The anterior cingulate cortex in autism: heterogeneity of qualitative and quantitative cytoarchitectonic features suggests possible subgroups

Autism is a behaviorally defined disorder with deficits in social interaction, communication, atypical behaviors, and restricted areas of interest. Postmortem studies of the brain in autism have shown a broad spectrum of abnormalities in the cerebellum and neocortex, involving limbic regions such as anterior cingulate cortex (ACC, Brodmann’s area 24). Using stereological techniques, we analyzed quantitatively cytoarchitectonic subdomains of the ACC (areas 24a, b, c) with regard to cell packing density and cell size. Microscopic examination of the ACC was also done to identify any neuropathologies. Results showed a significant decrease in cell size in layers I–III and layers V–VI of area 24b and in cell packing density in layers V–VI of area 24c. Direct comparisons revealed irregular lamination in three of nine autism brains and increased density of neurons in the subcortical white matter in the remaining cases. Because previous studies have suggested that von Economo neurons (VENs) may be altered in autism, a preliminary study of their density and size was undertaken. VEN density did not differ between autism and control brains overall. However, among the nine autism cases, there were two subsets; three brains with significantly increased VEN density and the remaining six cases with reduced VEN density compared to controls. Collectively, the findings of this pilot study may reflect the known heterogeneity in individuals with autism and variations in clinical symptomotology. Further neuroanatomic analyses of the ACC, from carefully documented subjects with autism, could substantially expand our understanding of ACC functions and its role in autism.     

Quantitative analysis of a vulnerable subset of pyramidal neurons in Alzheimer's disease: II. Primary and secondary visual cortex.

In this study we investigated the primary and secondary visual areas of normal and Alzheimer's disease brains by using the SMI32 antibody. It is known that in Alzheimer's disease primary sensory areas are usually less devastated than association cortices, although visual symptomatology has been documented early in the course of the disease. In area 17, the SMI32 antibody primarily labeled the perikarya and dentritic tree of the large Meynert cells and cells in layer IVB. Smaller neurons in layers III, V, and VI were also immunoreactive (ir). In area 18, very large SMI32-ir pyramidal neurons in layers III and V were observed. In both areas, staining intensity was correlated with cell size, the largest neurons being the most intensely stained. Only a few changes were observed in the Alzheimer's disease cases. The only statistically significant differences in SMI32-ir neuron counts between control and Alzheimer's disease brains occurred in layer IVB cells and Meynert cells in area 17, and in layer III cells in area 18. In contrast with association cortices, there were no changes in staining intensity in the visual areas. There were fewer neurofibrillary tangles and neuritic plaques in these areas than in prefrontal and inferior temporal cortex, and a correlation between neurofibrillary tangle counts and SMI32-ir neuron loss was only observed in layer III of area 18. These observations show that in the primary and secondary visual cortex, SMI32 also labeled a distinct subset of pyramidal cells that are known from data obtained in the monkey brain to furnish long corticocortical as well as subcortical projections. Interestingly, although there is much less cell and/or neurofibrillary tangle formation in these occipital regions than in prefrontal and temporal association areas, there is significant loss within key subsets of pyramidal cells. The selective loss of this particular subpopulation of pyramidal neurons will disrupt association pathways linking primary visual cortex with areas involved in higher level visual processing. The partial disconnection of such pathways may be relevant to the visual symptomatology frequently observed in Alzheimer's disease patients. These data further support the hypothesis that subtypes of pyramidal neurons with specific anatomical and molecular profiles may display a differential vulnerability in Alzheimer's disease.     

