Department of Anatomy and Neurobiology, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, USA
Alan Peters, Department of Anatomy and Neurobiology, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, USA. Email: apeters{at}cajal-1.bu.edu.
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Abstract |
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Introduction |
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The primitive neurons of layer 1 are the CajalRetzius cells, which are large neurons with long horizontal processes. The fate of these neurons is not clear. Some authors (Bradford et al., 1977) consider that they largely disappear during the course of cortical development, but they may spread out as the cortical mantle expands (Marin-Padilla, 1990
). Another possibility is that the CajalRetzius cells transform into other types of non-pyramidal cells (Parnavelas and Edmunds, 1983
), because Zhou and Hablitz (Zhou and Hablitz, 1996
) and Hestrin and Armstrong (Hestrin and Armstrong, 1996
) have shown that as well as CajalRetzius cells, other types of neurons are also present in layer 1 early in development. Certainly, a diverse population of neurons is present in layer 1 of the mature brain and most of them can be labeled with antibodies to GABA (Gabbot and Somogyi, 1986; Hendry et al., 1987
; Beaulieu et al., 1992
), suggesting that they are inhibitory in function.
While the dendrites of these intrinsic layer 1 neurons contribute to the neuropil, the great majority of dendrites in layer 1 are derived from the apical dendritic tufts of pyramidal cells with perikarya in layers 2/3 and 5. These apical dendritic tufts branch profusely to form cones of thin and spiny branches (Martin and Whitteridge, 1984) that extend as far as the glial limiting membrane.
In previous studies, we have examined the effects of age on layer 1 in prefrontal area 46 (Peters et al., 1998b) and in area 17, primary visual cortex (Peters et al., 2001
) of behaviorally tested (Herndon et al., 1997
) rhesus monkeys. It has been found that with age the glial limiting membrane and the neuropil of layer 1 undergo a number of structural changes. The glial limiting membrane becomes thicker and at the same time there is a decrease in the overall thickness of layer 1, accompanied by a loss of some dendrites and spines and a decrease in the frequency of synapses. In area 46 the decrease in thickness of layer 1 and the loss of synapses correlate with both the age and cognitive status of the monkeys, but in area 17 there are only correlations with age. The purpose of the present paper is to complete the picture of the effects of age on the constituent neurons and neuroglia of layer 1, by determining if their structure and numbers change.
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Materials and Methods |
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The details of the fixation protocol for the brains used in this study have been given in detail in earlier publications (Peters et al., 1994). The perfusions were carried out in full accordance with the approved Institutional Animal Care and Use Committee regulations. In brief, the monkeys were anesthetized with ketamine, and sodium pentobarbital (35 mg/kg) was administered i.v. until a state of areflexia was attained. The monkeys were then artificially respired using a mixture of 95% O2 and 5% CO2 and their brains fixed by vascular perfusion with a warm solution of 1% paraformaldehyde and 1.25% glutaraldehyde in either 0.1 M cacodylate or 0.1 M phosphate buffer at pH 7.4. Following this initial fixation, the brain was removed and one hemisphere placed for several days in a cold solution of 2% paraformaldehyde and 2.5% glutaraldehyde in 0.1 M cacodylate or phosphate buffer at pH 7.4.
Small blocks of cerebral cortex were then taken from two cortical areas: (1) from the primary visual cortex on the lateral surface of the occipital lobe, ~3 mm caudal to the lunate sulcus, where central vision is represented and (2) from the floor of the principal sulcus of the frontal lobe at the level of the rostral end of the corpus callosum, (Peters et al., 1998b), where area 46 (Walker, 1940
) is located. The pieces of cortex were osmicated, dehydrated in an ascending series of alcohols and embedded in Araldite. At least two blocks of cortex from each area were sectioned in a plane vertical to the pial surface. The tissue blocks were adjusted on the microtome until the plane of section passed exactly parallel to the lengths of the apical dendrites of the pyramidal cells. This ensured that the true thickness of the cortex would be displayed. When this had been achieved, a series of 1 µm thick sections was taken and stained with toluidine blue for light microscopic examination. Thin sections were also taken from these blocks for electron microscopy. Such thin sections were stained with uranyl acetate and lead citrate, for examination in a JEOL 100 S electron microscope.
