptic domains on the surface of their target cells. All three types elicit fast IPSPs, with moderate variability of amplitude and few failures of transmission. See also annotation [16*-l. .
Thomson AM, Deuchars J: Synaptic interactions in neocortical local circuits: dual intracellular recordings in vitro. Cereb Cortex 1997, 7:51 O-522. The authors studied the properties of local synaptic connections in slices of rat neocortex using dual intracellular recordings, which they correlated with cell and synaptic morphology. Repetitive firing of any one Input produces depression in pyramid-pyramid pairs, but facilitation in pyramid-interneuron pairs. Specific parameters for time-, frequency- and voltage-dependent properties are derived and network functional properties discussed. See also annotation [16**]. 19. ..
circuit
in rat
Jouve B, Rosenstiehl P, lmberi M: A mathematical approach to the connectivity between the cortical visual areas of the macaque monkey. Cereb Cortex 1998, 8:28-39. The authors attempted to use topological interpolation in conjunction with factonal analysis and clustering techniques to go beyond static connectional networks. They caution, however, that factors such as the very high density of internal connections still need to be incorporated into this and other network models. 31. .
32.
Innocenti GM, Lehmann P, Houzel J-C: Computational structure of visual callosal axons. Eur J Neurosci 1994, 6:918-935.
Complex
Chaudhuri A, Nissanor J, Larocque S, Rioux L: Dual activity maps in primate visual cortex produced by different temporal patterns of zif268 in RNA and protein expression. Proc Nat/ Acad Sci USA 1997, 94:2671-2675. The authors used a double-labeling strategy to exploit the different time course of expression of zlf268 mRNA (30 min) and zif268 protein (2 h) to separately visualize neuronal populations that are activated by dtffetent condltlons of visual exposure. 33. ..
34.
Erisir A, Van Horn SC, Sherman SM: Relative numbers cortical and brainstem inputs to the lateral geniculate Proc Nat/ Acad Sci USA 1997, 94:1517-l 520.
of nucleus.
35.
Vanduffel W, Payne BR, Lomber SG, Orban GA: Functional impact of cerebral connections. f’roc Nafl Acad Sci USA 1997, 94:7617-7620.
Lee C, Weyand TG, Malpeli JG: Thalamic control of cat lateral suprasylvian visual area: relation to patchy association projections from area 18. L?s Neurosci 1998, 15:15-25. Reversible blockade of the A, C, or MIN populations of the lateral geniculate nucleus produces a reduction in the activity levels of the lateral suprasylvian visual area. Reduced activity is reported to map as a system of partially overlapping patches, with reciprocal dependence on layer A or the MIN (associated, respectively, with conditions of high acuity or dim light). Patches with dependence on layer A are highly correlated with patchy projections from area 18, anatomically demonstrated by tracer injections of horseradish peroxidase and/or sH-proline. 36. ..
37.
Orbach D, Kaplan E, Everson R, Slrovich L, Knight B: Color columns in macaque Vl: two novel color systems are revealed by intrinsic optical imaging [abstract]. lnvesr Ophthalmol VIS Sci 1997, 38:S16.
38.
Horton JC, Hocking DR: Anatomical demonstration of ocular dominance columns in striate cortex of the squirrel monkey. J Neurosci 1996, 16:551 O-5522.
39.
Livingstone MS, Hubel DL: Anatomy and physiology of a color system in the primate visual cortex. J Neurosci 1994, 4:309356.
40.
Shlpp S. Zeki S: The organization of connections between areas V5 and Vl in macaque monkey visual cortex. Eur J Neurosci 1989, 1:309-332.
41.
42.
Fellernan DJ, Xlao Y, McClendon E: Modular organization of occipito-temporal pathways: cortical connections between visual area V4 and visual area V2 and posterior inferotemporal ventral area in macaque monkeys. j Neuroso 1997, 17:31853200. Hawkes R, Gravel C: The modular 1991, 36:309-327.
cerebellum.
Prog
Neurobiol
43. .
Hubener M, Shoham D, Grinvald A, Bonhoeffer T: Spatial relationships among three columnar systems in cat area 17. J Neurosci 1997, 17:9270-9284. Orderly geometric relationshIps, vlsuallred by optlcal Imaging, are reported between orientation and ocular dominance columns, and (somewhat more weakly) between onentation and spatial frequency domains. Low spatial frequency domalns showed a tendency to avoid border regions of the ocular dominance columns. Thus, although rules can be defined, they are not rigidly followed as might be expected for a ‘crystalline’ organization. The authors suggest that the cortex is composed of ‘mosaics’ for different properties that are arranged in a nonrandom manner (see Figure 2). 44.
Wiser AK, Callaway EM: Ocular dominance columns and local projections of layer 6 pyramidal neurons in macaque primary visual cortex. !/is Neurosci 1997, 14:241-251.
45.
Yoshioka T, Blasdel GG, Levitt JB, Lund JS: Relation between patterns of intrinsic lateral connectivity, ocular dominance, and cytochrome oxidase-reactive regions in Macaque monkey striate cortex. Cereb Cortex 1996, 6:297-310.
microstructures
46.
of sensory
cortical
connections
551
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Malach R, Amlr Y, Hare1 M, Grinvald A: Relationship between intrinsic connections and functional architecture revealed by optical imaging and in viva targeted biocytin injections in primate striate cortex. Proc Nat/ Acad Sci USA 1993, 90:1046910473.