Interconnections of the visual cortex with the frontal cortex in the rat

Horseradish peroxidase conjugated to wheat germ agglutinin (WGA-HRP) and autoradiography of tritiated leucine were used to trace the cortical origins and terminations of the connections between the visual and frontal cortices in the rat. Ipsilateral reciprocal connections between each subdivision of the visual cortex (areas 17, 18a and 18b) and the posterior half of the medial part of the frontal agranular cortex (PAGm), and their laminar organizations were confirmed. These connections did not appear to have a significant topographic organization. Although in areas 17 and 18b terminals or cells of origin in this fiber system were confined to the anterior half of these cortices, in area 18a they were observed spanning the anteroposterior extent of this cortex, with in part a column like organization. No evidence could be found for the participation of both the posterior parts of areas 17 and 18b and the anterior half of this frontal agranular cortex in these connections. Fibers from each subdivision of the visual cortex to the PAGm terminated predominantly in the lower part of layer I and in layer II. In area 17, this occipito-frontal projection was found to arise from the scattered pyramidal cells in layer V and more prominently from pyramidal cells in layer V of area 17/18a border. In area 18a, the fibers projecting to the PAGm originated mainly from pyramidal cells primarily in layer V and to a lesser extent in layers II, III and VI. Whereas in area 18b, this projection was found to arise mainly from pyramidal cells in layers II and III, to a lesser extent in layers V and VI, and less frequent in layer IV. On the other hand, the reciprocal projection to the visual cortex was found to originate largely from pyramidal cells in layers III and V of the PAGm. In areas 17 and 18a, these fibers terminated in layers I and VI, and in layers I, V and VI, respectively. Whereas in area 18b, they were distributed throughout all layers except layer II.     

An autoradiographic study of complementary laminar patterns of termination of afferent fibers to the olfactory cortex

The afferent projections to the olfactory cortical areas from the olfactory bulb and the prepiriform cortex have been studied in the rat, using the autoradiographic method for demonstrating axonal connections. In order to relate closely the results of these experiments to the structure of the olfactory cortical areas, the cytoarchitectonic characteristics of these areas have also been described. The olfactory cortical areas, which receive a direct input from the olfactory bulb, include the anterior olfactory nucleus, the ventral portion of the tenia tects, the olfactory tubercle, the prepiriform cortex, the nucleus of the lateral olfactory tract, the cortical amygdaloid nucleus, and the lateral entorhinal area. All of these areas are composed primarily of pyramidal cells and have three basic layers: a superficial plexiform layer containing the apical dendrites of the pyramidal cells (layer I), a pyramidal cell layer (layer II), and a deeper polymorphic cellular layer (layer III). In each area layer I may be divided into a superficial portion (IA) and a deeper portion (IB). The autoradiographic experiments have shown that all of the olfactory cortical areas receive projections from the prepiriform cortex as well as from the olfactory bulb, and that these two projections have complementary laminar patterns of termination which are the same in every area. Throughout the olfactory cortex the fibers from the olfactory bulb terminate exclusively in layer IA, in relation to the distal segments of the apical dendrite of the pyramidal cells, whereas the fibers from the prepiriform cortex terminate in layer IB, in relation to more proximal segments of the apical dendrites, and also in layer III. The boundary between the two projections within layer I is very sharp, with minimal overlap. In contrast to this precise laminar organization, there is little evidence for a topographical organization within these Projections.     

Distribution of calbindin D-28k in the entorhinal,perirhinal, and parahippocampal cortices of the macaque monkey

We examined the distribution of calbindin D-28k-immunoreactive (CB-IR) neurons, fibers, and neuropil in the entorhinal (area 28), perirhinal (areas 35 and 36), and parahippocampal (areas TH and TF) cortices in the macaque monkey. Two main findings are reported. First, except for CB-IR neurogliaform cells that are only observed in the parahippocampal cortex, the morphology of CB-stained pyramidal and nonpyramidal cells were similar across the three cortical areas examined. Second, we find that the topography of CB staining differed between the three areas. The entorhinal cortex exhibits the most striking gradient of CB staining such that the most anterior and medial portions are most strongly labeled, whereas posterior and lateral areas exhibit only weak labeling. The labeling throughout the perirhinal and parahippocampal cortices is more homogeneous. Area 35 contains only lightly stained neuropil and few CB-IR cells. Area 36 and areas TH and TF of the parahippocampal cortex contain a moderate to high density of CB-IR cells and fibers throughout their full rostrocaudal extents, although each area exhibits unique laminar patterns of staining. In all areas examined, the highest density of CB-positive cells and fibers is observed in superficial layers with lower densities of CB-positive cells and fibers present in deep layers. These findings, taken together with our current understanding of the connections of these areas may have implications for understanding the circuit properties of the entorhinal, perirhinal, and parahippocampal cortices areas in both normal and disease states.     

