Showing papers in "Hippocampus in 2003"

Impaired interleukin-1 signaling is associated with deficits in hippocampal memory processes and neural plasticity.

Abstract: The cytokine interleukin-1 (IL-1) is produced by peripheral immune cells as well as glia and neurons within the brain; it plays a major role in immune to brain communication and in modulation of neural, neuroendocrine, and behavioral systems during illness. Although previous studies demonstrated that excess levels of IL-1 impaired memory processes and neural plasticity, it has been suggested that physiological levels of IL-1 are involved in hippocampal-dependent memory and long-term potentiation (LTP). To examine this hypothesis, we studied IL-1 receptor type I knockout (IL-1rKO) mice in several paradigms of memory function and hippocampal plasticity. In the spatial version of the water maze test, IL-1rKO mice displayed significantly longer latency to reach a hidden platform, compared with wild-type controls. Furthermore, IL-1rKO exhibited diminished contextual fear conditioning. In contrast, IL-1rKO mice were similar to control animals in hippocampal-independent memory tasks; i.e., their performance in the visually guided task of the water maze and the auditory-cued fear conditioning was normal. Electrophysiologically, anesthetized IL-1rKO mice exhibited enhanced paired-pulse inhibition in response to perforant path stimulation and no LTP in the dentate gyrus. In vitro, decreased paired-pulse responses, as well as a complete absence of LTP, were observed in the CA1 region of hippocampal slices taken from IL-1rKO mice compared with WT controls. These results suggest that IL-1 contributes to the regulation of memory processes as well as short- and long-term plasticity within the hippocampus. These findings have important implications to several conditions in humans, which are associated with long-term defects in IL-1 signaling, such as mutations in the IL-1 receptor accessory protein-like gene, which are involved in a frequent form of X-linked mental retardation.

Navigation expertise and the human hippocampus: a structural brain imaging analysis.

Abstract: Grey matter volume in the posterior hippocampus of Lon- don taxi drivers is greater than in age-matched controls, and the size of this increase correlates positively with time spent taxi driving (E.A. Magu- ire et al., 2000. Proc Natl Acad Sc iUSA9 7:4398 - 4403). This change suggests that increased posterior hippocampal grey matter volume is acquired in response to increased taxi driving experience, perhaps reflect- ing their detailed representation of the city. However, an alternate hy- pothesis is that the difference in hippocampal volume is instead associated with innate navigational expertise, leading to an increased likelihood of becoming a taxi driver. To investigate this possibility, we used structural brain imaging and voxel-based morphometry (VBM) to examine a group of subjects who were not taxi drivers. Despite this group showing a wide range of navigational expertise, there was no association between exper- tise and posterior hippocampal grey matter volume (or, indeed, grey matter volume throughout the brain). This failure to find an association between hippocampal volume and navigational expertise thus suggests that structural differences in the human hippocampus reflect the detail and/or duration of use of the spatial representation acquired, and not innate navigational expertise per se. Hippocampus 2003;13:208 -217. © 2003 Wiley-Liss, Inc.

The entorhinal cortex of the mouse: organization of the projection to the hippocampal formation.

Abstract: The origin and the terminations of the projections from the entorhinal cortex to the hippocampal formation of the mouse (C57BL/6J strain) have been studied using anterogradely and retrogradely transported tracers. The entorhinal cortex is principally divided into two areas, the lateral entorhinal area (LEA) and the medial entorhinal area (MEA). LEA is the origin of the lateral perforant path that terminates in the outer one-third of the molecular layer of the dentate gyrus, and MEA is the origin of the medial perforant path that ends in the middle one-third of the molecular layer of the dentate gyrus. This projection is mostly to the ispsilateral dentate gyrus; only a few labeled axons and terminals are found in the contralateral dentate gyrus. The projection to the dentate gyrus originates predominantly from neurons in layer II of the entorhinal cortex. The entorhinal cortex also projects to CA3 and CA1 and to subiculum; in both CA3 and CA1, the terminals are present in stratum lacunosum-moleculare, whereas in the subiculum the terminals are in the outer part of the molecular layer. The projection from the entorhinal cortex to CA3, CA1, and subiculum is bilateral, and it originates predominantly from neurons in layer III, but a small number of neurons in the deeper layers of the entorhinal cortex contributes to this projection. The projection of entorhinal cortex to the hippocampus is topographically organized, neurons in the lateral part of both LEA and MEA project to the dorsal part (i.e., septal pole) of the hippocampus, whereas the projection to the ventral (i.e., temporal pole) hippocampus originates from neurons in medial parts of the entorhinal cortex.

