Spermine modulation of the glutamate(NMDA) receptor is differentially responsive to conantokins in normal and Alzheimer's disease human cerebral cortex

The pharmacology of the N -methyl-d-aspartate (NMDA) receptor site was examined in pathologically affected and relatively spared regions of cerebral cortex tissue obtained at autopsy from Alzheimer's disease cases and matched controls. The affinity and density of the [H-3]MK-801 binding site were delineated along with the enhancement of [H-3]MK-801 binding by glutamate and spermine. Maximal enhancement induced by either ligand was regionally variable; glutamate-mediated maximal enhancement was higher in controls than in Alzheimer's cases in pathologically spared regions, whereas spermine-mediated maximal enhancement was higher in controls in areas susceptible to pathological damage. These and other data suggest that the subunit composition of NMDA receptors may be locally variable. Studies with modified conantokin-G (con-G) peptides showed that Ala(7)-con-G had higher affinity than Lys(7)-con-G, and also defined two distinct binding sites in controls. Nevertheless, the affinity for Lys(7)-con-G was higher overall in Alzheimer's brain than in control brain, whereas the reverse was true for Ala(7)-con-G. Over-excitation mediated by specific NMDA receptors might contribute to localized brain damage in Alzheimer's disease. Modified conantokins are useful for identifying the NMDA receptors involved, and may have potential as protective agents.

Cadmium levels in the lung, liver, kidney cortex, and urine samples from Australians without occupational exposure to metals

The authors undertook this study to assess levels of cadmium exposure in the general population. Samples of lung, liver, and kidney were obtained from 61 cadavers (43 males, 18 females; 2-89 yr of age, mean age = 38.5 yr) who died from accidental causes and who were subject to postmortem examinations at the John Tonge Centre for Forensic Sciences, Queensland Health Scientific Services, Brisbane, Australia, in 1997 and 1998. Samples of bladder urine were also obtained from 22 cadavers. Tissue and urine samples were analyzed for cadmium, zinc, and copper with inductively coupled plasm (ICP) mass spectrometry. The overall mean values for cadmium in the lung, liver, and kidney cortex samples were 0.13, 0.95, and 15.45 mug/gm wet tissue weight. The average renal cadmium level in subjects with high lung-cadmium levels (n = 13) was 6 mug/gm wet tissue weight higher than that of similarly aged subjects who had medium lung-cadmium levels (n = 30). In females, the average level of cadmium in the liver was 74% greater than in males, and the average liver cadmium in females with high lung-cadmium levels was 100% higher than in males in the same age range who had the same high lung-cadmium levels. Renal cadmium accumulation tended to be greater in females than in males who were in the same age range and who had similar lung-cadmium levels, a result that suggested that there was a higher absorption rate of cadmium in females. The mean value for a urinary cadmium excretion of 2.30 mug/gm creatinine was found in a subset of samples that had a mean age of 39 yr and a renal cortex cadmium concentration of 18.6 mug/gm wet tissue weight. Urinary cadmium excretion rates were correlated more strongly with lung and kidney cadmium content than with age or liver cadmium levels. The results suggest that urinary cadmium excretion may be increased in smokers and could provide some estimate of body cadmium burdens in future Australian epidemiological studies.

The pyramidal cell of the sensorimotor cortex of the macaque monkey: Phenotypic variation

Recent studies have revealed striking differences in pyramidal cell structure among cortical regions involved in the processing of different functional modalities. For example, cells involved in visual processing show systematic variation, increasing in morphological complexity with rostral progression from V1 through extrastriate areas. Differences have also been identified between pyramidal cells in somatosensory, motor and prefrontal cortex, but the extent to which the pyramidal cell phenotype may vary between these functionally related cortical regions remains unknown. In the present study we investigated the structure of layer III pyramidal cells in somatosensory and motor areas 3b, 4, 5, 6 and 7b of the macaque monkey. Cells were intracellularly injected in fixed, flat-mounted cortical slices and analysed for morphometric parameters. The size of the basal dendritic arbours, the number of their branches and their spine density were found to vary systematically between areas. Namely, we found a trend for increasing complexity in dendritic arbour structure through areas 3b, 5 and 7b. A similar trend occurred through areas 4 and 6. The differences in arbour structure may determine the number of inputs received by neurons and may thus be an important factor in determining function at the cellular and systems level.