Bosking WH, Zhang Y, Schofield B, Fitzpatrick D: Orientation selectivity and the arrangement of horizontal connections in tree shrew striate cortex. J Neurosci 1997, 17:2112-2127. Combined optical imaging of orientation domains with extracellular injections of biocytin confirms that long-range lntnnsic connections preferentially link neural domains of like orientation, and further demonstrates that the connections are anisotropic with respect to the topographic map of visual space. Less specificity may govern very local connections withln 0.5mm of the InjectIon site. 47. ..
48. ..
Kisvarday ZF, Toth E, Rausch M, Eysel UT: Orientation-specific relationship between populations of excitatory and inhibitory lateral connections in the visual cortex of the cat Cereb Cortex 1997, 7:605-618. This paper presents a quantitative analysis of the anatomical pattern of lateral connectivity In cat visual cortex, as this is dtstlnguished by excitatory and inhibitory subpopulations. By extrapolating from electrode recordings of single- and multi-unit activity, the authors mapped the anatomlcal pattern in relation to orientation domains. Using high-resolution bouton analysis, they confirmed that excitatory termtnations have a preferential bias for iso-orientatlons, although they further report significant interpatch and cross-orientation labeling. lnhibltory connectIons, from basket cells, more commonly were between non-iso-orientation locatlons. There IS a careful review of these results in the context of previous work, and a thoughtful discussion of how apparently low anatomical specificity might give rise to high functlonal speciflclty. 49.
Malach R, Tootell RBH, Malonek D: Relationship between orientation domains, cytochrome oxidase stripes, and intrinsic horizontal connections in squirrel monkey area V2. Cereb Cortex 1994, 4:151-l 65.
50.
Roe AW, Ts’o DY: The functional architecture of area V2 in the macaque monkey: physiology, topography, and connectivity. In Cerebral Cortex, vol 12: Extrastriate Cortex in Primates. Edited by Rockland KS, Kaas JH, Peters A. New York: Plenum; 1997:295334.
51.
Olavarria JF, Van Essen DC: The global pattern of cytochrome oxidase stripes in visual area V2 of the macaque monkey. Cereb Cortex 1997, 7:395-404.
52. ..
Maldonado PE, GBdecke I, Gray CM, Bonhoeffer T: Orientation selectivity in pinwheel centers in cat striate cortex. Science 1997, 276:1551-1555. Optical imaging of orientation domains combrned with tetrode recordings indicates that pinwheel centers (regions of reduced brightness In polar maps) are not characterized by a relative lack of neuronal onentation selectivity; rather, they represent the summation of cellular responses with greater vanante in orientation preference. 53. ..
Das A, Gilbert CD: Distortions of visuotopic map match orientation singularities in primary visual cortex. Nafure 1997, 387:594-598. By comblmng optrcal recording of intnnslc signals with extracellular recording of receptive fields, the authors present evidence that the map of visual space shows strong and systematic local dtstortions In register with inhomogeneities in the onentation map. Correlated inhomogenelties in retinotopy and onentatlon may imply that cortlcal modules exhibit a wide range of functlonal relations and are differentially Interconnected by local lateral processing. 54.
Rausell E, Jones EG: Chemically distinct compartments of the thalamic VPM nucleus in monkeys relay principal and spinal trigeminal pathways to different layers of the somatosensory cortex. J Neurosci 1991, 11:226-237.
55.
Peters A, Cifuentes JM, Sethares C: The organization of pyramidal cells in area 18 of the rhesus monkey. Cereb 1997, 7:405-421.
Cortex
Complex microstructures
of sensory cortical connections
Kathleen S Rockland The neocortex organization. structure studies
has a distinctive Although
and function
microstructure. are rapidly intracellular designed
remain
a finer scale of synaptic
New findings
emerging
concerning
from approaches
recordings
of cell and synaptic
questions
at this level of organization,
are addressing
network in which
in vitro are combined
morphology,
to label multiple
systems),
laminar and modular
important
regarding recent
and network properties dual or triple
with analyses
as well as from experiments
cell populations.
review lesser
Iowa City, Iowa 52242-l e-mail:
053,
of Iowa, 200
Hawkins
Drive,
USA;
[email protected]
Current
Opinion
0 Current
Biology
in Neurobiology
Publications
1998,
8:545
-551
ISSN 0959-4388
Abbreviations co EM
cytochrome oxidase electron microscopic/microscopy
EPSP GABA
excitatory
on rodent
somatosensory
cortex.
although an important component are not addressed, and modeling
have also been
largely
identification is central
and
The to a
Cortical
of cortical approaches
excluded.
Neuronal types: elements networks types
University
extent,
oscillations, organization,
The Addresses Department of Neurology,
as a commentary on the ‘state-of-the-field’. focuses mainly on the visual cortex and,
of circuits and
characterization
to understanding
of neuronal cortical
sub-
organization,
and considerable progress has been made over the past 20 years. Cortical neurons can be classified into distinct subtypes of interneuron (mostly inhibitory) and projection neuron (i.e. pyramidal neurons). Classification has been easier for interneurons, and a small number of major categories of interneuron has been established on the basis of multiple correlative criteria (e.g. dendritic and axonal morphology, axonal connectivity, peptide co-localization, and firing patterns; see use of single criterion approaches, expected.
finer
[Z] for a recent review). Through [3] and multiple criteria [4”]
classification
of
interneurons
can
be
defined
on
postsynaptic
potential
IPSP
y-aminobutyric acid inhibitory postsynaptic
potential
LM
light microscopic/microscopy
Subcategories
VI v2
primary visual cortex secondary visual cortex
the basis of the correlation between projection targets, the particular dendritic morphology of the efferent neurons, and the branching patterns of their local axon collaterals [5,6]. This approach remains useful, and has been complemented by newer modifications, such as in vitro intracellular fills [7] and single-neuron fills by juxtacellular injections [S]. Immunohistochemical’ markers, either alone [9*] or in combination with other markers, provide another mearis of classifying pyramidal neurons. For example, SMI 32, an antibody against nonphosphorylated neurofilaments, is reported to co-localize in characteristic proportions with connectionally distinct subpopulations [lo].