Cortical connections between rat cingulate cortex and visual,motor, and postsubicular cortices

The connections of rat cingulate cortex with visual, motor, and postsubicular cortices were investigated with retrograde and anterograde tracing techniques. In addition, connections between visual and the postsubicular (area 48) and parasubicular (area 49) cortices were evaluated with the same techniques. The following conclusions were drawn Area 29 connections: Afferents to area 29 originate mainly from cingulate areas 24 and 25, visual cortex (primarily area 18b), motor cortex area 8, area 11 of frontal cortex, areas 48 and 49, and the subiculum. Efferent connections of area 29 within cingulate cortex and to visual areas differ for each cytoarchitectural subdivision of area 29. Thus, area 29c has limited projections both within cingulate cortex and to areas 48 and 49, while area 29d projects to these areas as well as to area 8, area 18b, and medial area 17. These visual cortex afferents originate mainly from layer V neurons of areas 29b and 29d, while areas 29a and 29c have virtually no projections to visual cortex Area 24 connections: Afferents to area 24 originate primarily from cingulate areas 25 and 29 and visual area 18b and medial area 17. Efferent projections of area 24a are distributed within cingulate cortex, while area 24b has more extensive projections to posterior cingulate and visual cortices. Area 24b is the cingulate subdivision which is both the primary recipient of visual cortex afferents as well as the source of most of the projections of anterior cingulate cortex to visual areas Visual cortex has reciprocal connections with parts of the postsubicular and parasubicular cortices. Neurons of the internal pyramidal cell layer of both areas 48 and 49 project to areas 17 and 18b, while layers I and III of these parahippocampal areas receive projections from areas 17 and 18b In conclusion, areas 29d and 24b have particularly extensive interconnections with visual cortex, while area 29d also maintains projections to area 8 of motor cortex. This connection scheme supports the view that cingulate cortex may have a role in feature extraction from the sensory environment, as well as in sensorimotor integration. Finally, the postsubiculum may be classified as alimbic association cortex in which extensive visual and cingulate efferents converge.     

Presubicular and parasubicular cortical neurons of the rat: Electrophysiological and morphological properties

Intracellular recordings and Neurobiotin-injection were used to examine the electrophysiology and morphology of presubicular and parasubicular cortical neurons in horizontal slices from rat brains. Evoked responses were obtained by stimulation of subicular and entorhinal cortices. Stellate cells were recorded in layers II and V of presubiculum and parasubiculum. Superficial layer cells had spiny dendrites that were found to reach layer I. Deep layer cells had sparsely spiny dendrites or dendrites without spines that did not reach past layer IV. Pyramidal cells were recorded in layers III and V of presubiculum and layers II and V of parasubiculum. Superficial layer cells had spiny dendrites that were found to reach layer I. Deep layer cells had sparsely spiny dendrites or dendrites without spines that could reach layer II. Electrophysiologically, stellate and pyramidal cells were similar to one another, regardless of cell layer, exhibiting repetitive single spiking in response to depolarizing current injection. No cells were found to burst in response to current injection. While there were subtle electrophysiological differences among the cell types, stellate cells were more similar to pyramidal cells from the same or adjacent layers than to other stellate cells from more distant layers. Similarly, pyramidal cells were electrophysiologically more similar to nearby stellate cells than to other distant pyramidal cells. Cells of all layers responded to subicular stimulation with a short latency (<9 ms), excitatory postsynaptic potential. Superficial layer cells responded at short (<9 ms), longer (10–20 ms) and very long latencies (>20 ms) to stimulation of superficial layers of medial entorhinal cortex. Deep layer cells responded at short latencies (<9 ms) to stimulation of deep layers of medial entorhinal cortex. Many cells responded to both subicular and entorhinal inputs. Both pyramidal and stellate cells in the deep layer of pre/parasubiculum could exhibit population bursting behavior in response to stimulation of subiculum or entorhinal cortex. The results define the cellular morphology and basic electrophysiology of presubicular and parasubicular neurons of the rat brain as a step toward understanding the physiology of the retrohippocampal cortices. Hippocampus 7:117–129, 1997. © 1997 Wiley-Liss, Inc.     

