Subpopulation Of Pyramidal Neurons Research Articles

Distinct ventral hippocampal inhibitory microcircuits regulating anxiety and fear behaviors

In emotion research, anxiety and fear have always been interconnected, sharing overlapping brain structures and neural circuitry. Recent investigations, however, have unveiled parallel long-range projection pathways originating from the ventral hippocampus, shedding light on their distinct roles in anxiety and fear. Yet, the mechanisms governing the emergence of projection-specific activity patterns to mediate different negative emotions remain elusive. Here, we show a division of labor in local GABAergic inhibitory microcircuits of the ventral hippocampus, orchestrating the activity of subpopulations of pyramidal neurons to shape anxiety and fear behaviors in mice. These findings offer a comprehensive insight into how distinct inhibitory microcircuits are dynamically engaged to encode different emotional states.

Nutritional Imbalance between Omega-6 and Omega-3 Polyunsaturated Fatty Acids during Pregnancy Increases the Number of Pyramidal Neurons in the Basolateral Amygdala and Anxiety-Related Behavior in Offspring.

Modern agriculture allows for the production of foods that are high in n-6 linoleic acid and low in n-3 α-linolenic acid (LAhigh/ALAlow), which are suggested to be associated with an increased risk for the onset of anxiety disorders. However, there is not sufficient evidence to understand its underlying brain mechanism. Given that mouse offspring derived from mothers fed a LAhigh/ALAlow diet during gestation and early lactation showed increased anxiety-related behaviors and that rodents exposed to a LAhigh/ALAlow diet are more vulnerable to stress, in this study, we investigated the effects of maternal LAhigh/ALAlow diet consumption on stress-induced anxiety-related behavior and the brain structures involved in the expression of negative emotional states in mouse offspring. In a standard environment, offspring exposed to either the control diet or the LAhigh/ALAlow diet in utero showed similar stay times in the center zone in the open field test. On the other hand, under stressful environments, offspring exposed to the LAhigh/ALAlow diet in utero showed decreased stay times in the center zone compared to those exposed to the control diet. We further found that the number of a subpopulation of pyramidal neurons in the basolateral amygdala, which can regulate negative emotional behaviors, was greater in the offspring exposed to the LAhigh/ALAlow diet compared to those exposed to the control diet. These data suggest that maternal dietary imbalance between n-6 and n-3 polyunsaturated fatty acids confers stress vulnerability to offspring during the process of brain development.

Genetic dissection of the glutamatergic neuron system in cerebral cortex

Diverse types of glutamatergic pyramidal neurons mediate the myriad processing streams and output channels of the cerebral cortex1,2, yet all derive from neural progenitors of the embryonic dorsal telencephalon3,4. Here we establish genetic strategies and tools for dissecting and fate-mapping subpopulations of pyramidal neurons on the basis of their developmental and molecular programs. We leverage key transcription factors and effector genes to systematically target temporal patterning programs in progenitors and differentiation programs in postmitotic neurons. We generated over a dozen temporally inducible mouse Cre and Flp knock-in driver lines to enable the combinatorial targeting of major progenitor types and projection classes. Combinatorial strategies confer viral access to subsets of pyramidal neurons defined by developmental origin, marker expression, anatomical location and projection targets. These strategies establish an experimental framework for understanding the hierarchical organization and developmental trajectory of subpopulations of pyramidal neurons that assemble cortical processing networks and output channels.

Mechanisms Underlying Serotonergic Excitation of Callosal Projection Neurons in the Mouse Medial Prefrontal Cortex.