Introduction Cortical organization is commonly discussed in terms of a columnar or modular architecture. Although there is considerable evidence supporting a columnar organization, the issue is complex-a system as basic as the ocular dominance columns of primates is still not fully understood anatomically and even less so functionally. The problem is compounded by the dynamic and plastic elements of cortical organization, in the sense that structure and function do not necessarily have any direct, immutable relationship. Factors such as synaptic weight and selective interaction among convergent inputs are now known to effect significant contextually related changes in neural architecture [ 11. Papers from the past year fall primarily into three groups. One group deals with the continuing effort to establish a functionally meaningful taxonomy of cell types. A second based largely on physiological recording from group, pairs of identified neurons, is concerned with elucidating connectivity rules, or network ‘syntax’. The third group attempts an even more fine-grained investigation of modular systems, in terms of their substructure and dynamics. Although no unifying framework has yet emerged, this review is organized around these three themes (i.e. cell types, network properties, and modular
of projection
neurons
have been
The prospect of an ever more finely fractionated ‘alphabet soup’ poses serious problems of functional significance and may not be entirely welcome. Systematic correlations of multiple criteria, however, such as firing patterns and biochemical patterns of co-expression [4**], raise the interesting prospect of something resembling a periodic chart of classification, whereby populational characteristics might be linked to different areas and/or functions.
Network properties of intrinsic connections Individual neuronal elements interact within networks of interneurons and pyramidal cells, but facts and principles of network organization are relatively scant. Some data on the synaptic organization of connections have been provided by electron microscopic (EM) analyses (see e.g. [ll-131). These pertain to the location and number of synapses between different neurons.
546
Sensory
Most
cortical
systems
neurons
appear
wide variety of postsynaptic proportions [2,13]. However, especially interneurons, of synaptic specificity. interneurons in primate
to form
synapses
elements, albeit some populations
with
a
in different of neurons,
appear to have a high degree For example, calretinin-positive area Vl (but not V2 or frontal
areas) have a laminar-specific synaptology, in that they form symmetric synapses with GABAergic elements in the upper layers, but with pyramidal cells in the deeper layers [ 14’1. An
interesting
new
finding
is that
the
degree
1 mV
of self-
innervation (‘autapses’) may be greater than previously believed for at least two cell types. Tarn& et al. [15*] have recently reported that GABAergic basket cells and dendrite-targeting interneurons have a higher number of autapses neurons.
than either double-bouquet cells or pyramidal They postulate that extensive self-innervation
may modulate integrative properties and/or pattern of these particular neurons in a manner correlated with their own activity.
-62
mV
the firing temporally
As sample sizes in EM studies are necessarily small, there are major gaps in the database. As summarized by Jones et al. [Z], “What is missing.. is knowledge of the relative contributions of individual forms of GABA cells to the inhibitory input to a single pyramidal cell, the degree of convergence of inputs from members of the same (or other) GABAergic cell class, and the variations that occur in these parameters among pyramidal cells of different types.. ”
A more network labeling
recent, powerful approach for characterizing organization is the combination of intracellular and EM analyses with dual or triple intra-
cellular recordings i~r vitro. This combined anatomical/physiological approach provides highly specific structural data regarding the number and location of synapses between interconnected neurons [ 16”, 17**, 18*, 19”,20”]. Using this approach, hlarkram et al. [16”] found tliat pairs of thick, tufted pyramidal neurons in layer 5 make four to eight synapses. Buhl et al. [17**] found that pyramidal-to-interneuron connections also invo!ve small numbers of synapses (i.e. one to two or five to seven, depending on the type of postsynaptic neuron); however, Tam& et al. [ 18*] have reported that the connections from interneurons to pyramidal neurons appear to involve more synapses-up to 17, depending on the cell type. Aside from articulating rules of anatomical interconnectivity, this approach is well suited for investigating functional properties of local synaptic connections, and the relationship between structure and function (see Figure 1). Partly at issue is what parameters determine synaptic efficacy. Recent work reports that these parameters may be tightly correlated with different classes of connections. Thomson and Deuchars [19**] found that higher presynaptic firing rates result in frequency-dependent, incre-
-67
mV
-62
mV
Current Op,n,on ,n Neurobiology
Intracellular interconnected architecture
recordings neurons
from histologically permit
and investigation
identified
quantitative
analysis
of the physiological
pairs of of network properties
of
local synaptic connections [15*,16**,17”,1 El’,1 9**,20**1. This schematic summary (modified slightly from figure 2 of Thomson
and
Deuchars [19*4) represents several local inputs to pyramidal cells (P). Typical synaptic locations (small filled circles) and averaged IPSPs are shown at the left for four types of inhibitory interneurons (CFS, classical fast spiking; LTS, low threshold spiking; RS, regular spiking;
?, unclassified
synaptic locations pyramid-to-pyramid (Pl)
or slow spiking).