Using fNIRS to examine occipital and temporal responses to stimulus repetition in young infants: Evidence of selective frontal cortex involvement

How does the developing brain respond to recent experience? Repetition suppression (RS) is a robust and well-characterized response of to recent experience found, predominantly, in the perceptual cortices of the adult brain. We use functional near-infrared spectroscopy (fNIRS) to investigate how perceptual (temporal and occipital) and frontal cortices in the infant brain respond to auditory and visual stimulus repetitions (spoken words and faces). In Experiment 1, we find strong evidence of repetition suppression in the frontal cortex but only for auditory stimuli. In perceptual cortices, we find only suggestive evidence of auditory RS in the temporal cortex and no evidence of visual RS in any ROI. In Experiments 2 and 3, we replicate and extend these findings. Overall, we provide the first evidence that infant and adult brains respond differently to stimulus repetition. We suggest that the frontal lobe may support the development of RS in perceptual cortices.     

Anatomical organization of primate visual cortex area VII

The Golgi Rapid and Kopsch techniques have been used to provide material for an examination of the internal neuronal organization of cortical area VII of the Macaca monkey. The afferent and efferent relationships of area VII, as shown by axoplasmic transport tracing techniques in our own material and in previous studies in other laboratories, are reviewed. Comparison is made between the internal organisation of VI and VII cortex in terms of (1) the marked different in spiny and nonspiny neurons populations of granular layer 4, (2) the difference in relationship of lamina 6 pyramidal neurons to the overlying layers with a shift away from any relationship to granular layer 4 in VII, and (3) differences in the organization of VI lamina 4B and VII lamina 3B--both similarly placed, fiber-rich bands in the two cortical areas. The extrinsic relationships of VI and VII with the lateral geniculate nucleus, superior colliculus, pulvinar, peristriate cortex, cortical area STS, and with each other are compared in terms of laminar locations of efferent neurons and afferent axon terminal fields. It is hoped that this anatomical survey will provide a better foundation for physiological explorations of the region.     

Architecture and morphology of the human ventromedial prefrontal cortex

A previous report identified the location of comparable architectonic areas in the ventral frontal cortex of the human and macaque brains [S. Mackey & M. Petrides (2010) Eur. J. Neurosci., 32 , 1940–1950]. The present article provides greater detail with regard to the definition of architectonic areas within the ventromedial part of the human ventral frontal cortex and describes their location: (i) in Montreal Neurological Institute proportional stereotactic space; and (ii) in relation to sulcal landmarks. Structural magnetic resonance scans of four brains were obtained before the preparation of the histological specimens, so that the architectonic parcellation could be reconstructed in its original three‐dimensional volume. The areal density of individual cortical layers was sampled quantitatively in the ventromedial prefrontal cortex of eight brains (16 hemispheres). The agranular cortex along the ventral edge of the corpus callosum and posterior margin of the ventromedial surface is replaced by a graded series of increasingly granular and more complexly laminated areas that succeed one another in a posterior‐to‐anterior direction. In parallel, the width of the supragranular layers (i.e. layers II and III) increases as compared with the infragranular layers (i.e. layers V and VI) from posterior to anterior. A measure of how rapidly cortical features change at areal boundaries also showed that the rate of change in the granule and pyramidal cell densities of layers IV and V, respectively, was greater at the borders between posterior areas than between anterior areas. This article will facilitate the anatomical identification and comparison of experimental data involving the human vmPFC.     