Serotonin (5-HT) selectively excites subpopulations of pyramidal neurons in the neocortex via activation of 5-HT2A (2A) receptors coupled to Gq subtype G-protein alpha subunits. Gq-mediated excitatory responses have been attributed primarily to suppression of potassium conductances, including those mediated by KV7 potassium channels (i.e., the M-current), or activation of non-specific cation conductances that underlie calcium-dependent afterdepolarizations (ADPs). However, 2A-dependent excitation of cortical neurons has not been extensively studied, and no consensus exists regarding the underlying ionic effector(s) involved. In layer 5 of the mouse medial prefrontal cortex, we tested potential mechanisms of serotonergic excitation in commissural/callosal (COM) projection neurons, a subpopulation of pyramidal neurons that exhibits 2A-dependent excitation in response to 5-HT. In baseline conditions, 5-HT enhanced the rate of action potential generation in COM neurons experiencing suprathreshold somatic current injection. This serotonergic excitation was occluded by activation of muscarinic acetylcholine (ACh) receptors, confirming that 5-HT acts via the same Gq-signaling cascades engaged by ACh. Like ACh, 5-HT promoted the generation of calcium-dependent ADPs following spike trains. However, calcium was not necessary for serotonergic excitation, as responses to 5-HT were enhanced (by >100%), rather than reduced, by chelation of intracellular calcium with 10 mM BAPTA. This suggests intracellular calcium negatively regulates additional ionic conductances gated by 2A receptors. Removal of extracellular calcium had no effect when intracellular calcium signaling was intact, but suppressed 5-HT response amplitudes, by about 50%, when BAPTA was included in patch pipettes. This suggests that 2A excitation involves activation of a non-specific cation conductance that is both calcium-sensitive and calcium-permeable. M-current suppression was found to be a third ionic effector, as blockade of KV7 channels with XE991 (10 μM) reduced serotonergic excitation by ∼50% in control conditions, and by ∼30% with intracellular BAPTA present. Together, these findings demonstrate a role for at least three distinct ionic effectors, including KV7 channels, a calcium-sensitive and calcium-permeable non-specific cation conductance, and the calcium-dependent ADP conductance, in mediating serotonergic excitation of COM neurons.

Diverse Patterns of Odor Representation by Neurons in the Anterior Piriform Cortex of Awake Mice

The mammalian piriform cortex receives direct synaptic input from the olfactory bulb and is likely the locus for the formation of odor percept. It remains unclear how individual cortical neurons encode olfactory information in unanesthetized animals. By single-cell recordings from head-restrained awake mice, we studied the odor response profiles of individual neurons in the anterior piriform cortex (aPCX). Neurons were juxtacellularly labeled, and their cell types were determined by their morphology and neurotransmitter phenotypes. We found a considerable level of variability in selectivity patterns among pyramidal neurons (PNs). Approximately one-quarter of PNs were broadly activated by structurally dissimilar odorants, whereas the excitations to the rest of PNs were highly selective. Broad inhibition was only observed from a subpopulation of PNs. GABAergic neurons displayed nonselective excitatory responses to test odorants and rarely exhibited inhibition. In contrast, non-GABAergic nonpyramidal neurons in the deep layer tended to be strongly inhibited by multiple different odorants. Our findings suggest that odor representation is accomplished by both broadly tuned and narrow-tuned PNs in the aPCX of awake animals. In addition, various types of interneurons may play different roles in the intracortical processing of olfactory information.

Focal Damage to the Adult Rat Neocortex Induces Wound Healing Accompanied by Axonal Sprouting and Dendritic Structural Plasticity

Accumulating evidence indicates that damage to the adult mammalian brain evokes an array of adaptive cellular responses and may retain a capacity for structural plasticity. We have investigated the cellular and architectural alterations following focal experimental brain injury, as well as the specific capacity for structural remodeling of neuronal processes in a subset of cortical interneurons. Focal acute injury was induced by transient insertion of a needle into the neocortex of anesthetized adult male Hooded-Wistar rats and thy1 green fluorescent protein (GFP) mice. Immunohistochemical, electron microscopy, and bromodeoxyuridine cell proliferation studies demonstrated an active and evolving response of the brain to injury, indicating astrocytic but not neuronal proliferation. Immunolabeling for the neuron-specific markers phosphorylated neurofilaments, α-internexin and calretinin at 7 days post injury (DPI) indicated phosphorylated neurofilaments and α-internexin but not calretinin immunopositive axonal sprouts within the injury site. However, quantitative studies indicated a significant realignment of horizontally projecting dendrites of calretinin-labeled interneurons at 14 DPI. This remodeling was specific to calretinin immunopositive interneurons and did not occur in a subpopulation of pyramidal neurons expressing GFP in the injured mouse cortex. These data show that subclasses of cortical interneurons are capable of adaptive structural remodeling.