Parvalbumin-, calbindin-, and calretinin-immunoreactive neurons in the prefrontal cortex of the owl monkey (Aotus trivirgatus): A standardized quantitative comparison with sensory and motor areas

Recent studies have revealed regional variation in the density and distribution of inhibitory neurons in different cortical areas, which are thought to reflect area-specific specializations in cortical circuitry. However, there are as yet few standardized quantitative data regarding how the inhibitory circuitry in prefrontal cortex (PFC), which is thought to be involved in executive functions such as cognition, emotion and decision making, compares to that in other cortical areas. Here we used immunohistochemical techniques to determine the density and distribution of parvalbumin (PV)-, calbindin (CB)-, and calretinin (CR)-immunoreactive (ir) neurons and axon terminals in the dorsolateral and orbital PFC of the owl monkey (Aotus trivirgatus), and compared them directly with data obtained using the same techniques in 11 different visual, somatosensory and motor areas. We found marked differences in the density of PV-ir, CB-ir, and CR-ir interneurons in several cortical areas. One hundred and twenty eight of all 234 possible between-area pairwise comparisons were significantly different. The density of specific subpopulations of these cells also varied among cortical areas, as did the density of axon terminals. Comparison of PFC with other cortical areas revealed that 40 of all 66 possible statistical comparisons of the density of PV-ir, CB-ir, and CR-ir cells were significantly different. We also found evidence for heterogeneity in the pattern of labeling of PV-ir, CB-ir, and CR-ir cells and axon terminals between the dorsolateral and orbital subdivisions of PFC. These data are likely to reflect basic differences in interneuron circuitry, which are likely to influence inhibitory function in the cortex. Copyright (C) 2003 S. Karger AG, Basel.

Cortex, cognition and the cell: New insights into the pyramidal neuron and prefrontal function

Arguably the most complex conical functions are seated in human cognition, the how and why of which have been debated for centuries by theologians, philosophers and scientists alike. In his best-selling book, An Astonishing Hypothesis: A Scientific Search for the Soul, Francis Crick refined the view that these qualities are determined solely by cortical cells and circuitry. Put simply, cognition is nothing more, or less, than a biological function. Accepting this to be the case, it should be possible to identify the mechanisms that subserve cognitive processing. Since the pioneering studies of Lorent de No and Hebb, and the more recent studies of Fuster, Miller and Goldman-Rakic, to mention but a few, much attention has been focused on the role of persistent neural activity in cognitive processes. Application of modern technologies and modelling techniques has led to new hypotheses about the mechanisms of persistent activity. Here I focus on how regional variations in the pyramidal cell phenotype may determine the complexity of cortical circuitry and, in turn, influence neural activity. Data obtained from thousands of individually injected pyramidal cells in sensory, motor, association and executive cortex reveal marked differences in the numbers of putative excitatory inputs received by these cells. Pyramidal cells in prefrontal cortex have, on average, up to 23 times more dendritic spines than those in the primary visual area. I propose that without these specializations in the structure of pyramidal cells, and the circuits they form, human cognitive processing would not have evolved to its present state. I also present data from both New World and Old World monkeys that show varying degrees of complexity in the pyramidal cell phenotype in their prefrontal cortices, suggesting that cortical circuitry and, thus, cognitive styles are evolving independently in different species.

Pyramidal cell heterogeneity in the visual cortex of the nocturnal new world owl monkey (aotus trivirgatus)

Recent studies have revealed marked variation in pyramidal cell structure in the visual cortex of macaque and marmoset monkeys. In particular, there is a systematic increase in the size of, and number of spines in, the arbours of pyramidal cells with progression through occipitotemporal (OT) visual areas. In the present study we extend the basis for comparison by investigating pyramidal cell structure in visual areas of the nocturnal owl monkey. As in the diurnal macaque and marmoset monkeys, pyramidal cells became progressively larger and more spinous with anterior progression through OT visual areas. These data suggest that: 1. the trend for more complex pyramidal cells with anterior progression through OT visual areas is a fundamental organizational principle in primate cortex; 2. areal specialization of the pyramidal cell phenotype provides an anatomical substrate for the reconstruction of the visual scene in OT areas; 3. evolutionary specialization of different aspects of visual processing may determine the extent of interareal variation in the pyramidal cell phenotype in different species; and 4. pyramidal cell structure is not necessarily related to brain size. Crown Copyright (C) 2003 Published by Elsevier Science Ltd on behalf of IBRO. All rights reserved.