Two averaged
EPSPs
and
(small triangles) are shown at the right for two pairs. EPSPs generated by nearer pyramidal cells
arise in the basal dendrites
and have a faster time course
than
more distal apical inputs, arismg from presynaptic pyramldal cells separated by > 100 km (P2). The number of active synapses required to fire a cell varies with different conditions. For example, EPSPs are typically large between closely neighboring pyramidal cells in layer 5, and small in the case of connections from layer 5 to layer 3 pyramidal cells.
mental facilitation of pyramidal-to-interneuron, but not of pyramidal-to-pyramidal connections. Moreover, efficacy may be labile. Synaptic connections between thick, tufted pyramidal neurons are reported to show a ZO-fold range in efficacy, which is attributed, primarily, to differences in
Complex microstructures
transmitter
release
probability
(16”,20”].
This
result
has
been interpreted to imply that a single target neuron in the network of layer .5 pyramidal cells can be recruited to ensemble activity by the synchronous activation of as fe\\ as five strongly interconnected neighboring neurons, or of as many as 100 weakly interconnected neurons. similar combined anatomical/ In the hippocampus, physiological experiments have redefined interneuronal subtypes. and have shown that interneuronal netlvorks regulate various aspects of pyramidal cell operations. including cooperati\,e synchrony and plasticity [21,22]. It seems likely that in the ncocortcx, as in the hippocampus, highly constrained inhibitory networks will be found to have prccisc and important ensemble activit)- [ 16*“].
functional
roles
in controlling
more
of sensory cortical connections
fragmentary
than
for
Rockland
thalamocortical
547
connections
(see [28] for a recent review). There is little information concerning postsynaptic distributions of cortico-cortical their interactions with other systems, or connections, anatomical/physiological correlations. At least two major categories of cortical connections occur in the early sensory areas, ‘feedforward’ and ‘feedback’. These systems originate from neurons in different terminal Because
layers. terminate in different layers, and have arbors with different spatial characteristics [28]. feedback connections terminate predominately
in layer dendrites
1, they are thought to target selectively apical of underlying pyramidal neurons. In rodents
[B], although not necessarily in primates [28], feedback connections have an unusually high proportion (97%) of direct excitatory contacts.
Network properties of extrinsic connections liltimatcly, tions with
we nitt need to understand extrinsic connccthe same anatomical/physiological detail as is
emerging for intrinsic net\vorks (described surprisingly, if only because of the spatial these
systems,
this has been
harder
abo\.e). Not dispersion of
to achieve.
The thalamocortical system is the most accessible of the major systems of extrinsic connections. Their axonal featurcs, synaptic targets, and functional propcrtics have been the subject of several combined anatomical/physiological investigations (see e.g. [2,3]). ‘I’hatamocortical connections to primary cortical arcas are known to have driving, as opposed to modulator): effects. This finding, although well documented, is somewhat paradoxical, as thrrc arc fcwcr thalamocortical connections than intrinsic ones [24’], and the mechanisms elucidated.
underlying
these
effects
remain
whisker
varies
with
temporal
investigations to rely
had
mainly
of extrinsic on
cortical
indirect
connections
methods.
There
are modeling ‘experiments’, many closely informed by concrete data (see e.g. [30]) and analytic approaches, that attempt to translate bet\veen anatomical and functional connectivity [31’]. Innocenti et al. [32] describe a model of action potential timing in tvhich they used a computer to ‘inject’ currents into callosal axons with different gcomctric characteristics. In an interesting new approach, used visual stimulation under time intervals to map neuronal by measuring the expression of protein in primary visual cortex
Chaudhuri ft a/. [33**] different conditions and activity at a cellular level ~$268 mRNA and zif268 of primates.
to be
Scl-cral interesting ne\v findings have been reported in rodent barrel cortex. Iising cross-correlation techniques, S\vadlow PI a/. [25*] ha1.e demonstrated that a highly branched subgroup of thalamocortical connections contacts a population of inhibitory neurons and is involved in nctlvorks of synchronous inhibition. (Ising combined optical-imaging-stimLllation approach, Sheth rt a/. [Xi*] have shown that functional mappings in rat barrel cortex are more labile than anatomical mappings, and that the spread of cortical activation following the deflection of a single
Functional have
The connectional strength of extrinsic systems has been estimated by comparing the number of synapses in a target structure derived from different sources [34], or the number of neurons giving rise to different connections (table III in [B]). These are useful interim measures, but they are relatively insensitive. A recent study has reported significant discrepancies between the predicted anatomical strength of a connection (visualized by labeling with jI_I-amino acids) and the effects of cooling deactivation of the injected areas [35].
area on deoxyglucose
uptake
in several
target
frequency.
Cortical modules Ilow thalamocortical and cortico-cortical connections interact in the primary cortices is another important issue, but one which has barely been addressed. A recent study, using combined physiological recording and pharmacological manipulation in a thalamocortical slice preparation, reports specific and differential suppression/enhancement effects consequent to neuromodulators and activity [27*]. For extrinsic cortico-cortical from light microscopic (Lhl)
connections, investigations
most data arc and are even
hlodular organization at the scale of 0.1-0.5 mm is a robust feature of cortical sensory architectures. One of the most dramatic examples is the cytochrome oxidase (CO) compartmentation in areas Vl and V2, but new instances of modularity are still being discovered. There is, for example, a recent report of patches in the lateral suprasylvian cortex of cats that are preferentially dominated by thatamic inputs from lamina A or from the medial interlaminar nucleus (MIN) [36”]. There is another recent report of two systems in L’l concerned with
548
Sensory systems
Figure 2
The visual cortex crystalline
fashion.
has multiple Optical
and spatial frequency. as contour
modular
imaging
systems
of intrinsic
(a) Spatial frequency
lines): iso-orientation
that interrelate signals
yields
(gray regions
in complex
patterns.
high-resolution
correspond
lines tend to cross the borders
to modules
between
(dark gray) tend to avoid the borders
of ODCs.