Continuous nicotine administration produces selective, age‐dependent structural alteration of pyramidal neurons from prelimbic cortex

Emerging evidence indicates that adolescence represents a developmental window of enhanced nicotine-induced neuroplasticity in rat forebrain. However, whether nicotine produces age-dependent structural alteration of neurons from medial prefrontal cortex remains to be determined. We characterized the dendritic morphology of layer V pyramidal neurons from prelimbic cortex following adolescent (P29-43) or adult (P80-94) nicotine pretreatment. Nicotine administration was via osmotic pump [initial dose 2.0 mg/(kg day), free base]. Five weeks after drug administration concluded, brains were processed for Golgi-Cox staining and pyramidal neurons digitally reconstructed for morphometric analysis. Overall, nicotine pretreatment produced increased basilar, but not apical, dendritic length of pyramidal cells, a finding consistent with previous work using adult animals. Given the compelling evidence for morphologically distinct functional subtypes of cortical pyramidal neurons, we endeavored to determine whether nicotine-induced dendritic alteration was specific to putative structural subtypes. Neurons were segregated into two groups based on the extent of dendritic arbor at the distal portion of the apical tree (i.e., the apical tuft). The size of the apical tuft was quantitatively determined using principal component analysis. Cells with small and elaborate apical tufts were classified as simple and complex, respectively. We found that adult nicotine pretreatment produced increased basilar dendritic length and branch number in simple but not complex pyramidal cells. In contrast, adolescent nicotine pretreatment produced a modest but significant increase in basilar dendritic length in complex but not simple cells. These data suggest that nicotine alters dendritic morphology of specific subpopulations of pyramidal neurons and that the subpopulation affected is dependent on the age of drug exposure.

Aromatase expression in the human temporal cortex

The expression of the human cyp19 gene, encoding P450 aromatase, the key enzyme for estrogen biosynthesis, involves alternative splicing of multiple forms of exon I regulated by different promoters. Aromatase expression has been detected in the human cerebral cortex, although the precise cellular distribution and promoter regulation are not fully characterized. We examined the variants of exon I of cyp19 by PCR analysis and the cellular distribution of the enzyme using immunohistochemistry in the human temporal cortex. We detected four different variants of exon I, suggesting a complex regulation of cyp19 in the cerebral cortex. In addition, the enzyme was localized mainly in a large subpopulation of pyramidal neurons and in a subpopulation of astrocytes. However, the majority of GABAergic interneurons identified by their expression of the calcium-binding proteins calbindin, calretinin and parvalbumin, did not display aromatase immunoreactivity. The broad range of potential modulators of the cyp19 gene in the cortex and the widespread expression of the protein in specific neuronal and glial subpopulations suggest that local estrogen formation may play an important role in human cortical function.

Mossy cells and different subpopulations of pyramidal neurons are immunoreactive for cocaine- and amphetamine-regulated transcript peptide in the hippocampal formation of non-human primates and tree shrew ( Tupaia belangeri)