Thickness of Layer 1
For those monkeys in which the thickness of layer 1 in area 17 and area 46 had not already been ascertained in our previous studies (Peters et al., 1998b, 2001
), the thickness was determined by making camera lucida drawings of the 1 µm thick sections using an Olympus microscope. A x20 objective lens was used and drawings of 250 µm long strips of layer 1 were scanned into a computer. NIH Image v.1.55 was used to determine the area of layer 1 contained in the strips and from this, the mean thickness of layer 1 was ascertained. The locations of the cell bodies of the pyramidal cells in upper layer 2 were taken to mark the boundary between layers 1 and 2 (Peters et al., 1998b
).
In terms of the measurements of the thickness of layer 1, it is pertinent to point out that there is no indication that the overall depth of the cerebral cortex changes appreciably with age (Vincent et al., 1989) and although it is not known if there is a change in the volume of cortex when it is fixed by perfusion, it is known that when fixed cortex is prepared and embedded for electron microscopy there is a linear shrinkage that amounts to only ~0.7% (Peters et al., 1985
).
Frequency of Neurons and Neuroglial Cells
In Nissl-stained material prepared for light microscopy it is frequently difficult to distinguish between the profiles of the various cell types in layer 1. For this reason a stereological analysis of the effects of age on the populations of the individual cell types in layer 1 cannot be carried out using such material. However, it is easy to distinguish between neurons and astrocytes in semithick, plastic-embedded and osmicated tissue stained for light microscopy with toluidine blue, although even in this material it is not always possible to distinguish between oligodendrocytes and microglial cells. Consequently, it was decided to group the profiles of oligodendrocytes and microglial cells together and to put them into a category referred to as dark cells.
To determine if there is a change in the frequency of neurons, astrocytes and dark cells in layer 1 with age, using a x40 objective lens drawings were made of 500 µm long strips of layer 1 to show the locations of the profiles of every neuron and neuroglial cell that contained a nucleus. For each monkey at least six separate drawings were made, utilizing a minimum of two tissue blocks, with the added proviso that drawings of sections from the same block had to be from sections at least 10 µm apart. In this way the same cells were not included in different drawings. Counts were then made of the numbers of profiles of neurons, astrocytes and dark cells displaying nuclei in the drawings of 500 µm long strips of layer 1. From the counts derived from the six drawings, the mean numbers of profiles of each cell type per 500 µm length of layer 1 were determined (see Table 1).
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Glial filament antibody labeling of astrocytes
To visualize the filament-containing processes of astrocytes in layer 1, an antibody to glial filament protein (GFAP) was used. Vibratomed sections 50 µm thick were taken from area 17 of four monkeys: AM 76 (5 years old), AM 47 (9 years old), AM 62 (27 years old) and AM 41 (32 years old). The sections were treated with 1% sodium borohydride and incubated overnight in a monoclonal mouse anti-human GFAP antibody (Dako). The binding sites were then visualized with a fluoroscein (FITC) conjugated AffiniPure F(ab') 2 fragment, goat anti-mouse IgG (Jackson Laboratories, Burlingame, CA) and the sections examined by confocal fluorescent microscopy.
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Results |
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Morphology of Cells in Layer 1 of Young Monkeys
In semithick plastic sections taken from layer 1 of young monkeys and stained with toluidine blue, one of the most common elements in the neuropil of layer 1 are the dendrites (Fig. 1). These are largely derived from the apical tufts of the pyramidal cells in layers 2/3 and 5, and they appear as pale profiles of various sizes. Scattered through the neuropil, profiles of myelinated axons are also evident.
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The nuclei of astrocytes have smooth contours, and their nuclear envelopes rarely show folds (Fig. 1, A). Their nuclei stain slightly darker and more evenly than those of neurons and, in addition to the dark nucleolus, the chromatin usually has several condensations located just beneath the nuclear envelope. The cytoplasm of the astrocytes is very pale, often forms only a thin rim around the nucleus and may contain inclusions. These cells have irregular shapes and sometimes thick pale processes can be seen to emerge from the perikaryon. Astrocytes occur throughout layer 1 and their processes form the glial limiting membrane at the surface of the cortex. Interestingly, in some monkeys there are only few astrocytic perikarya associated with the glial limiting membrane, while in others the cell bodies of astrocytes are regularly spaced just beneath it (Fig. 2
).