Anatomical
color selectivity, blobs [37]. A reasonable and current systems will interdigitation. is evidence
neither
of which
studies
indicate
to the CO
hypothesis that has motivated much previous research is that different patchy or modular be tightly organized in a pattern of overlap or Although this possibility is attractive, there that it may not hold in all situations. Variable
are arranged
features low spatial
domains
in a nonrandom,
such as ocular frequency)
at right angles,
but not rigidly
dominance,
and orientation and ‘pinwheel’
orientation, maps (shown centers
favor
(ODCs) and orientation maps: iso-orientation lines tend to cross are in the middle of the ODCs. (c) Low spatial frequency domalns that horizontal
patterns may differ for excitatory et al. [43-l.
may be related
preferring
spatial frequency
the center of the spatial frequency modules. (b) Ocular dominance columns the borders between ODCs (shaded) at right angles, and ‘pinwheel’ centers functional characteristics, although the connectivity was modified from figures 4, 9 and 12 of Hijbener
The modules
maps for stimulus
intrinsic
and inhibitory
connections networks
tend to link zones with similar
(Kisvarday
et a/. [48”]).
This figure
visual cortex, there are many instances of only partial correspondence [43’]. Of the interlaminar connections in Vl from layer 6 to 4, some arc restricted to an overlying ocular dominance column, but others are not [44]. Intrinsic connections interlink ocular dominance columns, but only a subset of about 70% of the connections are confined to like-eye columns or to borders between columns [45,46].
patterns can occur as a function of species differences. In squirrel monkeys, unlike macaques, CO blobs do not
Horizontal intrinsic connections between orientation domains have been taken as a strong instance of like-to-like
align with Variability
connectivity. This has been strikingly confirmed by recent studies in the tree shrew. In this species, the horizontal connections between orientation domains exhibit sprcificity both for neuronal modules of similar orientation preference and for an axis in visual space that corresponds to the preferred orientation of the injection site [47”]. Even in this case, however, the pattern of connections within a radius of 0.5 mm from the injection site is less specific, with boutons found along every axis and thus contacting sites with a wide range of preferred orientations.
the centers of ocular dominance columns [38]. also occurs in different projection systems.
Patches of extrinsically projecting neurons from layer 3 of area Vl have been reported to match closely with CO compartments [39], but the groups of neurons in layer 4B projecting to llIT/VS do not seem to match with the overlying CO compartments [40]. Neurons in V2 projecting to V4 have a patchy distribution, but, again, this may not match exactly with the pattern of CO stripes [41]. In the cerebellum, various connectional or molecular markers reveal some kind of modular organization, but only some of the systems are co-registered by clear overlap or interdigitation [42]. Continuing investigations of cortical modularity similarly reveal instances of complex relationships between different feature mappings (see e.g. [43*] and Figure 2). In point of fact, it may be that of the several modular systems identified in the primate
In a recent high-resolution analysis of the relation between horizontal connections and orientation domains in areas 17 and 18 of the cat, Kisvarday et al. [48”] report that excitatory connections have only a moderate preference for iso-orientation, and inhibitory connections have an even weaker preference. In another study, hlalach rl al. [49] reported that there is only an approximate specificity in
Complex
the relationship and intrinsic
between horizontal
orientation connections
domains,
CO stripes,
in area \‘2 of squirrel
monkeys.
microstructures
of sensory
cortical
connections
Rockland
549
On a positive note, we have gained substantial insight into aspects of cortical workings. This is not the same as knowring how the cortex works, but is a significant step in that direction.
Some of the inexactness may be apparent only, and result from, problems in achieving matches between systems that are themselves complex. That is, horizonral intracorcical connections are a mix of inhibitory and excitatory connections [48”]. CO blobs in VI, CO compartments in \‘2 (50,51], and orientation pinwheels (i.e. singularity points where linear zones of iso-orientation converge) in Vl [SZ”] are all known to have that the many examples
substructure. Assuming, of weak or approximate
ho\i,ever, matching
are not artefactual, there are several interpretations. One interpretation is that the overall cortical organization is much more complex than we yet realize, even if all the components do fit into the machinery of a larger unit (or hypercolumn). A high degree of complexity is suggested by recent physiological mapping experiments that report correlated inhomogeneities in orientation and retinotop); [53**]. ‘I‘hese inhomogeneitics may, in turn, be subserved by intrinsic modules with a wide range of functional relations
[53”].
tween connectional systems. Some systems have terminal fields that are spatially delimited; others, that are spatial]) divergent (cortical feedforward and feedback populations, respectively [28]; or, in the somatosensory cortex, parvalbumin and calbindin thalamocortical populations [%I). at the
very
small
scale
of dendritic
and
axonal
bundles (
‘l‘hc authoris
\upportcd by I ISA fcdcrutf’undinp through the Nationst Scicncc t~wndmon (IUN Y421970) md the Nutionat Inatitutcs of Health (KIti i.35YX md NS lOh32).