Cocaine- and amphetamine-regulated transcript peptide mRNA was discovered in the rat striatum following cocaine and amphetamine administration. Since both psychostimulants elicit memory-related effects, localization of cocaine- and amphetamine-regulated transcript peptide in the hippocampal formation may have functional importance. Previous studies demonstrated different cellular localizations of cocaine- and amphetamine-regulated transcript peptide in humans and in rodents. Mossy cells were cocaine- and amphetamine-regulated transcript-positive in the human dentate gyrus, whereas granule cells contained this peptide in the rat. In the present study, the localization of cocaine- and amphetamine-regulated transcript peptide was examined using immunohistochemistry in the hippocampal formation of the rhesus monkey ( Macaca mulatta), the common marmoset monkey ( Callithrix jacchus) and in the tree shrew ( Tupaia belangeri). In these species principal neurons of the hippocampal formation were cocaine- and amphetamine-regulated transcript-immunoreactive. In both monkeys and tree shrews, mossy cells of the hilus were cocaine- and amphetamine-regulated transcript-positive whereas granule cells of the dentate gyrus were cocaine- and amphetamine-regulated transcript-negative. The dense cocaine- and amphetamine-regulated transcript-immunoreactive axonal plexus of the associational pathway outlined the inner one-third of the dentate molecular layer. In the hippocampus of the tree shrew and marmoset monkey, a subset of CA3 pyramidal cells were cocaine- and amphetamine-regulated transcript-immunoreactive. In the marmoset monkey, cocaine- and amphetamine-regulated transcript labeling was found only in layer V pyramidal cells of the entorhinal cortex, while in the rhesus monkey, pyramidal cells of layers II and III were cocaine- and amphetamine-regulated transcript-immunopositive. Our results show that cocaine- and amphetamine-regulated transcript positive neurons in the dentate gyrus of non-human primates are similar to that of the human. Furthermore, in the hippocampal formation of the tree shrew similar cocaine- and amphetamine-regulated transcript-immunoreactive cell-types were observed as in monkeys, supporting their evolutionary relationship with primates. Mossy cells and granule cells are members of a mutual excitatory intrahippocampal circuitry, therefore cocaine- and amphetamine-regulated transcript-immunoreactivity of these neurons in primates and rodents suggests that psychostimulants cocaine and amphetamine may induce memory-related effects at different points of the same excitatory circuitry in the hippocampal formation.

Altered cortical glutamate neurotransmission in schizophrenia: evidence from morphological studies of pyramidal neurons.

Multiple lines of evidence from pharmacological, neuroimaging, and postmortem studies implicate disturbances in cortical glutamate neurotransmission in the pathophysiology of schizophrenia. Given that pyramidal neurons are the principal source of cortical glutamate neurotransmission, as well as the targets of the majority of cortical glutamate-containing axon terminals, understanding the nature of altered glutamate neurotransmission in schizophrenia requires an appreciation of both the types of pyramidal cell abnormalities and the specific class(es) of pyramidal cells that are affected in the illness. In this chapter, we review evidence indicating that a subpopulation of pyramidal neurons in the dorsolateral prefrontal cortex exhibits reductions in dendritic spine density, a marker of the number of excitatory inputs, and in somal volume, a measure correlated with a neuron's dendritic and axonal architecture. Specifically, pyramidal neurons located in deep layer 3 of the dorsolateral prefrontal cortex and that lack immunoreactivity for nonphosphorylated neurofilament protein may be particularly involved in the pathophysiology of schizophrenia. The presence of similar changes in pyramidal neurons located in deep layer 3 of auditory association cortex suggests that a shared property, which remains to be determined, confers cell type-specific vulnerability to a subpopulation of cortical glutamatergic neurons in schizophrenia.

The distribution and morphology of prefrontal cortex pyramidal neurons identified using anti-neurofilament antibodies SMI32, N200 and FNP7. Normative data and a comparison in subjects with schizophrenia, bipolar disorder or major depression

Alterations in the density and size of pyramidal neurons in the prefrontal cortex have been described in schizophrenia and mood disorder. However, the changes are generally modest and have not always been replicated. We investigated the possibility that specific pyramidal neuron sub-populations, defined by their immunoreactivity with the anti-neurofilament antibodies SMI32, N200, and FNP7, are differentially affected in these disorders. First, we assessed the distribution and characteristics of pyramidal neurons labelled by the antibodies in the human dorsolateral prefrontal cortex (Brodmann areas 9, 32, 46), using single and double label immunocytochemistry and immunofluorescence. Three largely separate sub-populations of pyramidal neurons were identified, although with more substantial overlap between SMI32- and FNP7-positive neurons in lamina V. We then determined the density, size and shape of the three pyramidal neuron sub-populations in area 9 in patients with schizophrenia, bipolar disorder, or major depressive disorder, compared to controls ( n=15 in each group). We found a lower density of lamina III N200-positive neurons in major depressive disorder than in schizophrenia or bipolar disorder. There were no other overall differences in neuronal density, or in neuronal size or shape, although a planned secondary analysis supported the previously reported decrease of neuronal size in lamina V in bipolar disorder. In summary, our study illustrates a conceptual and methodological approach which may be of value for investigating the differential neuropathological involvement of pyramidal neuron sub-populations. However, we found no clear evidence that the prefrontal neuropathology of schizophrenia or mood disorders preferentially affects SMI32-, N200- or FNP7-immunoreactive pyramidal neurons.

