Morphometry of the parahippocampal gyrus in schizophrenics and controls. Some anatomical considerations

Summary Volumetry of the parahippocampal gyrus was performed applying stereological methods. No difference was found comparing 18 schizophrenic brains with 18 sex- and age-matched controls. Variable sulcal pattern may contribute to inconsistency with previous findings.Supported by a grant from the DFG (Be 602/6-1). Presented in part at the 8th World Congress of Psychiatry, Athens, Greece, October 12–19, 1989.     

Spatial selectivity of unit activity in the hippocampal granular layer

Single neuron activity was recorded in the granular layer of the fascia dentata in freely moving rats, while the animals performed a spatial “working” memory task on an eight-arm maze. Using recording methods that facilitate detection of units with low discharge rates, it was found that the majority (88%) of cells in this layer have mean rates below 0.5 Hz, with a minimum of 0.01 Hz or less. The remaining recorded cells exhibited characteristics typical of the theta interneurons found throughout the hippocampus. Based on several criteria including relative proportion and the relation of their evoked discharges to the population spike elicited by perforant path stimulation, it was concluded that the low-rate cells correspond to granule cells. Granule cells exhibited clear spatially and directionally selective discharge that was at least as selective as that of a sample of CA3 pyramidal cells recorded under the same conditions. Granule cells had significantly smaller place fields than pyramidal cells, and tended to have more discontiguous subfields. There was no spatial correlation among simultaneously recorded adjacent granule cells. Granule cells also exhibited burst discharges reminiscent of complex spikes from pyramidal cells while the animals sat quietly; however, the spike duration of granule cells was significantly shorter than CA3 pyramidal cell spike durations. Under conditions of environmental stability, granule cell place fields were stable for at least several days. Following occasional maze rotations relative to the (somewhat impoverished) visual stimuli of the recording room, granule cell place fields were maintained relative to the distal spatial cues; however, frequent rotations of the maze sometimes resulted in a shift in the reference frame to the maze itself. These observations indicate that granule cells of the fascia dentata provide their CA3 targets with a high degree of spatial information, in the form of a sparsely coded, distributed representation.     

Distribution of quinolinic acid phosphoribosyltransferase in the human hippocampal formation and parahippocampal gyrus

The morphological distribution of quinolinic acid phosphoribosyltransferase (QPRT), the degradative enzyme of the endogenous excitotoxin quinolinic acid, was studied in the human hippocampal formation and parahippocampal gyrus by immunohistochemical techniques. In seven neurologically normal human brains obtained at autopsy, QPRT-immunoreactivity (QPRT-i) was found in both glial cells and neurons. Glial cells exhibiting QPRT-immunoreactivity morphological features of astrocytes, were observed in all hippocampal subfields. The polymorphic layer of the dentate gyrus contained the highest density of QPRT-i glial cells. Numerous QPRT-i glial cells were also found along both sides of the fused hippocampal fissure and in the white matter including the alveus of Ammon's horn, whereas only a few were observed in the granule cell layer and the stratum pyramidale. Neurons containing QPRT-i were found mainly in the subiculum and in the strata oriens and pyramidale of CA1. They were mostly small and polymorphic or fusiform, thus indicating that they may belong to a subpopulation of interneurons. Moderate numbers of QPRT-i glial cells and neurons were also observed throughout layers II-VI of parahippocampal cortex. The localization of QPRT-i in selected glial cells and neurons suggests that in the regions examined these cellular elements might play specific roles in the regulation of quinolinic acid function.     

Place-related neural responses in the monkey hippocampal formation in a virtual space

Place cells in the rodent hippocampal formation (HF) are suggested to be the neural substrate for a spatial cognitive map. This specific spatial property of the place cells are regulated by both allothetic cues (i.e., intramaze local and distal cues) as well as idiothetic sensory inputs; the context signaled by the distal cues allows local and idiothetic cues to be employed for spatial tuning within the maze. To investigate the effects of distal cues on place-related activity of primate HF neurons, 228 neurons were recorded from the monkey HF during virtual navigation in a similar situation to a rodent water maze, in which distal cues were important to locate the animal's position. A subset of 72 neurons displayed place-related activity in one or more virtual spaces. Most place-related responses disappeared or changed their spatial tuning (i.e., remapping) when the arrangements of the distal cues were altered/moved in the virtual spaces. These specific features of the monkey HF might underlie neurophysiological bases of human episodic memory.     

