Hippocampal efferents reach widespread areas of cerebral cortex and amygdala in the rhesus monkey.

The subiculum of the primate hippocampal formation stands at the end of a polarized sequence of intrinsic hippocampal efferents and is the source of efferents to the medial frontal cortex, the caudal cingulate gyrus, and the parahippocampal area and amygdala in the temporal lobe. In addition, the subiculum sends subcortical efferents to the septum and diencephalon.

Subicular input from temporal cortex in the rhesus monkey.

The subicular cortices of the primate hippocampal formation form a physical and connectional link between the cortex of the temporal lobe and the hippocampus. Their direct connections with all classes of cortex in the temporal lobe except primary sensory cortex underscore the pivotal role of these areas in the potential interplay between the hippocampal formation and the association cortices.

Cortical afferents to the entorhinal cortex of the Rhesus monkey.

Although the entorhinal cortex is a major contributor of afferents to the hippocampus and dentate gyrus, knowledge of its own afferents has been vague. Regions of both the frontal and temporal lobes were found to contribute afferents to this region of the brain. These afferents form probable multisynaptic links in pathways connecting the classical sensory areas of the cortex and the limbic system.

Alzheimer's disease: cell-specific pathology isolates the hippocampal formation.

Examination of temporal lobe structures from Alzheimer patients reveals a specific cellular pattern of pathology of the subiculum of the hippocampal formation and layers II and IV of the entorhinal cortex. The affected cells are precisely those that interconnect the hippocampal formation with the association cortices, basal forebrain, thalamus, and hypothalamus, structures crucial to memory. This focal pattern of pathology isolates the hippocampal formation from much of its input and output and probably contributes to the memory disorder in Alzheimer patients.

Posterior parahippocampal gyrus pathology in Alzheimer's disease.

The posterior parahippocampal gyrus (PPHG) of the non-human primate brain has a distinct dual role in cortical neural systems. On the one hand, it is a critical link in providing the entorhinal cortex and hippocampal formation with cortical input, while on the other hand it receives output from these structures and projects widely by disseminating the medial temporal lobe output to the cortex. Layer III of TF and TH areas largely mediate the former (input) while layer V mediates the latter (output). We have examined areas TF and TH in the normal human brain and in Alzheimer's disease (AD) using pathological stains (Nissl, Thioflavin S) and phenotype specific stains non-phosphorylated neurofilament protein (SMI32) and parvalbumin (PV). Seven clinically and pathologically confirmed AD cases have been studied along with six age-compatible normal cases. Our observations reveal that neurofibrillary tangles (NFTs) heavily invest the area TF and TH neurons that form layers III and V. In both cortical areas, the large pyramids that form layer V contain a greater number of NFTs. These changes, and possibly, pyramidal cell loss, greatly alter the cytoarchitectural picture and diminish SMI32 staining patterns. Layer III of area TH loses the majority of SMI32 immunoreactivity, whereas this change is more conspicuous in layer V of area TF. PV-staining in both areas is largely unaffected. Normal cases contained no evidence of pathology or altered cytoarchitecture. These observations reveal a further disruption of memory-related temporal neural systems in AD where pathology selectively alters both the input to the hippocampal formation and its output to the cortex.

Modular and laminar pathology of Brodmann's area 37 in Alzheimer's disease.

Previous studies suggested a relationship between severity of symptoms and the degree of neurofibrillary tangles (NFTs) clustering in different areas of the cortex in Alzheimer's disease (AD). The posterior inferior temporal cortex or Brodmann's area (BA 37) is involved in object naming and recognition memory. But the cellular architecture and connectivity and the NFT pathology of this cortex in AD received inadequate attention. In this report, we describe the laminar distribution and topography of NFT pathology of BA 37 in brains of AD patients by using Thionin staining for Nissl substance, Thioflavin-S staining for NFTs, and phosphorylated tau (AT8) immunohistochemistry. NFTs mostly occurred in cortical layers II, III, V and VI in the area 37 of AD brain. Moreover, NFTs appeared like a patch or in cluster pattern along the cortical layers III and V and within the columns of pyramidal cell layers. The abnormal, intensely labeled AT8 immunoreactive cells were clustered mainly in layers III and V. Based on previously published clinical correlations between cognitive abnormalities in AD and the patterns of laminar distributed NFT cluster pathology in other areas of the brain, we conclude that a similar NFT pathology that severely affected BA 37, may indicate disruption of some forms of naming and object recognition-related circuits in human AD.