Epilepsy and Excitation Explored

Human temporal lobe epilepsy is a severe and potentially life-threatening disorder. Cohen et al. (see the Perspective by Köhling) recorded from neurons in specimens from epileptic patients who had undergone surgery for treatment of the disease. In a brain area called the subiculum, they observed synchronous discharges reminiscent of the patients' EEG records. In a subpopulation of pyramidal neurons from this area, GABAergic input was not inhibitory but rather depolarizing and therefore excitatory. I. Cohen, V. Navarro, S. Clemenceau, M. Baulac, R. Miles, On the origin of interictal activity in human temporal lobe epilepsy in vitro. Science 298 , 1418-1421 (2002). [Abstract] [Full Text] R. Köhling, GABA becomes exciting. Science 298 , 1350-1351 (2002). [Summary] [Full Text]

Neuronal expression of glutamine synthetase in Alzheimer’s disease indicates a profound impairment of metabolic interactions with astrocytes

A considerable body of evidence indicates that the activity of glutamine synthetase is decreased in the cerebral cortices of brains affected by Alzheimer’s disease. It is difficult to discern the reason for this decrease because it is not known whether the cellular distribution of glutamine synthetase is altered in Alzheimer’s disease. Therefore the present study has used immunocytochemistry to compare the cellular distributions of glutamine synthetase in the inferior temporal cortices of six Alzheimer’s diseased brains and six age-matched, non-demented brains. Double-label immunocytochemistry has been used to examine whether the distribution of cellular glutamine synthetase is influenced by the distribution of senile plaques. It was found that glutamine synthetase expression in astrocytes is diminished in Alzheimer’s disease, particularly in the vicinity of senile plaques. The most striking finding of the present study was that glutamine synthetase was expressed in a subpopulation of pyramidal neurons in all six Alzheimer’s diseased brains, whereas glutamine synthetase was not observed in any neurons from control brains. The changed expression of glutamine synthetase may be triggered by toxic agents in senile plaques, a reduced noradrenergic supply to the cerebral cortex, and increased brain ammonia levels. That such dramatic changes occur in the distribution of this critical, and normally stable enzyme, suggests that the glutamate–glutamine cycle is profoundly impaired in Alzheimer’s disease. This is significant because impairments of the glutamate–glutamine cycle are known to cause alterations of mood and behaviour, disturbance of sleeping patterns, amnesia, confusion and reduced awareness. Since these behavioural changes are also seen in Alzheimer’s disease, it is speculated that they might be attributable to the reduced expression of glutamine synthetase or to impairments of the glutamate–glutamine cycle.

Immunohistochemical localization of connective tissue growth factor in the rat central nervous system

Connective tissue growth factor (CTGF) is an immediate early growth-responsive gene but its distribution and significance in the central nervous system (CNS) are unknown. We investigated the distribution of CTGF-like immunoreactivity (CTGF-IR) in the rat CNS using a specific antiserum against CTGF oligopeptide. The majority of CTGF-IR was observed in astrocytes. Ependymal cells lining the wall of the cerebral ventricle and tanycytes lining the central canal of the spinal cord showed the strongest CTGF-IR, while there was a diffuse but weak signal in the gray matter of the spinal cord. CTGF-IR was also detected in the cytoplasm of a subpopulation of pyramidal neurons in the cerebral cortex. Our results showed that CTGF-IR is widely distributed in the CNS at both regional and cellular levels, suggesting a complex functional role in the CNS.