The functional role of human right hippocampal/parahippocampal theta rhythm in environmental encoding during virtual spatial navigation

Low frequency theta band oscillations (4–8 Hz) are thought to provide a timing mechanism for hippocampal place cell firing and to mediate the formation of spatial memory. In rodents, hippocampal theta has been shown to play an important role in encoding a new environment during spatial navigation, but a similar functional role of hippocampal theta in humans has not been firmly established. To investigate this question, we recorded healthy participants’ brain responses with a 160‐channel whole‐head MEG system as they performed two training sets of a virtual Morris water maze task. Environment layouts (except for platform locations) of the two sets were kept constant to measure theta activity during spatial learning in new and familiar environments. In line with previous findings, left hippocampal/parahippocampal theta showed more activation navigating to a hidden platform relative to random swimming. Consistent with our hypothesis, right hippocampal/parahippocampal theta was stronger during the first training set compared to the second one. Notably, theta in this region during the first training set correlated with spatial navigation performance across individuals in both training sets. These results strongly argue for the functional importance of right hippocampal theta in initial encoding of configural properties of an environment during spatial navigation. Our findings provide important evidence that right hippocampal/parahippocampal theta activity is associated with environmental encoding in the human brain. Hum Brain Mapp 38:1347–1361, 2017. © 2016 Wiley Periodicals, Inc.     

The velocity‐related firing property of hippocampal place cells is dependent on self‐movement

Hippocampal place cells have the interesting property of increasing their firing rate when a freely moving animal increases its running speed through the cell's place field. A previous study from this laboratory showed that this movement‐related firing property is disrupted by lesions of the perirhinal cortex (PrhC). It is possible, therefore, that PrhC lesions disrupt speed‐modulated sensory information such as optic flow or motor efferent or proprioceptive input that might be available to the hippocampus from the PrhC. To test this hypothesis, rats with single unit recording electrodes implanted in the CA1 region of the hippocampus received different levels of optic flow stimulation in both a freely moving and a passive movement condition. The effects of PrhC lesions were also tested. Although increasing the amount of optic flow information available decreased place field size, it had no discernable effect on the movement‐firing rate relationship in the place cells of control animals run in the free‐movement condition. In lesioned animals the relationship was disrupted, replicating our previous results. In the passive movement condition many place cells stopped firing. In those cells that did fire, however, the movement‐firing rate relationship was no longer evident. These data indicate that the movement‐firing rate relationship is not driven by vestibular or optic flow cues, but rather depends on either motor efferent or proprioceptive input, or that it results from some other form of input that may be modulated by self‐motion, such as from the vibrissae. © 2009 Wiley‐Liss, Inc.     

Parvalbumin- and calbindin D28k-immunoreactive neurons in the hippocampal formation of the macaque monkey.

Calcium-binding proteins calbindin D28k (CaBP) and parvalbumin (PV) were localized in neurons of the monkey hippocampal formation. CaBP immunoreactivity is present in all granule cells and in a large proportion of CA1 and CA2 pyramidal neurons, as well as in a distinct population of local circuit neurons. In the dentate gyrus, CaBP-immunoreactive nongranule cells are present in the molecular layer and in the hilar region, but they do not include the pyramidal basket cells at the hilar border. In the Ammon's horn, CaBP-positive, nonpyramidal neurons are more frequent in the CA3 area than in any other parts of the hippocampal formation. They are concentrated in the strata oriens and pyramidale of areas CA1-3, whereas only a few small neurons were found in the strata lucidum and radiatum of CA3 and in the stratum moleculare of the CA1 area. PV is exclusively present in local circuit neurons both in the dentate gyrus and in Ammon's horn. In the dentate gyrus the presumed basket cells at the hilar border exhibit PV immunoreactivity. In the hilar region and molecular layer only a relatively small number of cells are immunoreactive for PV. Most of these PV-positive cell bodies are located in the inner half of the molecular layer, with occasional horizontal cells at the hippocampal fissure. In Ammon's horn, strata oriens and pyramidale of areas CA1-3 contain a large number of PV-positive cells. There are no PV-immunoreactive cells in the strata lucidum, radiatum, or lacunosum moleculare. The CaBP- and PV-containing neurons form different subpopulations of cells in the monkey hippocampal formation. With the exception of a basket cell type in the monkey dentate gyrus, the CaBP- and PV-positive cell types were found to be remarkably similar in rodents and primates.     