Non-hippocampal cortical projections from the entorhinal cortex in the rat and rhesus monkey

The entorhinal cortices are known to give rise to powerful projections that terminate in the hippocampus and dentate gyrus. Collectively, these link the hippocampal formation to many parts of the cortex and to subcortical structures like the amygdala. Non-hippocampal projections from the entorhinal cortices are understood poorly. Such projections to neighboring temporal areas in the rat and rhesus monkey have been investigated using the autoradiographic and horseradish peroxidase (HRP) tracing procedures. In the rat, HRP-labeled neurons were observed in the intermediate and lateral fields of the entorhinal cortices after injections of temporal cortical areas 20, 35, 36 and 41. They were located predominantly in layers II, III and IV. In the monkey , HRP-labeled neurons were observed in the entorhinal cortices after injections of the rostral superior temporal gyrus (area TA or 22); the temporal polar cortex (area TG or 38); the inferior temporal cortex (area TE or 20); the perirhinal cortex (area 35) and the posterior parahippocampal cortices (areas TF and TH). Unlike the rat, labeled entorhinal neurons in the monkey were located in layer IV. Autoradiographic experiments in the monkey yielded complimentary results. In view of the fact that layer IV of the entorhinal cortex in both the rat and monkey receives a powerful projection from the subicular-CA1 fields of the hippocampal formation, the results imply that this layer mediates an indirect non-fornical connection between the hippocampal formation and the temporal cortex.     

Recent advances in defining the neuropathology of schizophrenia

The search for the defining neuropathology of schizophrenia continues to be one of the highest priority areas of research into this severely debilitating and common neuropsychiatric disorder. While lesions that are diagnostic of the disorder have not yet been identified, recent efforts employing molecule-specific probes and quantitative methods of analysis have enumerated many potentially important findings in the brains of patients with schizophrenia that warrant confirmation and elucidation. In this review, the major findings of six broad areas of neuropathological investigation are summarized and discussed. While substantial controversy exists in all areas, in sum: (1) diagnostic neuropathological investigations find only assorted and nonspecific abnormalities in the brains of schizophrenics that are likely to be representative of lesions found in age-compatible control groups; (2) morphometric studies of gross structures generally confirm the clinical in vivo neuroimaging findings of enlarged ventricles, decreased size of ventromedial temporal lobe structures, and decreased parahippocampal cortical thickness; (3) morphometric microscopy studies find frequent alterations in neuron density and decreased neuron size in limbic, temporal, and frontal regions; (4) investigations of connectivity are at an early stage but describe abnormal dendritic spine densities in the cortex, various changes in synaptic vesicle protein expression in limbic, temporal, and frontal cortices, and alterations in glutamatergic, catecholaminergic, and intrinsic innervation in anterior cingulate cortex – together, these findings suggest a “miswiring” in the schizophrenic brain; (5) investigations of aberrant neurodevelopment in schizophrenia describe abnormalities in cortical cytoarchitecture and several developmentally regulated proteins in the hippocampal region suggesting abnormal neuronal migration, differentiation, and/or cell pruning; and (6) studies of neurodegeneration and neural injury find a general lack of neurodegenerative disease lesions or ongoing astrocytosis that would indicate post-maturational neural injury. Received: 2 January 1996 / Revised: 15 March 1996 / Accepted: 29 March 1996     

Regional specificity in the neuropathologic substrates of schizophrenia: a morphometric analysis of Broca's area 44 and area 9

BACKGROUND: Numerous recent studies of postmortem schizophrenic brains have reported the presence of structural abnormalities in the dorsolateral prefrontal cortex (dlPFC) that are consistent with a reduction of neuropil. Ventrolateral prefrontal areas have been studied less extensively, and therefore it is not clear whether these cortices exhibit pathologic abnormalities of the same type and magnitude. Because thought disturbances in schizophrenic patients involve language processing, we have performed a morphometric analysis of Broca's area in the ventral frontal lobe. METHODS: Neuronal and glial density and somal size were assessed via stereologic cell counting in postmortem samples of Broca's area 44 in 9 schizophrenic patients and 14 normal controls. Cell density was reexamined in dorsolateral prefrontal area 9 as an internal control. RESULTS: We did not detect abnormalities in overall or laminar neuronal density, glial density, cortical thickness, or somal size in area 44 of schizophrenic patients. In contrast, neuronal density in area 9 exhibited a 12% increase in the schizophrenic cohort, replicating previous findings. In addition, there was a significant effect of disease on laminar neuronal density in area 9, with neuronal density tending to be higher (7%-29%) in all layers. CONCLUSIONS: The absence of significant cytoarchitectonic abnormalities in Broca's area in the same brains in which the dlPFC exhibited an increase in neuronal density suggests that the neuropil deficit is a regionally specific pathologic finding in schizophrenia and indicates that the dlPFC is a particularly vulnerable target of the disease process.     