Evidence for direct projections from the basal nucleus of the amygdala to retrosplenial cortex in the Macaque monkey.

The role of the primate retrosplenial cortex (RSC) in memory processing and spatial navigation has been well established. Recently, processing emotionally salient information has been attributed to the RSC as well. Little anatomical data, however, exist linking the RSC with known emotional processing centers within the brain. The amygdala has been implicated as a substrate for modulating memory for emotionally salient events; yet no study to date has demonstrated that this area has a direct connection in the primate brain. With modern retrograde tracer injections into the RSC and adjacent cortical areas of the monkey (Macaca fascicularis), we demonstrate that there are efferent projections from the basal nucleus of the amygdala to the RSC and area 31. These projections offer anatomical data supporting the hypothesis that the RSC might receive emotionally salient input directly from the amygdala and suggest a role for the RSC as a node within a neural system potentially capable of integrating emotional information for use in memory or other cognitive processes.

The modern concept of association cortex.

Although enormous amounts of new neuroanatomical, neurophysiological and neurobehavioral data have been gathered on the association cortices in the past decade, it seems more permissible now than ever to use this functionally loaded concept. Its generality helps enormously, but the modern recognition of multiple interactive neural systems all contributing to cognition has diffused previous concerns relating to strict localization.

Some cytoarchitectural abnormalities of the entorhinal cortex in schizophrenia.

The cytoarchitecture of the entorhinal cortex was examined in the brains of six patients with a diagnosis of schizophrenia and in 16 controls. All six brains of schizophrenic patients showed abnormalities of the rostral and intermediate portions of the entorhinal cortex. The abnormalities included aberrant invaginations of the surface, disruption of cortical layers, heterotopic displacement of neurons, and paucity of neurons in superficial layers. These changes suggest disturbed development. Because the entorhinal cortex is pivotal for neural systems that mediate corticohippocampal interactions, early disruption of its structure could lead to important neuropsychological changes during development and in adult life and could contribute to the symptomatology of schizophrenia.

Neuron numbers in Alzheimer's disease: cell-specific pathology.

The significance of the particular neurons lost in Alzheimer's disease is discussed in the context of their likely anatomic role as projection neurons. The location and function of affected neurons is emphasized, rather than absolute number.

Alteration in the pattern of nerve terminal protein immunoreactivity in the perforant pathway in Alzheimer's disease and in rats after entorhinal lesions.

Neurons in layer II of the entorhinal cortex consistently develop neurofibrillary tangles in Alzheimer's disease (AD). Experimental neuroanatomical studies have shown that these neurons give rise to the perforant pathway, a major excitatory projection to the hippocampal formation, which terminates in a discrete pattern in the outer portion of the molecular layer of the dentate gyrus. The distribution of two nerve terminal associated proteins, synaptophysin and NT75, was studied in the molecular layer of the dentate gyrus in AD and control cases to determine whether Alzheimer neuronal pathology is associated with loss of synaptic markers. In parallel studies, the effect of ablation of the entorhinal cortex in rats was evaluated. In AD as compared to controls, a decrease in synaptophysin immunostaining was evident in the terminal zone of the perforant pathway. NT75 nerve terminal immunostaining was too weak to interpret in the human hippocampal formation. Both synaptophysin and NT75 immunoreactivity were found in association with some neuritic plaques. In rats, entorhinal lesions resulted in diminished immunoreactivity for both synaptophysin and NT75 in the perforant pathway terminal zone. These results suggest that nerve terminal protein loss is a concomitant feature of neuronal pathology in AD.

Entorhinal cortex modules of the human brain.

Much is known about modular organization in the cerebral cortex, but this knowledge is skewed markedly toward primary sensory areas, and in fact, it has been difficult to demonstrate elsewhere. In this report, we test the hypothesis that a unique form of modules exists in the entorhinal area of the human cortex (Brodmann's area 28). We examined this issue using classic cyto- and myeloarchitectonic stains, immunolabeling for various neurochemicals, and histochemistry for certain enzymes. The findings reveal that the entorhinal cortex in the human is formed by a mosaic of cellular aggregates whose most conspicuous elements are the cell islands of layer II and myelinated fibers around the cell islands, the disposition of glutamic acid decarboxylase-positive neurons and processes, cytochrome oxidase staining, and the pattern of cholinergic afferent fibers. The neuropathology of Alzheimer's disease cases highlights the modules, but inversely so, by destroying their features. The findings are of interest because 1) anatomically defined modules are shown to be present in areas other than the sensory and motor cortices, 2) the modules are morphological entities likely to reflect functions of the entorhinal cortex, and 3) the destruction of entorhinal cortex modules may account disproportionately for the severity of memory impairments in Alzheimer's disease.