Astrocytosis in the molecular layer of the dentate gyrus: A study in Alzheimer's disease and schizophrenia

Recently, several authors have claimed prominent abnormalities in the entorhinal cortex of both patients with Alzheimer's disease (AD) and schizophrenia. The entorhinal cortex is the origin of the perforant pathway, a major input to granule cells of the dentate gyrus of the hippocampus. The present study explored the possibility of a lesion in the entorhinal cortex of both AD and schizophrenic patients by quantitating astrocytic markers within the terminal fields of the perforant pathway. An increase in fibrillary astrocytes was found in half ( ) of the AD patients while none of the schizophrenic (n = 6) or control (n = 7) brains exhibited gliosis. Since the redistribution and hyperplasia of astrocytes within the molecular layer of the partially deafferented dentate gyrus depend on the chronicity of the entorhinal lesion, the abnormalities observed in AD patients are consistent with the progressive course of the illness. Furthermore, the presence of gliosis in the subiculum of three out of six AD patients suggested pathology secondary to projections from the entorhinal region, amygdala, or prepyriform cortex. The absence of similar changes in schizophrenic patients does not disprove previous claims of entorhinal pathology but suggests that the lesion, if it exists, is either static in nature or occurred long before death.     

Abnormal medial temporal activity for bound information during working memory maintenance in patients with schizophrenia

Alterations of binding in long‐term memory in schizophrenia are well established and occur as a result of aberrant activity in the medial temporal lobe (MTL). In working memory (WM), such a deficit is less clear and the pathophysiological bases remain unstudied. Seventeen patients with schizophrenia and 17 matched healthy controls performed a WM binding task while undergoing functional magnetic resonance imaging. Binding was assessed by contrasting two conditions comprising an equal amount of verbal and spatial information (i.e., three letters and three spatial locations), but differing in the absence or presence of a link between them. In healthy controls, MTL activation was observed for encoding and maintenance of bound information but not for its retrieval. Between‐group comparisons revealed that patients with schizophrenia showed MTL hypoactivation during the maintenance phase only. In addition, BOLD signals correlated with behavioral performance in controls but not in patients with schizophrenia. Our results confirm the major role that the MTL plays in the pathophysiology of schizophrenia. Short‐term and long‐term relational memory deficits in schizophrenia may share common cognitive and functional pathological bases. Our results provide additional information about the episodic buffer that represents an integrative interface between WM and long‐term memory. © 2009 Wiley‐Liss, Inc.     

Spatial- and task-dependent neuronal responses during real and virtual translocation in the monkey hippocampal formation.

Neuropsychological data in humans demonstrated a pivotal role of the medial temporal lobe, including the hippocampal formation (HF) and the parahippocampal gyrus (PH), in allocentric (environment-centered) spatial learning and memory. In the present study, the functional significance of the monkey HF and PH neurons in allocentric spatial processing was analyzed during performance of the spatial tasks. In the tasks, the monkey either freely moved to one of four reward areas in the experimental field by driving a cab that the monkey rode (real translocation task) or freely moved a pointer to one of four reward areas on the monitor (virtual translocation task) by manipulating a joystick. Of 389 neurons recorded from the monkey HF and PH, 166 had place fields that displayed increased activity in a specific area in the experimental field and/or on the monitor (location-differential neurons). More HF and PH neurons responded in the real translocation task. These neurons had low mean spontaneous firing rates (0.96 spikes/sec), similar to those of rodent HF place cells. The remaining nonresponsive neurons had significantly higher mean firing rates (8. 39 spikes/sec), similar to interneurons or theta cells in the rodent HF. Furthermore, most location-differential neurons showed different responses in different tasks. These results suggest that the HF and PH are crucial in allocentric information processing and, moreover, that the HF can encode different reference frames that are context or task-dependent. This may be the neural basis of episodic memory.     