A familiarity signal in human anterior medial temporal cortex

Abstract: The medial temporal lobe (MTL) comprises the hippocampal complex and amygdala, along with distinct cortical regions, including the parahippocampal, entorhinal, and perirhinal cortices. It has been suggested that different components of the MTL support dissociable memory functions (see, e.g., Eichenbaum et al., 1994). Of particular relevance to the present report is evidence from lesion studies in nonhuman primates suggesting that the perirhinal region plays a key role in visual recognition memory (Meunier et al., 1993; Bachevalier et al., 2002). Consistent with this suggestion, electrophysiological studies have identified neurons in perirhinal and nearby cortical areas of the monkey in which object-selective responses decrease after previous exposure to the object (Brown and Xiang, 1998). These repetition-related decreases can be found over intervals of 24 h, as might be expected of a neural signal contributing to a form of long-term memory. Together, lesion and single neuron evidence has led to the proposal (Brown and Aggleton, 2001) that perirhinal cortex contributes to recognition memory through the assessment of relative familiarity, and that neuronal response decrements provide one basis for such assessments. In the present study, we report that experimentally familiar items elicit smaller hemodynamic responses in human anterior MTL, consistent with the findings from nonhuman primates. Evidence for a role of perirhinal cortex in recognition memory comes almost exclusively from work with experimental animals. There are few data to suggest that the region has an equivalent role in humans (but see Buffalo et al., 1998). We report findings from four memory studies recently conducted in our laboratory using event-related functional magnetic resonance imaging (fMRI). In each case, we found evidence of a reduction in the anterior MTL response to experimentally familiar (“Old”) items relative to experimentally novel (“New”) items—a “New-Old” effect. These studies were conducted independent of one another and are described in detail in separate publications. With the exception of one study (Rugg et al., 2003), however, the data reported in the present study have not been described elsewhere. The four experiments, A–D, shared many methodological features, including scanner hardware, data acquisition parameters, and data analysis methods. They differed along a number of psychological dimensions (see Detailed Methods). In three of the studies, participants explicitly discriminated Old from New items; in the remaining study, the repetition of items was task-irrelevant (experiment D). Two studies used words (experiments A and B), one used pictures (experiment C), and one used faces (experiment D). In two of the studies (experiments B and C), the task required retrieval of contextual information associated with the prior presentation of Old items. The pattern of responses to Old and New items was the same in all cases: Old items elicited a smaller response in anterior MTL than did New items (Fig. 1). The effect Grant sponsor: Wellcome Trust; Grant sponsor: MRC; Grant sponsor: DGAPA, National Autonomous University of Mexico; Grant number: IN303798. *Correspondence to: M.D. Rugg, Insititute of Cognitive Neuroscience, University College London, 17 Queen Square, London WC1N 3AR, UK. E-mail: m.rugg@ucl.ac.uk Accepted for publication 22 August 2002 DOI 10.1002/hipo.10117 HIPPOCAMPUS 13:259–262 (2003)

Age-related differences in the functional connectivity of the hippocampus during memory encoding

Abstract: The purpose of the current experiment was to examine the functional connectivity of the hippocampus during encoding in young and old adults, and the way in which this connectivity was related to recognition performance. Functional connectivity was defined as the correlation between activity in the hippocampus and activity in the rest of the brain, as measured by neuroimaging. During encoding of words and pictures of objects in young adults, hippocampal activity was correlated with activity in the ventral prefrontal and extrastriate regions, and increased activity in all these regions was associated with better recognition. In contrast, older adults showed correlations between hippocampal activity and the dorsolateral prefrontal and parietal regions, and positive correlations between activity in these regions and better memory performance. This ventral/dorsal distinction suggests a shift in the cognitive resources used with age from more perceptually based processes to those involved in executive and organizational functions. The results of this study provide evidence that aging is associated with alterations in hippocampal function, including how it is functionally connected with prefrontal cortex, and that these alterations have an impact on memory performance. Hippocampus 2003;13:572–586. © 2003 Wiley-Liss, Inc.

Rapid induction of BDNF expression in the hippocampus during immobilization stress challenge in adult rats.