Reduced nicotinamide adenine dinucleotide phosphate-diaphorase/nitric oxide synthase profiles in the human hippocampal formation and perirhinal cortex

Nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d)-stained profiles were evaluated throughout the human hippocampal formation (i. e., dentate gyrus, Ammon's horn, subicular complex, entorhinal cortex) and perirhinal cortex. NADPH-d staining revealed pleomorphic cells, fibers, and blood vessels. Within the entorhinal and the perirhinal cortices, darkly stained (type 1) NADPH-d pyramidal, fusiform, bipolar, and multipolar neurons with extensive dendrites were scattered mainly within deep layers and subjacent white matter. Moderately stained (type 2) NADPH-d round or oval neurons were seen mainly in layers II and III of the entorhinal and perirhinal cortices, in the dentate gyrus polymorphic layer, in the CA fields stratum pyramidal and radiatum, and in the subicular complex. The distribution of type 2 cells was more abundant in the perirhinal cortex compared to the hippocampal formation. Lightly stained (type 3) NADPH-d pyramidal and oval neurons were distributed in CA4, the entorhinal cortex medial subfields, and the amygdalohippocampal transition area. Sections concurrently stained for NADPH-d and nitric oxide synthase (NOS) revealed that all type 1 neurons coexpressed NOS, whereas types 2 and 3 were NOS immunonegative. NADPH-d fibers were heterogeneously distributed within the different regions examined and were frequently in close apposition to reactive blood vessels. The greatest concentration of fibers was in layers III and V–VI of the entorhinal and perirhinal cortices, dentate gyrus polymorphic and molecular layers, and CA1 and CA4. A band of fibers coursing within CA1 divided into dorsal and ventral bundles to reach the presubiculum and entorhinal cortex, respectively. Although the distribution of NADPH-d fibers was conserved across all ages examined (28–98 years), we observed an increase in the density of fiber staining in the aged cases. These results may be relevant to our understanding of selective vulnerability of neuronal systems within the human hippocampal formation in aging and in neurodegenerative diseases. © 1995 Wiley-Liss, Inc.     

Prefrontal cortex in the rat: projections to subcortical autonomic, motor, and limbic centers

This paper describes the quantitative areal and laminar distribution of identified neuron populations projecting from areas of prefrontal cortex (PFC) to subcortical autonomic, motor, and limbic sites in the rat. Injections of the retrograde pathway tracer wheat germ agglutinin conjugated with horseradish peroxidase (WGA-HRP) were made into dorsal/ventral striatum (DS/VS), basolateral amygdala (BLA), mediodorsal thalamus (MD), lateral hypothalamus (LH), mediolateral septum, dorsolateral periaqueductal gray, dorsal raphe, ventral tegmental area, parabrachial nucleus, nucleus tractus solitarius, rostral/caudal ventrolateral medulla, or thoracic spinal cord (SC). High-resolution flat-map density distributions of retrogradely labelled neurons indicated that specific PFC regions were differentially involved in the projections studied, with medial (m)PFC divided into dorsal and ventral sectors. The percentages that WGA-HRP retrogradely labelled neurons composed of the projection neurons in individual layers of infralimbic (IL; area 25) prelimbic (PL; area 32), and dorsal anterior cingulate (ACd; area 24b) cortices were calculated. Among layer 5 pyramidal cells, approximately 27.4% in IL/PL/ACd cortices projected to LH, 22.9% in IL/ventral PL to VS, 18.3% in ACd/dorsal PL to DS, and 8.1% in areas IL/PL to BLA; and 37% of layer 6 pyramidal cells in IL/PL/ACd projected to MD. Data for other projection pathways are given. Multiple dual retrograde fluorescent tracing studies indicated that moderate populations (<9%) of layer 5 mPFC neurons projected to LH/VS, LH/SC, or VS/BLA. The data provide new quantitative information concerning the density and distribution of neurons involved in identified projection pathways from defined areas of the rat PFC to specific subcortical targets involved in dynamic goal-directed behavior.     