Prenatal and postnatal development of synapses and acetylcholinesterase staining in the dentate gyrus of the rhesus monkey

Morphogenesis, distribution of cholinergic enzyme acetylcholinesterase and synaptogenesis in the dentate gyrus of the rhesus monkey during the pre- and postnatal periods of development were examined using histological, histochemical and ultrastructural methods. The pattern of neuronal differentiation in the dentate gyrus demonstrated distinct superficial-to-deep and lateral-to-medial gradients. The histochemical reaction for acetylcholinesterase was present on gestation day 120 as minimal staining in the supragranular band and in the inner one-third of the dentate molecular layer. At term, the laminar distribution of the enzyme assumed mature pattern although considerable enhancement in staining intensity was achieved postnatally. At term and at 9 months of postnatal age, the most pronounced enzyme activity was found in the supragranular band and in the inner one-third of the molecular layer. Synaptogenesis in the dentate molecular layer was characterized by the early formation of axo-dendritic contacts on dendritic trunks and branches followed by the appearance of synapses on simple and complex spines. Spines were detected infrequently on gestation day 132. On day 148, they ranged in morphology from short stubby protrusions to pedunculated, triangular processes. The majority of the spines exhibited flat postsynaptic surfaces. Complex, synapse-bearing U- and W-shaped spines were observed rarely at this age but appeared more frequently at term and at 15 months of postnatal age. However, at all ages, including 15 months postnatally, synapses on flat-surfaced simple spines predominated. Most synapses were of the asymmetric variety.With certain exceptions, these features of development of the rhesus dentate gyrus resemble the reported patterns of postnatal ontogenesis of this structure in the rat. However, the ingrowth of cholinergic afferents and the major modifications in synapse structure occur prenatally in the rhesus monkey during the second half of the gestation period. This temporal difference between the two species should receive consideration in the planning of neuroplasticity experiments designed to explore lesion-induced adaptations in afferent growth and synaptogenesis in the rhesus dentate gyrus.     

Partially segregated neural networks for spatial and contextual memory in virtual navigation

Finding our way in a previously learned, ecologically valid environment concurrently involves spatial and contextual cognitive operations. The former process accesses a cognitive map representing the spatial interactions between all paths in the environment. The latter accesses stored associations between landmark objects and their milieu. Here, we aimed at dissociating their neural basis in the context of memory-based virtual navigation. To do so, subjects freely explored a virtual town for 1 h, then were scanned using fMRI while retrieving their way between two locations, under four navigation conditions designed to probe separately or jointly the spatial and contextual memory components. Besides prominent commonalities found in a large hippocampo-neocortical network classically involved in topographical navigation, results yield evidence for a partial dissociation between the brain areas supporting spatial and contextual components of memory-based navigation. Performance-related analyses indicate that hippocampal activity mostly supports the spatial component, whereas parahippocampal activity primarily supports the contextual component. Additionally, the recruitment of contextual memory during navigation was associated with higher frontal, posterior parietal and lateral temporal activity. These results provide evidence for a partial segregation of the neural substrates of two crucial memory components in human navigation, whose combined involvement eventually leads to efficient navigation behavior within a learned environment.     

Reward related neuronal activity in monkey dorsolateral prefrontal cortex during feeding behavior

Extracellular single neuron activity was recorded in the dorsolateral prefrontal cortex (DL) during bar pressing for food reward. Most of the reward-related neurons were located around the rostral end of the principal sulcus. Neuronal activity was diminished, abolished, or reversed when quinine adulterated food (aversive food) was given as a reinforcement. Cue-related neurons tended to be located more caudally in the DL. The activity of these neurons was not modulated by the nature of the reward as much as that of the reward-related neurons. The results suggest that DL neurons are not functionally homogeneous.     