Abstract: Brain-derived neurotrophic factor (BDNF) is strongly expressed in the hippocampus, where it has been associated with memory processes. In the central nervous system, some learning processes, as well as brain insults, including stress, induce modifications in BDNF mRNA expression. Because stress and memory appear to share some neuronal pathways, we studied BDNF mRNA and BDNF peptide variations in response to short times of immobilization stress. Using an RNase protection assay, we demonstrated that short-time stress application induced a significant increase (at 60 min) in BDNF mRNA levels in the whole rat hippocampus. Changes in BDNF mRNA content appear to reflect increased expression of BDNF transcripts containing exons I, II, and III, that were also significantly modified at this time. The time course of stress-induced changes in BDNF transcript levels revealed that mRNA containing exon III was the first increased, significantly elevated by 15 min, attaining maximal levels at 60 min, as BDNF transcripts containing exons I and II. However, at longer times of stress (180 min), BDNF mRNA levels were decreased as well as mRNA containing exon IV. In situ hybridization analysis of discrete hippocampal layers demonstrated that BDNF mRNA expression increased as early as 15 min in most hippocampal regions, with no modification in the number of labeled cells. The same signal pattern, although less pronounced, was determined at 60 min, but at this time a significant increase in BDNF-positive cells was visualized in the CA3 layer. The peptide, measured by immunoassay, was significantly augmented after 180 min of stress exposure whereas at 300 min, levels were similar to those measured in control animals. These data suggest that rapid changes in BDNF expression may be part of a compensatory response to preserve hippocampal homeostasis or a form of neuronal plasticity to cope with new stimuli.

Regional analysis of hippocampal activation during memory encoding and retrieval: fMRI study.

Abstract: Investigators have recently begun to examine the differen- tial role of subregions of the hippocampus in episodic memory. Two distinct models have gained prominence in the field. One model, outlined by Moser and Moser (Hippocampus 1998;8:608 - 619), based mainly on animal studies, has proposed that episodic memory is subserved by the posterior two-thirds of the hippocampus alone. A second model, derived by Lepage et al. (Hippocampus 1998;8:313-322) from their review of 52 PET studies, has suggested that the anterior hippocampus is activated by memory encoding while the posterior hippocampus is activated by mem- ory retrieval. Functional magnetic resonance imaging (fMRI) studies have tended to show limited activation in the anteriormost regions of the hippocampus, providing support for the Moser and Moser model. A potential confounding factor in these fMRI studies, however, is that susceptibility artifact may differentially reduce signal in the anterior versus the posterior hippocampus. In the present study, we examined activation differences between hippocampal subregions during encoding and retrieval of words and interpreted our findings within the context of these two models. We also examined the extent to which susceptibility artifact affects the analysis and interpretation of hippocampal activation by demonstrating its differential effect on the anterior versus the posterior hippocampus. Both voxel-by-voxel and region-of-interest analyses were conducted, allowing us to quantify differences between the anterior and posterior aspects of the hippocampus. We detected significant hippocam- pal activation in both the encoding and retrieval conditions. Our data do not provide evidence for regional anatomic differences in activation between encoding and retrieval. The data do suggest that, even after accounting for susceptibility artifact, both encoding and retrieval of ver- bal stimuli activate the middle and posterior hippocampus more strongly than the anterior hippocampus. Finally, this study is the first to quantify the effects of susceptibility-induced signal loss on hip- pocampal activation and suggests that this artifact has significantly biased the interpretation of earlier fMRI studies. Hippocampus 2003;13:164 -174.

The role of NMDA glutamate receptors, PKA, MAPK, and CAMKII in the hippocampus in extinction of conditioned fear.

Abstract: Pavlovian conditioning involves the association of initially neutral conditioned stimuli (CS) with unconditioned stimuli (US) that elicit a response. In contextual fear conditioning in rodents, the CS is the context of a training apparatus and the US is a foot shock. Retrieval of memory of the training is tested by presenting the CS alone. But a retrieval test also initiates extinction of the conditioned response. That is, presentation of the CS alone results in new learning, i.e., the CS no longer predicts the US. Here we report that extinction is triggered by two hippocampal signaling pathways underlying retrieval (the cAMP-dependent protein kinase and the mitogen-activated protein kinase pathways) and two other mechanisms that become activated at the same time and are not necessary for retrieval (N-methyl-D-aspartate glutamatergic receptors and the calcium/calmodulin-dependent protein kinase II signaling pathway). Thus, the molecular mechanisms underlying acquisition and/or consolidation of the memory for extinction are similar to those described for the acquisition and/or consolidation of the original contextual fear. Hippocampus 2003;13:53–58. © 2003 Wiley-Liss, Inc.