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Morphology of Cells in Layer 1 of Old Monkeys
As pointed out in earlier publications (Peters, 1991, 1999
; Peters et al., 1991a
), each of the cell types in layer 1 undergoes some alterations with age. In semithick sections most neurons appear to be unchanged beyond the appearance of some granules of lipofuscin in their cytoplasm. However, infrequent neuronal profiles appear to have a watery cytoplasm with irregularly dispersed organelles in their perikarya, while other rare neurons appear dense, suggesting that they have become pyknotic. Neurons displaying these kinds of changes are shown in Figures 3 and 4
, which are from layer 1 in area 46 of a 27-year-old monkey. The neuron in Figure 3
has a nucleus that appears normal, but a broken-down perikaryal cytoplasm that contains few organelles, is watery at the periphery and has membranous inclusions. It is assumed that neurons with such features are dying, but by a process that is different from that shown by the pyknotic neuron in Figure 4
. This neuron has become electrondense and has an irregular outline, suggesting that it has become shrunken. In its dense cytoplasm the cisternae have become swollen and some of them contain membranous inclusions.
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The Frequency of Cell Types in Young and Old Monkeys
To ascertain if there is a change in the frequency of occurrence of neurons, astrocytes and dark cells (microglia plus oligodendrocytes) in layer 1 with age, 1 µm thick sections stained with toluidine blue were used (see Fig. 1). A comparison was made between the number of profiles of cell bodies of each cell type that display nuclei in 500 µm long strips of layer 1 in young (512 years of age) and old (>25 years of age) monkeys. Both area 17 and area 46 were examined and the results are given in Table 1
.
In comparing the cell counts obtained from areas 17 and 46, it is evident that there are about twice as many neurons and astrocytes in layer 1 of area 46 than in area 17. Presumably this is related to the fact that layer 1 in area 46 is about twice as thick as that is area 17 (Table 1). But, interestingly, the frequencies of dark cells in areas 46 and 17 are similar.
Within area 17 and within area 46, there is not a great deal of variation in the numbers of profiles of neurons and of dark glial cells among individual monkeys, but there are large variations in the numbers of profiles of astrocytic cell bodies. In general, the highest numbers of astrocytic cell body profiles occur in layer 1 of those monkeys with a large number of these cells just beneath the glial limiting membrane (Fig. 2). However, it is evident from the data shown in Table 1
that there are no significant differences in the mean numbers of profiles of either neurons, astrocytes, or dark cells in layer 1 between young and old monkeys. There are also no differences in the mean sizes of the nuclear profiles of neurons and astrocytes in layer 1 of young and old monkeys, in either area 17 or area 46. Consequently, our data indicate that with age there are no significant losses of neurons from layer 1 and no significant increases in the numbers of astrocytes.
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Discussion |
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However, with age each of the cell types undergoes some morphological alterations. In the case of the neurons, this involves the formation of lipofuscin in the cell body and degenerative changes in a small number of neurons. But even though we have found a few examples of dying neurons, any loss of layer 1 neurons as a result of degeneration cannot be extensive, as indicated by the fact that there is no significant change in the numbers of neuronal profiles in either area 17 or area 46 with age (see Table 1). Indeed, the existing evidence suggests that neurons are not lost in significant numbers from any portion of the cerebral cortex of primates (Leuba and Krafstik, 1994; Morrison and Hof, 1997
; Peters et al., 1998a
) and O'Donnell et al. (O'Donnell et al., 1999
) have pointed out that the volume of area 46 is totally preserved in aged monkeys, while Peters et al. (Peters et al., 1997
) have shown that there is no change in the volume of area 17 with age in rhesus monkeys.