Axosomatic input to subpopulations of cortically projecting pyramidal neurons in primate prefrontal cortex.

Pyramidal cells, the major class of cortical excitatory neurons, can be divided into different subpopulations based upon the target region of their principal axon projection. The activity of pyramidal neurons is regulated in part through inhibitory synaptic inputs to the soma from local circuit neurons. However, little is known about how the density of these axosomatic inputs differs among subpopulations of pyramidal neurons in the prefrontal cortex of primates. In this study, retrograde transport of wheat germ agglutinin-horseradish peroxidase (WGA-HRP) was used to identify pyramidal neurons in monkey prefrontal cortex (areas 9 and 46), which were labeled via either associational (ipsilateral hemisphere) or callosal (contralateral hemisphere) principal axon projections. Ultrastructural analysis revealed that the relative number of terminals apposed to the somatic membrane did not differ between associational and callosal neurons. However, neurons in the supragranular layers were apposed by a significantly greater number of axon terminals than were neurons in the infragranular layers. These findings suggest that the laminar environment of a neuron may play a more important role than principal axon projection in determining the amount of axosomatic inhibitory input it receives.

Collateral projections from the rat hippocampal formation to the lateral and medial prefrontal cortex.

Projections from the hippocampal formation to the medial prefrontal cortex are well known. In this report we used two retrogradely transported tracers to show that a small but significant subpopulation of pyramidal neurons in area CA1 and subiculum of the hippocampal formation projects to the lateral prefrontal cortex. About half of these neurons also possess collateral projections to the medial prefrontal cortex. The neurons projecting only to the lateral PFC are found in the intermediate hippocampal formation and in the most ventral part of the temporal subdivision. On the other hand, most of the neurons projecting to the medial prefrontal cortex only are present in the temporal and ventral intermediate hippocampal formation, and their number decreases in the dorsal intermediate subdivision. The distribution of neurons having collateral projections is comparable to that of neurons projecting to the medial prefrontal cortex only. In view of proposed functional differences between the septal one-third and the temporal two-third of the hippocampal formation, it is of interest that the neurons projecting to the prefrontal cortex are only present in the temporal two-thirds.

Structure and Cellular Distribution of Mouse Brain Testican: ASSOCIATION WITH THE POSTSYNAPTIC AREA OF HIPPOCAMPUS PYRAMIDAL CELLS

The complete deduced primary structure of mouse brain testican has been established from cDNA cloning. The cDNA encodes a polypeptide of 442 amino acids belonging to the proteoglycan family. The mouse brain testican core protein is 95% identical to its human testicular counterpart. In situ hybridization investigations revealed that mouse testican mRNA is mainly present in a subpopulation of pyramidal neurons localized in the CA3 area of the hippocampus. An immunocytochemical approach, with antibodies directed against an overexpressed chimeric antigen, produced in bacterial systems, showed that testican is associated with the postsynaptic region of these pyramidal neurons. Testican includes several putative functional domains related to extracellular or pericellular proteins associated with binding and/or regulatory functions. On the basis of its structural organization and its occurrence in postsynaptic areas, this proteoglycan might contribute to various neuronal mechanisms in the central nervous system.

Layer I of primary sensory neocortex: where top-down converges upon bottom-up

A fundamental paradigm shift is underway in the behavioural neurosciences which promotes renewed discussion of neural correlates of conscious sensation. A growing body of evidence that the primary sensory areas are central to conscious processing is inconsistent with conventional bottom-up models of passive sensory transformation. The new paradigm emphasizes the interaction of top-down corticocortical influences with bottom-up sensory feedback. This review develops the new interactive paradigm with respect to the behaviourally relevant N1 component of the somatosensory evoked response in primary somatosensory neocortex which is only observed during conscious states and predicts touch discrimination behaviour. N1 is generated by layer I excitation apparently in response to backward projections from higher order cortical areas. The backward corticocortical projections mediating top-down influences are anatomically concentrated in layer I where they strongly excite the subpopulation of pyramidal neurons with extensive distal apical dendrites. This subpopulation includes the forward-projecting pyramids subserving corticocortical reentrance as well as the corticobulbar projections mediating cortical control over fine sensory-oriented movements. This interactive paradigm views conscious sensation as an active behaviour with the optimal spatial resolution of primary areas serving as the sensory-motor interface at the major convergence point between reentrant bottom-up and top-down pathways. A device is proposed for the reconstruction of cortical sensory processing based upon the central importance of the primary area as the focus of convergent top-down cortical projections.