Cingulate input to the primary and supplementary motor cortices in the rhesus monkey: evidence for somatotopy in areas 24c and 23c.

We examined the distribution of cingulate projections to the somatotopically related parts of the primary (M1) and supplementary (M2) motor cortices of the monkey by using fluorescent dyes. Labeled neurons were found in layers 3, 5 and 6 of areas 24c and 23c and were heaviest following injections placed in M2. Projections to analogous somatotopic areas in M1 and M2 arose from similar cingulate regions. In area 24c, neurons projecting to the face area of M1 and M2 were located anteriorly, those to the hindlimb were located posteriorly, and neurons projecting to the forelimb area of M1 and M2 were located in between. In area 23c, neurons projecting to the forelimb area of M1 and M2 were located anteriorly and those to the hindlimb area of M1 and M2 were located posteriorly. The face area of M1 and M2 was not found to receive afferents from area 23c. In contrast to this discreteness, cingulate projections to Woolsey's axial representation of M1 were diffuse. The results support the presence of a separate and somatotopically organized cingulate motor cortex in area 24c. This is predicated on the facts that: (1) small injections of retrograde tracers placed in analogous somatotopic parts of M1 and M2 resulted in similar patterns of labeling within the electrophysiologically "excitable" portion of the anterior cingulate cortex, and (2) this organized topography infers somatotopy. Our data fail to support a somatotopically organized cingulate motor area in area 23c if the criterion of all body parts is demanded. By virtue of its anatomical location and its connectional relation to the spinal cord and isocortical motor fields on the one hand and to the limbic cortex on the other, area 24c may be considered as M3 and provide limbic influences at several levels of motor control.

Frontal granular cortex input to the cingulate (M3), supplementary (M2) and primary (M1) motor cortices in the rhesus monkey.

Although frontal lobe interconnections of the primary (area 4 or M1) and supplementary (area 6m or M2) motor cortices are well understood, how frontal granular (or prefrontal) cortex influences these and other motor cortices is not. Using fluorescent dyes in rhesus monkeys, we investigated the distribution of frontal lobe inputs to M1, M2, and the cingulate motor cortex (area 24c or M3, and area 23c). M1 received input from M2, lateral area 6, areas 4C and PrCO, and granular area 12. M2 received input from these same areas as well as M1; granular areas 45, 8, 9, and 46; and the lateral part of the orbitofrontal cortex. Input from the ventral part of lateral area 6, area PrCO, and frontal granular cortex targeted only the ventral portion of M1, and primarily the rostral portion of M2. In contrast, M3 and area 23c received input from M1, M2; lateral area 6 and area 4C; granular areas 8, 12, 9, 46, 10, and 32; as well as orbitofrontal cortex. Only M3 received input from the ventral part of lateral area 6 and areas PrCO, 45, 12vl, and the posterior part of the orbitofrontal cortex. This diversity of frontal lobe inputs, and the heavy component of prefrontal input to the cingulate motor cortex, suggests a hierarchy among the motor cortices studied. M1 receives the least diverse frontal lobe input, and its origin is largely from other agranular motor areas. M2 receives more diverse input, arising primarily from agranular motor and prefrontal association cortices. M3 and area 23c receive both diverse and widespread frontal lobe input, which includes agranular motor, prefrontal association, and frontal limbic cortices. These connectivity patterns suggest that frontal association and frontal limbic areas have direct and preferential access to that part of the corticospinal projection which arises from the cingulate motor cortex.

Comparison of the efferents of the amygdala and the hippocampal formation in the rhesus monkey: II. Reciprocal and non-reciprocal connections.