Intrinsic connections of the macaque monkey hippocampal formation: I. Dentate gyrus

We have carried out a detailed analysis of the intrinsic connectivity of the Macaca fascicularis monkey hippocampal formation. Here we report findings on the topographical organization of the major connections of the dentate gyrus. Localized anterograde tracer injections were made at various rostrocaudal levels of the dentate gyrus, and we investigated the three-dimensional organization of the mossy fibers, the associational projection, and the local projections. The mossy fibers travel throughout the transverse extent of CA3 at the level of the cells of origin. Once the mossy fibers reach the distal portion of CA3, they change course and travel for 3-5 mm rostrally. The associational projection, originating from cells in the polymorphic layer, terminates in the inner one-third of the molecular layer. The associational projection, though modest at the level of origin, travels both rostrally and caudally from the injection site for as much as 80% of the rostrocaudal extent of the dentate gyrus. The caudally directed projection is typically more extensive and denser than the rostrally directed projection. Cells in the polymorphic layer originate local projections that terminate in the outer two-thirds of the molecular layer. These projections are densest at the level of the cells of origin but also extend several millimeters rostrocaudally. Overall, the topographic organization of the intrinsic connections of the monkey dentate gyrus is largely similar to that of the rat. Such extensive longitudinal connections have the potential for integrating information across much of the rostrocaudal extent of the dentate gyrus.     

Beneficial effect of cilostazol‐mediated neuronal repair following trimethyltin‐induced neuronal loss in the dentate gyrus

Cilostazol acts as an antiplatelet agent and has other pleiotropic effects based on phosphodiesterase‐3‐dependent mechanisms. We evaluated whether cilostazol would have a beneficial effect on neuronal repair following hippocampal neuronal damage by using a mouse model of trimethyltin (TMT)‐induced neuronal loss/self‐repair in the hippocampal dentate gyrus [Ogita et al. (2005) J Neurosci Res 82:609?621]; these mice will hereafter be referred to as impaired animals. A single treatment with cilostazol (10 mg/kg, i.p.) produced no significant change in the number of 5‐bromo‐2′‐deoxyuridine (BrdU)‐incorporating cells in the dentate granule cell layer (GCL) or subgranular zone on day 3 after TMT treatment. However, chronic treatment with cilostazol on days 3–15 posttreatment resulted in an increase in the number of BrdU‐incorporating cells in the dentate GCL of the impaired animals, and these cells were positive for neuronal nuclear antigen or doublecortin. Cilostazol was effective in elevating the level of phosphorylated cyclic adrenosine monophosphate response element‐binding protein (pCREB) in the dentate gyrus of impaired animals. The results of a forced swimming test revealed that the chronic treatment with cilostazol improved the depression‐like behavior seen in the impaired animals. In the cultures of hippocampal neural stem/progenitor cells, exposure to cilostazol produced not only enhancement of proliferation activity but also elevation of pCREB levels. Taken together, our data suggest that cilostazol has a beneficial effect on neuronal repair following neuronal loss in the dentate gyrus through promotion of proliferation and/or neuronal differentiation of neural progenitor cells in the subgranular zone. © 2014 Wiley Periodicals, Inc.     

Neurons in hippocampal afferent zones of rat striatum parse routes into multi-pace segments during maze navigation

Hippocampal 'place' neurons discharge when rats occupy specific regions within an environment. This finding is a cornerstone of the theory of the hippocampus as a cognitive map of space. But for navigation, representations of current position must be implemented by signals concerning where to go next, and how to get there. In recordings in hippocampal output structures associated with the motor system (nucleus accumbens and ventromedial caudate nucleus) in rats solving a plus-maze, neurons fired continuously from the moment the rat left one location until it arrived at the next goal site, or at an intermediate place, such as the maze centre. While other studies have shown discharges during reward approach behaviours, this is the first demonstration of activity corresponding to the parsing of complex routes into sequences of movements between landmarks, similar to the lists of instructions we often employ to communicate directions to follow between points on a map. As these cells fired during a series of several paces or re-orientation movements, perhaps this is homologous to 'chunking'. The temporal overlaps in the activity profiles of the individual neurons provide a possible substrate to successively trigger movements required to arrive at the goal. These hippocampally informed, and in some cases, spatially selective responses support the view of the ventral striatum as an interface between limbic and motor systems, permitting contextual representations to have an impact on fundamental action sequences for goal-directed behaviour.     