References
and recommended
Papers of particular interest, published have been highlighted as: . l
.
reading
within the annual period of review,
of special interest of outstanding Interest
1.
GIlbert CD: Adult cortical dynamics. Physiol Rev 1998, 78:467485.
2.
Jones EG, Hendry SHC, DeFelipe J, Benson DL: GABA neurons and their role in activity-dependent plasticity of adult primate visual cortex. In Cerebral Cortex, vol 10. fr~mary l/isual Cortex Yn Primates. Edited by Peters A, Rockland KS. New York: Plenum Press; 1994:61-l 40.
3.
Lund JS, Wu CQ: Local circuit neurons of macaque monkey striate cortex: IV. Neurons of laminae 1-3A. 1 Comp Neural 1997, 384:109-l 26.
Caull B, Audinat E, Lambolez B, Angulo MC, Ropert N, Tsuzuki K, Hestnn S, Rossier J: Molecular and physiological diversity of cortical nonpyramidal cells. J Neurosci 1997, 17:3894-3906. This multidisciplinary investigation combined electrophyslological whole-cell recordings in slices of rat sensory-motor cortex with the simultaneous detection of mRNA encoding for three calcium-binding proteins (i.e. calbindin, parvalbumin and calretlnm) and four neuropeptides (i.e. neuropeptlde Y, vasoactive intestinal polypeptide, somatostatin, and cholecystokinin) using singlecell reverse transcription PCR. Three broad subpopulations of cortical cells were identified on the basis of correlations between firing properties (i.e. fast spiking, regular spiking, and irregular spiking) and biochemical co-expression patterns; however, within two of these (fast and regular spiking), the pattern of expression of the biochemical markers itself was complex. The expression of neuropeptides did not seem to be tightly correlated with either the firing pattern or a particular calcium-binding protein. The authors conclude that the full charactenration of the elements comprising a homogeneous network may require additional parameters. 4. ..
Another interpretation is that cortical structure is fundamentally mixed, similar to the caudate nucleus, which has both patch and matrix compartments. There is some indication, for example, of a basic geometric dichotomy be-
Finally,
Acknowledgements
5.
Lund JS, Lund RD, Hendrickson AE, Fuchs AF: The origin of efferent pathways from the primary visual cortex, area 17, of the macaque monkey as shown by the retrograde transport of horseradish peroxidase. J Camp Neural 1975, 164:287-304.
6.
Katz LC: Local circuitry of identified projection neurons in cat visual brain slices. J Neurosci 1987, 7:1223-l 249.
[SS].
Wiser AK, Callaway EM: Contributions of individual layer 6 pyramidal neurons to local circuitry in macaque primary visual cortex. J Neurosci 1996, 16:2724-2739.
Conclusions We are still far from understanding even the basic cortical machinery, let alone its modes of operation. In part, this is simply because we do not know enough. hlany questions remain. At the cellular level, what are the fundamental classes of pyramidal and nonpyramidal cells? At the network level, what are the operational rules and dynamics! How do network subsystems interact? At the modular level, how many systems are there in a given area? Do they interrelate in a regular or approximate manner? In addition, however, there are important basic, even philosophical issues. Mappings from structure to function are not necessarily linear. It is known that high functional specificity can result from apparently low anatomical specificity [48”], but how this comes about is less apparent.
Zhang Z-W, Deschgnes M: lntracortical axonal projections of lamina Vl cells of the primary somatosensory cortex in the rat: a single-cell labeling study. J Neurosci 1997, 17:6365-6379. Lander C, Kind P, Maleski M, Hockfield S: A family of activitydependent neuronal cell-surface chondroitin sulfate proteoglycans in cat visual cortex. J Neurosci 1997, 17:19281939. In thrs lmmunohlstochemlcal study, the authors report on two new monoclonal antibodies, Cat-315 and Cat-316, which, together with Cat-301, define a family of at least seven related but distinct chondroitin sulfate proteoglycans expressed on the extracellular surface of cell bodies and proximal dendrites. The three antibodies define nonidentical subsets of neurons in the cat visual cortex, and the authors conclude that different neuronal subpopulations express distinct complements of cell-surface antigens. 0.
Hof PR, Ungerleider LG, Adams MM, Webster MJ, Gattass R, Blumberg DM, Morrison JH: Callosally projecting neurons in the macaque monkey Vl/V2 border are enriched in nonphosphorylated neurofilament protein. l/is Neurosci 1997, 5:981-988.
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Meskenaite V: Calretinin-immunoreactive local circuit neurons in area 17 of the cynomolgus monkey, Macaca fascicularis. J Comp Neural 1997, 379:l 13-l 32. This paper demonstrates, using combined EM-immunocytochemistry, that the population of calretinin-positive interneurons in area 17 is polymorphic and has a dual laminar-specific projection pattern. In the superficial layers, most of the postsynaptic targets are other GABAergic neurons (81%). Collaterals also extend to the deeper layers (in area 17 but not area 18), and here synapses are formed mainly with spiny neurons, probably pyramidal cells (80%). The author concludes that calretinin-positive neurons act both to disinhibit supragranular neurons and to inhibit pyramidal output neurons in the deeper layers. 15. .
Tam& G, Buhl EH, Somogyi P: Massive autaptic self-innervation of GABAergic neurons in cat visual cortex. J Neurosci 1997, 17:6352-6364.