Expression of hNP22 is altered in the frontal cortex and hippocampus of the alcoholic human brain

Background: Human neuronal protein (hNP22) is a gene with elevated messenger RNA expression in the prefrontal cortex of the human alcoholic brain. hNP22 has high homology with a rat protein (rNP22). These proteins also share homology with a number of cytoskeleton-interacting proteins. Methods: A rabbit polyclonal antibody to an 18-amino acid epitope was produced for use in Western and immunohistochemical analysis. Samples from the human frontal and motor cortices were used for Western blots (n = 10), whereas a different group of frontal cortex and hippocampal samples were obtained for immunohistochemistry (n = 12). Results: The hNP22 antibody detected a single protein in both rat and human brain. Western blots revealed a significant increase in hNP22 protein levels in the frontal cortex but not the motor cortex of alcoholic cases. Immunohistochemical studies confirmed the increased hNP22 protein expression in all cortical layers. This is consistent with results previously obtained using Northern analysis. Immunohistochemical analysis also revealed a significant increase of hNP22 immunoreactivity in the CA3 and CA4 but not other regions of the hippocampus. Conclusions: It is possible that this protein may play a role in the morphological or plastic changes observed after chronic alcohol exposure and withdrawal, either as a cytoskeleton-interacting protein or as a signaling molecule.

The pyramidal neuron in occipital, temporal and prefrontal cortex of the owl monkey (Aotus trivirgatus): regional specialization in cell structure

Recent studies have revealed marked regional variation in pyramidal cell morphology in primate cortex. In particular, pyramidal cells in human and macaque prefrontal cortex (PFC) are considerably more spinous than those in other cortical regions. PFC pyramidal cells in the New World marmoset monkey, however, are less spinous than those in man and macaques. Taken together, these data suggest that the pyramidal cell has become more branched and more spinous during the evolution of PFC in only some primate lineages. This specialization may be of fundamental importance in determining the cognitive styles of the different species. However, these data are preliminary, with only one New World and two Old World species having been studied. Moreover, the marmoset data were obtained from different cases. In the present study we investigated PFC pyramidal cells in another New World monkey, the owl monkey, to extend the basis for comparison. As in the New World marmoset monkey, prefrontal pyramidal cells in owl monkeys have relatively few spines. These species differences appear to reflect variation in the extent to which PFC circuitry has become specialized during evolution. Highly complex pyramidal cells in PFC appear not to have been a feature of a common prosimian ancestor, but have evolved with the dramatic expansion of PFC in some anthropoid lineages.

Dendritic branching of pyramidal cells in the visual cortex of the nocturnal owl monkey: A fractal analysis

The branching structure of neurones is thought to influence patterns of connectivity and how inputs are integrated within the arbor. Recent studies have revealed a remarkable degree of variation in the branching structure of pyramidal cells in the cerebral cortex of diurnal primates, suggesting regional specialization in neuronal function. Such specialization in pyramidal cell structure may be important for various aspects of visual function, such as object recognition and color processing. To better understand the functional role of regional variation in the pyramidal cell phenotype in visual processing, we determined the complexity of the dendritic branching pattern of pyramidal cells in visual cortex of the nocturnal New World owl monkey. We used the fractal dilation method to quantify the branching structure of pyramidal cells in the primary visual area (V1), the second visual area (V2) and the caudal and rostral subdivisions of inferotemporal cortex (ITc and ITr, respectively), which are often associated with color processing. We found that, as in diurnal monkeys, there was a trend for cells of increasing fractal dimension with progression through these cortical areas. The increasing complexity paralleled a trend for increasing symmetry. That we found a similar trend in both diurnal and nocturnal monkeys suggests that it was a feature of a common anthropoid ancestor.