Areal and synaptic interconnectivity of prelimbic (area 32), infralimbic (area 25) and insular cortices in the rat

This study investigated the interconnectivity of areas in the medial prefrontal and insular cortices in the rat. The areas studied were the prelimbic (PL, area 32) and infralimbic (IL, area 25) cortices and the dorsal anterior agranular insular (AId) and regions of posterior insular cortex (PI-comprising the agranular, dysgranular and granular fields). Following injections of the anterograde tracer biotinylated dextran amine (BDA) into layers 2-5 of each area, labelled axonal varicosities were found ipsilaterally in the other cortical areas. The most prominently labelled pathways were PL-->AId, AId-->PL, IL-->AId/PI, and PI-->IL. Qualitative and quantitative examinations of the laminar distribution of labelled axonal varicosities in the terminal fields indicated the existence of topographically organised 'feed-forward' (insular to PL/IL) and 'feed-back' (PL/IL to insular) pathways. The identity of the post-synaptic targets innervated by the PL/IL to AId pathways were investigated ultrastructurally. An analysis of 250 anterogradely labelled synaptic boutons (taken from layers 2/3) indicated that spine heads (presumed to originate from pyramidal cells) were the principal (88-93%) targets; all identified synaptic junctions were asymmetric. The results define an interconnected network of reciprocal pathways between cortical areas processing general and specific 'viscerosensory' information (AId and PI) and medial areas involved in cognitive (PL) and visceromotor (IL) functions. The data provide important aspects of the cortical circuitry underlying the integration of cognitive and emotional processing mechanisms, not only in rats, but also in primates.     

Distribution of m1 muscarinic acetylcholine receptors in the hippocampus of patients with Alzheimer's disease and dementia with Lewy bodies-an immunohistochemical study.

Of the five subtypes (m1-m5) of muscarinic acetylcholine receptors (mAChR), the m1 subtype is the most abundant in the human cerebral cortex and hippocampus. Impairment of the muscarinic cholinergic system in the brain may cause cognitive dysfunction in patients with Alzheimer's disease (AD), and choline esterase inhibitors (ChE-I) are used to improve cognitive dysfunction. Severe impairment of the cholinergic system has also been reported in the brains of subjects with dementia with Lewy bodies (DLB). There have been a few reports about the distribution of mAChR subtypes in the human brain. In the present study, we investigated the distribution of m1 mAChR in the human hippocampus using an antibody against the m1 subtype.In the control brains, m1 immunoreactivity was observed in the apical dendrites and cell bodies of granular neurons of the dentate gyrus and pyramidal neurons of CA1-3 and the subiculum. The dendrites and the cell bodies of the pyramidal neurons in layers III and V of the parahippocampal cortex and other temporal cortices were also positive for m1 immunoreactivity. This m1 immunoreactivity was markedly reduced in AD and DLB brains.     

Quantitative demonstration of comparable architectonic areas within the ventromedial and lateral orbital frontal cortex in the human and the macaque monkey brains

The orbital and ventromedial frontal cortical regions of the human and the macaque monkey brains include several spatially discrete areas which are defined histologically by their distinctive laminar architecture. Although considerable information has been collected on the function and anatomical connections of specific architectonic areas within the orbital and ventromedial frontal cortex of the macaque monkey, the location of comparable areas in the human brain remains controversial. We re-examined the comparability of orbital and ventromedial frontal areas across these two species and provide the first quantitative demonstration of architectonically comparable cortical areas in the human and the macaque brains. Images of Nissl-stained sections of the cortex were obtained at low magnification. Differences in the typical size of neurons in alternating pyramidal and granule cell layers were exploited to segregate the cortical layers before sampling. Profiles of areal neuronal density were sampled across the width of the cortex. The location of individual cortical layers was identified on each profile by sampling a set of equally sized images on which the cortical layers had been manually traced. The rank order of sampled architectonic features in comparable architectonic areas in the two species was significantly correlated. The differences in measured features between gyral and sulcal parts of the same architectonic area are at a minimum 3-4 times smaller than the differences between architectonic areas for the areas examined. Furthermore, the quantified architectonic features arrange areas within the orbital and ventromedial frontal cortex along two dimensions: an anterior-to-posterior and a medial-to-lateral dimension. On the basis of these findings, and in light of known anatomical connections in the macaque, this region of the human cortex appears to comprise at least two hierarchically structured networks of areas.     