The authors determined the numbers and subcellular position of autapses on different smooth dendritic and spiny (pyramidal and nonpyramidal cell types, at the LM level, for 58 intracellularly filled neurons in cat visual cortex (areas 17 and 18). Subsequent EM analysis revealed that the degree of self-innervation (i.e. the number of autapses) is cell specific. Autapses were found to be abundant for GABAergic basket and dendrite-targeting interneurons (respectively, 12 ?7 and 22 *I 2 - mean *SD), but relatively sparse for double bouquet and pyramidal cells. 16. ..
Markram H, Lijbke J, Frotscher M, Roth A, Sakmann B: Pathology and anatomy of synaptic connections between thick tufted pyramidal neurons in the developing rat neocortex. J Physiol 1997,
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This and the following group of four papers [I 7”,18’,19”,20**] report on technically demanding experiments that have elucidated principles of functlonal connectivity between pairs or triplets of identified neurons (in vitro). These studies have provided exquisitely precise data about the location, number, and efficacy of the synaptic contacts, and should permit further development and testing of predictions about network properties. In this study, the authors used dual-voltage recordings to demonstrate first-order reciprocal feedback, and then filled pre- and postsynaptic neurons in layer 5 of rat somatosensory cortex with biocytin and analyzed by correlated LM and EM. Among other results, the authors report a 20.fold range in efficacy of the synaptic contacts. The continuum in synaptic efficacy implies that layer 5 pyramidal neurons can be recruited to ensemble activity by as few as five strongly connected neighbors or by as many as 100 weakly connected pyramidal neighbors. I 7. ..
Buhl EH, Tamas G, Szilagyi T, Stricker C, Paulsen 0, Somogyi P: Effect number, and location of synapses made by single pyramidal cells onto aspiny interneurones of cat visual cortex. J Physiol 1997, 500:689-713. Five synaptically coupled pyramidal-to-interneuron pairs in slices of cat visual cortex were physiologically characterized, labeled with biocytin, and analyzed by correlated LM and EM. Among other results, the authors report a lack of correlation for the interneurons between synapse efficacy and location (perhaps because of the electrotonic compactness of the interneurons), and a small degree of paired-pulse depression (this is in variance with the results reported in [19”] and the authors discuss possible reasons for the discrepancy). Because of a rapid decay of EPSPs, the authors postulate a requirement for a high degree of temporal synchrony among the input population, and infer that the three classes of interneurons examined may be predisposed to act as coincidence detectors. See also annotation (16”l.
Markram H: A network of tufted layer 5 pyramidal neurons. Cereb Cortex 1997, 7:523-533. %s is an experimentally based characterization of a recurrent network of layer 5 pyramidal neurons and an examination of how the dynamics of electrical activity might influence the functional coupling of neurons (‘network configuration’). Evidence is presented that extensive, nonrandom interconnections occur among layer 5 pyramidal cells, and that these are in parallel from multiple points of the network. Activity-dependent synaptic modification, which enables the association of activity patterns, is discussed as an added dimension to network dynamics. See also annotation [16”1. 20.
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Ahmed B, Anderson JC, Martin KAC, Nelson JC: Map of the synapses onto layer 4 basket cells of the primary visual cortex of the cat. J Comp Neural 1997, 380:230-242. The authors used a ‘template-matching’ approach whereby the major sets of inputs to basket cells were sorted and distinguished by size (resolved by EM). Best-fit results show that about equal numbers of excitatory synapses are provided by layer 6 pyramidal cells (43%) and spiny stellates of layer 4 (440/o), whereas thalamic afferents contribute fewer (only 13%). Symmetric synapses may originate from other layer 4 basket cells. 24. .
Swadlow HA, Beloozerova IN, Sirota MG: Sharp, local synchrony among putative feed-forward inhibitory interneurons of rabbit somatosensory cortex. J Neurophysiol 1998, 79:567-582. A subgroup of highly branched thalamocortical axons is postulated to contact monosynaptically a population of barrel-specific inhibitory neurons. Cross-correlation techniques were used to substantiate the existence of such a highly interconnected thalamocortical network by actually demonstrating the predicted patterns of intra- or cross-barrel sharp synchrony. This network of synchronous inhibition may be viewed as a ‘complete transmission line’, and may be especially effective in suppressing excitatory dnve to target cells that is weak and asynchronous. 25. .
Sheth BR, Moore Cl, Sur M: Temporal modulation of spatial borders in rat barrel cortex. J Neurophysiol 1998, 79:464-470. ;)ptical imaging was used to visualize the region of rat barrel cortex actlvated by deflection of a single whisker at different frequencies. Stimulation at higher frequencies was found to result in more focussed physiological responses. Given that spread of activation is modulated in a dynamic fashion by the frequency of vibrissa stimulation, the authors suggest a labile and complex functional mapping that extends beyond the CO-based anatomical maps of rat barrel cortex. 26.
Gil Z, Connors BW, Amitai Y: Differential regulation of neocortical synapses by neuromodulators and activity. Neuron 1997, 19:679-686. The authors used various experimental manipulations in slice preparations of rodent somatosensory cortex and ventrobasal thalamus in order to test the specificity of regulation in the excitatory thalamocortical (TC) and intracorhcal (IC) pathways. They report differential suppression/enhancement effects: only IC synapses were suppressed by activation of GABAs receptors; only TC synapses were enhanced by nicotinic acetylcholine receptors; and both were suppressed by muscarinic acetylcholine receptors. 27.