Spindle neurons of the human anterior cingulate cortex.

The human anterior cingulate cortex is distinguished by the presence of an unusual cell type, a large spindle neuron in layer Vb. This cell has been noted numerous times in the historical literature but has not been studied with modern neuroanatomic techniques. For instance, details regarding the neuronal class to which these cells belong and regarding their precise distribution along both ventrodorsal and anteroposterior axes of the cingulate gyrus are still lacking. In the present study, morphological features and the anatomic distribution of this cell type were studied using computer-assisted mapping and immunocytochemical techniques. Spindle neurons are restricted to the subfields of the anterior cingulate cortex (Brodmann's area 24), exhibiting a greater density in anterior portions of this area than in posterior portions, and tapering off in the transition zone between anterior and posterior cingulate cortex. Furthermore, a majority of the spindle cells at any level is located in subarea 24b on the gyral surface. Immunocytochemical analysis revealed that the neurofilament protein triple was present in a large percentage of these neurons and that they did not contain calcium-binding proteins. Injections of the carbocyanine dye DiI into the cingulum bundle revealed that these cells are projection neurons. Finally, spindle cells were consistently affected in Alzheimer's disease cases, with an overall loss of about 60%. Taken together, these observations indicate that the spindle cells of the human cingulate cortex represent a morphological subpopulation of pyramidal neurons whose restricted distribution may be associated with functionally distinct areas.

The iron-binding protein lactotransferrin is present in pathologic lesions in a variety of neurodegenerative disorders: a comparative immunohistochemical analysis

Lactotransferrin is a glycoprotein that specifically binds and transports iron. This protein is also believed to transport other metals such as aluminum. Several lines of evidence indicate that iron and aluminum are involved in the pathogenesis of many dementing diseases. In this context, the analysis of the iron-binding protein distribution in the brains of patients affected by neurodegenerative disorders is of particular interest. In the present study, the distribution of lactotransferrin was analyzed by immunohistochemistry in the cerebral cortex from patients presenting with Alzheimer's disease, Down syndrome, amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam, sporadic amyotrophic lateral sclerosis, or Pick's disease. The results show that lactotransferrin accumulates in the characteristic lesions of the different pathologic conditions investigated. For instance, in Alzheimer's disease and Guamanian cases, a subpopulation of neurofibrillary tangles was intensely labeled in the hippocampal formation and inferior temporal cortex. Senile plaques and Pick bodies were also consistently labeled. These staining patterns were comparable to those obtained with antibodies to the microtubule-associated protein tau and the amyloid βA4 protein, although generally fewer neurofibrillary tangles were positive for lactotransferrin than for tau protein. Neuronal cytoplasmic staining with lactotransferrin antibodies, was observed in a subpopulation of pyramidal neurons in normal aging, and was more pronounced in Alzheimer's disease, Guamanian cases, Pick's disease, and particularly in Down syndrome. Lactotransferrin was also strongly associated with Betz cells and other motoneurons in the primary motor cortex of control, Alzheimer's disease, Down syndrome, Guamanian and Pick's disease cases. These same lactotransferrin-immunoreactive motoneurons were severely affected in the cases with amyotrophic lateral scleorosis. It is possible that in these neurodegenerative disorders affected neurons either take up or synthesize lactotransferrin to an abnormally elevated rate. An excessive accumulation of lactotransferrin, as well as transported iron and aluminum, may lead to a cytotoxic effect resulting in the formation of intracellular lesions and neuronal death.