Neuroanatomical study of somatomotor cortex in microcephalic mice induced by cytosine arabinoside

Somatomotor cortex of mice with microcephaly induced by DNA polymerase inhibitor cytosine arabinoside (Ara-C), has been studied with a modified Golgi-Cox staining and a HRP retrograde tracing method. Microcephalic mice were prepared by prenatal injections of cytosine arabinoside on days 13.5 and 14.5 of pregnancy. Cytoarchitectonically, the cerebral cortices of adult microcephalic mice are characterized by atypical pyramidal cells with abnormal dendrites and irregular patterns of cellular lamination. Semiquantitative analyses of the abnormality of dendrites in Golgi-Cox preparation indicate that both the degree and direction of ramification are severely affected in Ara-C treated mice. In adult control cerebrum, original neurons of corticospinal tract labeled after HRP injection into the lumbar cord were situated in layer V. In the microcephalic brains, however, HRP labeled neurons, some of which had abnormal polarity, were scattered throughout all layers. This HRP study for corticospinal tract neurons also confirms the irregular pattern of the cortex in which only three layers are recognized.     

Human cingulate cortex: Surface features,flat maps,and cytoarchitecture

The surface morphology land cytoarchitecture of human cingulate cortex was evaluated in the brains of 27 neurologically intact individuals. Variations in surface features included a single cingulate sulcus (CS) with or without segmentation or double parallel sulci with or without segmentation. The single CS was deeper (9.7 ± 0.81 mm) than in cases with double parallel sulci (7.5 ± 0.48 mm). There were dimples parallel to the CS in anterior cingulate cortex (ACC) and anastomoses between the CS and the superior CS. Flat maps of the medial cortical surface were made in a two-stage reconstruction process and used to plot areas. The ACC is agranular and has a prominent layer V. Areas 33 and 25 have poor laminar differentiation, and there are three parts of area 24: area 24a adjacent to area 33 and partially within the callosal sulcus has homogeneous layers II and III, area 24b on the gyral surface has the most prominent layer Va of any cingulate area and distinct layers IIIa-b and IIIc, and area 24c in the ventral bank of the CS has thin layers II–III and no differentiation of layer V. There are four caudal divisions of area 24. Areas 24a′ and 24b′ have a thinner layer Va and layer III is thicker and less dense than in areas 24a and 24b. Area 24c′ is caudal to area 24c and has densely packed, large pyramids throughout layer V. Area 24c'g is caudal to area 24c′ and has the largest layer Vb pyramidal neurons in cingulate cortex. Area 32 is a cingulofrontal transition cortex with large layer IIIc pyramidal neurons and a dysgranular layer IV. Area 32′ is caudal to area 32 and has an indistinct layer IV, larger layer IIIc pyramids, and fewer neurons in layer Va. Posterior cingulate cortex has medial and lateral parts of area 29, a dysgranular area 30, and three divisions of area 23: area 23a has a thin layer IIIc and moderate-sized pyramids in layer Va, area 23b has large and prominent pyramids in layers IIIc and Va, and area 23c has the thinnest layers V and VI in cingulate cortex. Area 31 is the cinguloparietal transition area in the parasplenial lobules and has very large layer IIIc pyramids. Finally, variations in architecture between cases were assessed in neuron perikarya counts in area 23a. There was an age-related decrease in neuron density in layer IV (r = ?0.63; ages 45–102), but not in other layers. These observations provide structural underpinnings for interpreting functional imaging studies of the human medial surface. © 1995 Wiley-Liss, Inc.