Lag-sensitive repetition suppression effects in the anterior parahippocampal gyrus

Single-unit recording studies of monkeys have shown that neurons in perirhinal and entorhinal cortex exhibit activity reductions following stimulus repetition, and some have suggested that these "repetition suppression" effects may represent neural signals that support recognition memory. Critically, repetition suppression effects are most pronounced at short intervals between stimulus repetitions. Here, we used event-related functional magnetic resonance imaging (fMRI) to identify repetition suppression effects in the human medial temporal lobe and determine whether these effects are sensitive to the length of the interval between repetitions. Twenty-one participants were scanned while performing a continuous recognition memory task in which the interval between item repetitions was parametrically varied from 2 to 32 intervening items. We found evidence of repetition suppression in the anterior parahippocampal gyrus, but only when the repetition interval was relatively short. Moreover, bilateral hippocampal regions showed lag-sensitive repetition effects. Our results demonstrate that activity in the human medial temporal cortex, like that of monkeys, exhibits repetition suppression effects that are sensitive to the length of the interval between repetitions.     

A Comparison of the neural correlates that underlie rule‐based and information‐integration category learning

The influential competition between verbal and implicit systems (COVIS) model proposes that category learning is driven by two competing neural systems—an explicit, verbal, system, and a procedural‐based, implicit, system. In the current fMRI study, participants learned either a conjunctive, rule‐based (RB), category structure that is believed to engage the explicit system, or an information‐integration category structure that is thought to preferentially recruit the implicit system. The RB and information‐integration category structures were matched for participant error rate, the number of relevant stimulus dimensions, and category separation. Under these conditions, considerable overlap in brain activation, including the prefrontal cortex, basal ganglia, and the hippocampus, was found between the RB and information‐integration category structures. Contrary to the predictions of COVIS, the medial temporal lobes and in particular the hippocampus, key regions for explicit memory, were found to be more active in the information‐integration condition than in the RB condition. No regions were more activated in RB than information‐integration category learning. The implications of these results for theories of category learning are discussed. Hum Brain Mapp 37:3557–3574, 2016. © 2016 Wiley Periodicals, Inc.     

GAP-43 mRNA and protein expression in the hippocampal and parahippocampal region during the course of epileptogenesis in rats

In order to reveal axonal rewiring in the hippocampal and parahippocampal regions after status epilepticus, we investigated the temporal evolution of growth-associated protein-43 (GAP-43) mRNA and protein expression in two rat models of mesial temporal lobe epilepsy (MTLE). Status epilepticus (SE) was induced by electrical stimulation of the angular bundle or by intraperitoneal kainic acid (KA) injections. Despite increased GAP-43 mRNA expression in dentate granule cells at 24 h after SE, GAP-43 protein expression in the inner molecular layer (IML) of the dentate gyrus decreased progressively after 24 h after SE in both models. Nevertheless robust mossy fiber sprouting (MFS) was evident in the IML of chronic epileptic rats. Remaining GAP-43 protein expression in the IML in chronic epileptic rats did not correlate with the extent of MFS, but with the number of surviving hilar neurons. In the parahippocampal region, GAP-43 mRNA expression was decreased in layer III of the medial entorhinal area (MEAIII) in parallel with extensive neuronal loss in this layer. There was a tendency of GAP-43 mRNA up-regulation in the presubiculum, a region that projects to MEAIII. With regard to this parahippocampal region, however, changes in GAP-43 mRNA expression were not followed by protein changes. The presence of the presynaptic protein GAP-43 in a neurodegenerated MEAIII indicates that fibers still project to this layer. Whether reorganization of fibers has occurred in this region after SE needs to be investigated with tools other than GAP-43.