Although the numbers of astrocytes in layer 1 do not appear to increase with age, those contributing to the glial limiting membrane hypertrophy. This is evidenced by the marked thickening of the glial limiting membrane, which becomes thicker because of an increase in the numbers of processes of astrocytes that contribute to it. This thickening may occur in response to the loss of dendrites from the apical dendritic tufts of pyramidal cells and the consequent loss of synapses. There is also an obvious increase in the numbers of intermediate filaments in the cell bodies and processes of astrocytes throughout layer 1. This can be seen in both electron micrographs and in material labeled with antibody to GFAP, since the latter preparations show a marked increase in the thickness and frequency of staining of filament bundles in the long astrocytic processes that extend from layers 1 and 2 into the upper half of the cortex. This strong labeling of astrocytes with GFAP antibody has been remarked upon earlier by Hanson et al. (Hanson et al., 1987), who examined the labeling in human cerebral cortex and commented upon the fact that the numbers of labeled astrocytes in layer 1 vary widely among individuals, but show no correlation with advancing age. Other studies have recorded an overall increase in GFAP with age, both in terms of the increase in the intensity of labeling of GFAP with antibodies (O'Callaghan and Miller, 1991
; Colombo et al., 1995
,1998
; Kohama et al., 1995
; Sloane et al., 2000
) and an increase in GFAP mRNA (Nichols et al., 1993
; Kohama et al., 1995
), in brains of aged mice, rats, monkeys and humans. Also, in morphological studies Colombo (Colombo, 1996
) has drawn attention to the long interlaminar processes of astrocytes that extend through the outer layer of the cortex (see Fig. 7
). They suggest that these long processes are characteristic of primates and may play a role in the modular organization of the cerebral cortex (Colombo et al., 1999
).
As well as the marked increase in the content of intermediate filaments, the perikarya of astrocytes come to contain inclusions. Inclusions are also usually present within microglia in layer 1 of old monkeys and presumably they are derived from materials that have been phagocytosed by the astrocytes and microglia. The source of these phagocytosed materials cannot be determined from the morphology of the inclusions. However, degenerating dendrites may be one source of these inclusions, since it is known from our earlier studies that some dendrites from the apical tufts of pyramidal cells in both area 46 (Peters et al. 1998b) and area 17 (Peters et al., 2001
) are lost with age.
Sheffield and Berman (Sheffield and Berman, 1998) have shown that in the brains of Macaca nemestrina the microglial expression of major histocompatibility complex (MHC) class II antigens increases with age, indicating that these cells are more activated. However, the effect is most pronounced in white matter, in which Sheffield and Berman (Sheffield and Berman, 1998
) suggest the microglial cells may influence myelin loss with age (Sloane et al., 1999
). Nevertheless, most of the microglial cells in layer 1 accumulate phagocytosed material as they age, and this is particularly evident in microglial cells associated with the glial limiting membrane.
Whether myelinated axons are lost from layer 1 with age is not known, but it is clear that many of the myelin sheaths in the axonal plexus of layer 1 undergo age-related changes of the kinds that occur elsewhere (Feldman and Peters, 1998; Peters et al., 2000
). Also, the oligodendrocytes in old monkeys show accumulations of dense bodies in both their perikarya and in swellings of their processes, as they do in other cortical layers (Peters, 1996
). At present, the nature and source of these inclusions is not known.
In summary, age has little affect on the frequency of cells in layer 1. However, each cell type is affected by age and some of the intrinsic neurons may degenerate. All of the cell types accumulate some inclusions in their cell bodies. In the case of the neurons and the oligodendrocytes it is essentially age pigment, but with astrocytes and microglial cells the inclusions are formed through phagocytosis. There is also some hypertrophy of the astrocytes, so that the glial limiting membrane becomes thickened, perhaps forming a scar in response to the age-related loss of some dendrites and synapses from layer 1 and, in addition, the processes and cell bodies of astrocytes throughout layer 1 come to contain increased amounts of fibrillary protein.
In terms of what effect aging has on the functioning of layer 1, its inputs need to be considered. The inputs come from a wide variety of sources. These include: backward projecting axons; the axons of the local intrinsic neurons; axons of pyramidal cells that ascend into layer 1; subpopulations of neurons in both specific and unspecific thalamic nuclei; and cholinergic and monaminergic inputs from brain stem nuclei (Vogt, 1991; Cauller and Connors, 1994
). Cauller and Connors (Cauller and Connors, 1994
) have shown that in the somatosensory cortex of the rat the horizontally projecting glutaminergic axons of layer 1 give a powerful excitation to pyramidal cells with apical tufts in layer 1. Since aging results in a pruning of the apical tufts of pyramidal cells and a loss of synapses (Peters et al., 1998b
, 2001), inputs to the apical dendritic tufts will be reduced, so that this excitation of pyramidal cells through their apical dendritic tufts can be expected to be diminished with age. But so far, this has not been examined and there is no information available about whether only some, or all of the axonal types entering layer 1 are affected by the normal aging process.
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Notes |
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References |
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