The pattern of direct connections between the amygdala and the hippocampal formation in the rhesus monkey (Macaca mulatta) was delineated by using both anterograde and retrograde tract-tracing techniques. From the amygdala the accessory basal, medial basal, and the cortical nuclei and the cortical amygdaloid transition area send projections to the hippocampal formation. The efferents from the magnocellular part of the accessory basal nucleus and the cortical nuclei terminate in the molecular layer of subfields CA3, CA2, and CA1', and to a lesser extent in the molecular layer and the superficial part of the pyramidal cell layers of the prosubiculum. In contrast, the projections from the medial basal nucleus and the cortical amygdaloid transition area terminate in the molecular layer and the superficial part of the pyramidal cell layers of the prosubiculum only. From the hippocampal formation, subfield CA1' and the prosubiculum send efferents that terminate in the medial basal nucleus, the cortical transition area, and the ventral part of the cortical nuclei. In addition, the CA1' subfield projects to the ventral, parvicellular part of the accessory basal nucleus. The present data emphasize an important role for the prosubiculum and the CA1' subfield in medial temporal lobe area connections. Both regions, in addition to supporting direct connections between the amygdala and the hippocampal formation, also have extensive connections with the entorhinal cortex. As for the amygdala, the accessory basal nucleus sends efferents to both the hippocampal formation and the entorhinal cortex. The data demonstrate an anatomical means by which the amygdala, hippocampal formation, and the entorhinal cortex may interact. It is proposed that these connections may be important in the limbic memory system.

Olfactory bulb projections to the parahippocampal area of the rat.

Recent evidence suggests that the main olfactory bulb projects caudally beyond the prepiriform cortex and the cortical amygdaloid nuclei to the region of the piriform lobe called the parahippocampal area. Included within this area is the entorhinal cortex, which is composed of six major subdivisions. Since questions remain as to which of these subdivisions receives centripetal fibers from the bulb, we reexamined these projections using autoradiography and HRP histochemistry and correlated the sites of termination with the cytoarchitecture of the entorhinal cortex. The results indicate that olfactory bulb axons reach all parts of the parahippocampal area, including the cortex which forms the medial and lateral banks of the amygdaloid sulcus (area TR), and both subdivisions of the laterally located entorhinal cortex (28L' and 28L). Also, label is observed over the more medially located fields of the entorhinal cortex, including the cortex posterior to the cortical amygdaloid nucleus (28M'), as well as the ventrolateral parts of medial entorhinal cortex (28M). In addition, evidence of label occurs over the full extent of the transition zone (28i) which separates areas 28L and 28M. These results suggest that the olfactory bulb has a more extensive projection to the parahippocampal area in the rat than previously thought, and may provide at least some input to all of the parahippocampal areas which project to the hippocampal formation.

Widespread corticostriate projections from temporal cortex of the rhesus monkey.

The corticostriate projections of temporal areas TA, TE, TF, TG, 35, and 28 were studied in the rhesus monkey with the use of autoradiography. Widespread projections were observed to rostral as well as caudal parts of the striatum for all areas except area 28. For example, areas TA and TG have sizable projections to the medial or periventricular part of the head of the caudate nucleus, as well as to the medial part of the tail of this structure and the dorsally adjacent putamen. Areas TE and TF also were observed to send strong projections to the head of the caudate nucleus. In addition, they project to the rostral putamen. Both have projections to the tail of the caudate nucleus and caudal putamen. The widespread distribution of temporostriate axons to the rostral striatum suggests strongly that previous silver impregnation studied have not only underestimated the strength of the temporal cortical contribution to the corticostriate system, but also failed to identify the major projection zone of temporostriate axon terminals. For example, while all temporal cortical areas contribute projections to an organized topography in the tail of the caudate nucleus and the ventrocaudal putamen, they were observed consistently to have larger projections to the head of the caudate nucleus and rostral putamen. These results add to a growing body of evidence which demonstrates the existence of widespread nonmotor cortical input to the basal ganglia, and an organization of this input far greater in complexity than that demonstrated by earlier suppressive silver impregnation methods.

An HRP study of the connections of the subfornical organ of the rat.

The connections of the subfornical organ (SFO) were investigated by using the HRP technique. Injections into the SFO labeled neurons in the medial septum, but not in lateral septum nor in the diagonal band nucleus. Labeled cells were observed in the median preoptic nucleus, below the ependyma of the third ventricle, in the dorsal preoptic region near the anterior commissure, and diffusely throughout the medial preoptic and anterior hypothalamic areas. Fibers were followed from the ventral stalk of the SFO. Precommissural fibers enter the median preoptic nucleus where many of them appear to terminate. Others continue on to the medial septum, the OVLT, the supraoptic nucleus, and suprachiasmatic nucleus. HRP injections into the median preoptic nucleus labeled many neurons in the SFO. Postcommissural fibers reach the hypothalamus by descending along the walls of the ventricle in the subependymal space, by traveling in the columns of the fornix and the medial corticohypothalamic tract, or by passing through the paraventricular nucleus of the thalamus. Some postcommissural fibers turn rostrally and enter the median preoptic nucleus while others join precommissural fibers bound for the supraoptic nucleus. More caudally directed fibers appear to innervate the paraventricular nucleus of the hypothalamus and the medial preoptic and anterior hypothalamic areas. HRP injections into the paraventricular nucleus of the hypothalamus labeled neurons in the SFO. These findings corroborate and extend previous work in describing neural connections between two brain regions that are important for fluid balance.