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Rockland KS: Elements of cortical architecture: hierarchy revisited. In Cerebra/ Cortex, vol 12. Extrastriate Cortex in Primates. Edited by Rockland KS, Kaas JH, Peters A. New York: Plenum; 1997:243-294.
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Tam& G, Buhl EH, Somogyi P: Fast IPSPs elicited via multiple synaptic release sites by different types of GABAergic neurons in the cat visual cortex. J Physiol 1997, 500:715-738. This paper applies similar techniques to [I 7”] to investigate interneuron-topyramidal cell interactions and further discusses network properties. Three classes GABAergic neurons are identified and shown to have distinctive synaptic domains on the surface of their target cells. All three types elicit fast IPSPs, with moderate variability of amplitude and few failures of transmission. See also annotation [16*-l. .
Thomson AM, Deuchars J: Synaptic interactions in neocortical local circuits: dual intracellular recordings in vitro. Cereb Cortex 1997, 7:51 O-522. The authors studied the properties of local synaptic connections in slices of rat neocortex using dual intracellular recordings, which they correlated with cell and synaptic morphology. Repetitive firing of any one Input produces depression in pyramid-pyramid pairs, but facilitation in pyramid-interneuron pairs. Specific parameters for time-, frequency- and voltage-dependent properties are derived and network functional properties discussed. See also annotation [16**]. 19. ..
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Jouve B, Rosenstiehl P, lmberi M: A mathematical approach to the connectivity between the cortical visual areas of the macaque monkey. Cereb Cortex 1998, 8:28-39. The authors attempted to use topological interpolation in conjunction with factonal analysis and clustering techniques to go beyond static connectional networks. They caution, however, that factors such as the very high density of internal connections still need to be incorporated into this and other network models. 31. .
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Chaudhuri A, Nissanor J, Larocque S, Rioux L: Dual activity maps in primate visual cortex produced by different temporal patterns of zif268 in RNA and protein expression. Proc Nat/ Acad Sci USA 1997, 94:2671-2675. The authors used a double-labeling strategy to exploit the different time course of expression of zlf268 mRNA (30 min) and zif268 protein (2 h) to separately visualize neuronal populations that are activated by dtffetent condltlons of visual exposure. 33. ..
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Lee C, Weyand TG, Malpeli JG: Thalamic control of cat lateral suprasylvian visual area: relation to patchy association projections from area 18. L?s Neurosci 1998, 15:15-25. Reversible blockade of the A, C, or MIN populations of the lateral geniculate nucleus produces a reduction in the activity levels of the lateral suprasylvian visual area. Reduced activity is reported to map as a system of partially overlapping patches, with reciprocal dependence on layer A or the MIN (associated, respectively, with conditions of high acuity or dim light). Patches with dependence on layer A are highly correlated with patchy projections from area 18, anatomically demonstrated by tracer injections of horseradish peroxidase and/or sH-proline. 36. ..
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Hubener M, Shoham D, Grinvald A, Bonhoeffer T: Spatial relationships among three columnar systems in cat area 17. J Neurosci 1997, 17:9270-9284. Orderly geometric relationshIps, vlsuallred by optlcal Imaging, are reported between orientation and ocular dominance columns, and (somewhat more weakly) between onentation and spatial frequency domains. Low spatial frequency domalns showed a tendency to avoid border regions of the ocular dominance columns. Thus, although rules can be defined, they are not rigidly followed as might be expected for a ‘crystalline’ organization. The authors suggest that the cortex is composed of ‘mosaics’ for different properties that are arranged in a nonrandom manner (see Figure 2). 44.
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Bosking WH, Zhang Y, Schofield B, Fitzpatrick D: Orientation selectivity and the arrangement of horizontal connections in tree shrew striate cortex. J Neurosci 1997, 17:2112-2127. Combined optical imaging of orientation domains with extracellular injections of biocytin confirms that long-range lntnnsic connections preferentially link neural domains of like orientation, and further demonstrates that the connections are anisotropic with respect to the topographic map of visual space. Less specificity may govern very local connections withln 0.5mm of the InjectIon site. 47. ..
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Kisvarday ZF, Toth E, Rausch M, Eysel UT: Orientation-specific relationship between populations of excitatory and inhibitory lateral connections in the visual cortex of the cat Cereb Cortex 1997, 7:605-618. This paper presents a quantitative analysis of the anatomical pattern of lateral connectivity In cat visual cortex, as this is dtstlnguished by excitatory and inhibitory subpopulations. By extrapolating from electrode recordings of single- and multi-unit activity, the authors mapped the anatomlcal pattern in relation to orientation domains. Using high-resolution bouton analysis, they confirmed that excitatory termtnations have a preferential bias for iso-orientatlons, although they further report significant interpatch and cross-orientation labeling. lnhibltory connectIons, from basket cells, more commonly were between non-iso-orientation locatlons. There IS a careful review of these results in the context of previous work, and a thoughtful discussion of how apparently low anatomical specificity might give rise to high functlonal speciflclty. 49.
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Das A, Gilbert CD: Distortions of visuotopic map match orientation singularities in primary visual cortex. Nafure 1997, 387:594-598. By comblmng optrcal recording of intnnslc signals with extracellular recording of receptive fields, the authors present evidence that the map of visual space shows strong and systematic local dtstortions In register with inhomogeneities in the onentation map. Correlated inhomogenelties in retinotopy and onentatlon may imply that cortlcal modules exhibit a wide range of functlonal relations and are differentially Interconnected by local lateral processing. 54.
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