Interhemispheric pathways of the hippocampal formation, presubiculum, and entorhinal and posterior parahippocampal cortices in the rhesus monkey: the structure and organization of the hippocampal commissures.

The interhemispheric pathways originating in the hippocampal formation, presubiculum, and entorhinal and posterior parahippocampal cortices and coursing through the fornix system were investigated by autoradiographic tracing in 29 rhesus monkeys (Macaca mulatta). The results revealed that crossing fibers are segregated into three contiguous systems. A ventral hippocampal commissure lies at the transition between the body and anterior columns of the fornix in the vicinity of the subfornical organ and the interventricular foramina of Monro; it is formed by axons arising in the most anterior (uncal and genual) subdivisions of the hippocampal formation. A dorsal hippocampal commissure lies inferior to the posterior end of the body of the corpus callosum; it is formed by axons arising in the presubiculum and entorhinal cortex of the anterior parahippocampal gyrus and the proisocortical and neocortical subdivisions of the posterior parahippocampal gyrus but not in the hippocampal formation. A hippocampal decussation lies between the ventral hippocampal commissure and dorsal hippocampal commissure; it is formed by axons arising in the body of the hippocampal formation. In contrast to the fibers of the ventral hippocampal commissure and dorsal hippocampal commissure, which terminate in contralateral cortical areas, these decussating fibers terminate in the contralateral septum. Thus, the ventral hippocampal commissure and dorsal hippocampal commissure of the rhesus monkey appear to be homologous to similarly designated structures in other mammals. To the extent that these observations also apply to the interhemispheric fibers of the human hippocampal formation and parahippocampal areas, their possible preservation must be considered when interpreting the effect of callosal transection on seizures and the results of "split-brain" studies, since callosal transection may fail to sever the hippocampal commissures in their entirety.

Fields of origin and pathways of the interhemispheric commissures in the temporal lobe of macaques.

The interhemispheric connections of the cortical areas of the temporal lobe and some neighboring regions were investigated in monkeys (Macaca mulatta and Macaca fascicularis) by anterograde autoradiographic tracing, following injection of radioactively labeled amino acids. The results revealed that the interhemispheric projections of the temporal lobe course through three interhemispheric commissures on their way to the opposite hemisphere. The anterior commissure receives fibers from virtually the entire temporal lobe, including the temporal pole, superior and inferior temporal gyri, and parahippocampal gyrus. Moreover, area 13 of the orbitofrontal cortex, the frontal and temporal subdivisions of the prepiriform cortex, and the cortical and deep nuclei of the amygdala also contribute fibers to the anterior commissure. The heaviest projections arise in the rostral third of the temporal isocortex. These projections become progressively lighter from more caudal regions. By contrast, the corpus callosum receives fibers from the caudal two-thirds of the temporal lobe, including the temporal pole, superior and inferior temporal gyri, and parahippocampal gyrus. The heaviest projections arise in the caudal third of the temporal lobe and cross primarily in the caudal third of the corpus callosum, including the splenium. Progressively lighter projections arise more rostrally. Fibers from proisocortical and isocortical areas of the posterior parahippocampal gyrus cross in the ventralmost part of the splenium (inferior forceps), whereas cortical areas lateral to the occipitotemporal sulcus give rise to fibers that cross in the caudal part of the body of the corpus callosum and dorsal splenium. The dorsal hippocampal commissure receives fibers exclusively from the parahippocampal gyrus. The fibers of the corpus callosum, hippocampal commissure, and, to a lesser extent, the anterior commissure are intimately associated with the ventricular system as they course through the white matter of the temporal lobe. The fields of origin of the anterior commissure and corpus callosum overlap extensively over the caudal two-thirds of the temporal lobe. The posterior parahippocampal gyrus is unique in that it gives rise to fibers that cross in all three commissures.