Para/autocrine regulation of estrogen receptors in hippocampal neurons.

Abstract: Previous studies have shown that estrogens, originating from ovaries, have a wide variety of estrogen receptor (ER)-mediated effects in the hippocampus. In the present study, we have investigated whether estrogens, which are synthesized in the hippocampus, could induce these effects as well. As a parameter, we used ER expression in response to estrogen synthesis, because estrogen receptors are ligand-inducible transcription factors. The experiments were carried out with cultures of isolated adult rat hippocampal cells, which contained about 95% neurons and about 5% oligodendrocytes in serum-free and steroid-free medium. Hippocampal neurons express both estrogen receptor isoforms (ERα and ERβ), as shown by reverse transcription-polymerase chain reaction (RT-PCR) and in situ hybridization. The release of estrogens by hippocampal neurons was quantified by radioimmunoassay (RIA). The ER isoforms (α and β) were studied by semiquantitative immunocytochemical image analysis. Hippocampal cells precultured for 4 days were found to synthesize 17β-estradiol for the next 8 days. This synthesis was completely inhibited by letrozol, an aromatase inhibitor. Inhibition of estrogen synthesis by letrozol induced a significant decrease in ERα expression, but an increase in ERβ. As a control, supplementation of the medium with 17β-estradiol resulted in a significant increase of ERα expression, whereas ERβ was downregulated. Our findings provide evidence for a de novo synthesis of estrogens in the hippocampus, differential regulation of estrogen receptor isoforms by estrogen and consequently for a para/autocrine loop of estrogen action in the hippocampus. Hippocampus 2003;13:226–234. © 2003 Wiley-Liss, Inc.

Function of hippocampus in "insight" of problem solving.

Abstract: Since the work of Wolfgang Kohler, the process of "insight" in problem solving has been the subject of considerable investigation. Yet, the neural correlates of "insight" remain unknown. Theoretically, "insight" means the reorientation of one's thinking, including breaking of the unwarranted "fixation" and forming of novel, task-related associations among the old nodes of concepts or cognitive skills. Processes closely related to these aspects have been implicated in the hippocampus. In this research, the neural correlates of "insight" were investigated using Japanese riddles, by imaging the answer presentation and comprehension events, just after participants failed to resolve them. The results of event-related functional magnetic resonance imaging (fMRI) analysis demonstrated that the right hippocampus was critically highlighted and that a wide cerebral cortex was also involved in this "insight" event. To the best of our knowledge, this work is the first neuroirnaging study to have investigated the neural correlates of "insight" in problem solving. (C) 2003 Wiley-Liss, Inc.

Transitivity, flexibility, conjunctive representations, and the hippocampus. I. An empirical analysis.

Abstract: After training on a set of four ordered, simultaneous, odor discrimination problems (A+B-, B+C-, C+D-, D+E), intact rats display transitivity: When tested on the novel combination BD, they choose B. Rats with damage to the hippocampus, however, do not show transitivity (Dusek and Eichenbaum, 1997. Proc Natl Acad Sci U S A 94:7109-7114). These results have been interpreted as support for the idea that the hippocampus is a relational memory storage system that enables the subject to make comparisons among representations of the individual problems and choose based on inferential logic. We provide evidence for a simpler explanation. Specifically, subjects make their choices based on the absolute excitatory value of the individual stimuli. This value determines the ability of that stimulus to attract a response. This conclusion emerged because after training on a five-problem set (A+B-, B+C-, C+D-, D+E-, E+F-) rats preferred B when tested with BE, but not when tested with BD. The implication of these results for how to conceptualize the role of the hippocampus in transitive-like phenomena is discussed.

Mossy fiber plasticity and enhanced hippocampal excitability, without hippocampal cell loss or altered neurogenesis, in an animal model of prolonged febrile seizures

Abstract: Seizures induced by fever (febrile seizures) are the most frequent seizures affecting infants and children; however, their impact on the developing hippocampal formation is not completely understood. Such understanding is highly important because of the potential relationship of prolonged febrile seizures to temporal lobe epilepsy. Using an immature rat model, we have previously demonstrated that prolonged experimental febrile seizures render the hippocampus hyperexcitable throughout life. Here we examined whether (1) neuronal loss, (2) altered neurogenesis, or (3) mossy fiber sprouting, all implicated in epileptogenesis in both animal models and humans, were involved in the generation of a pro-epileptic, hyperexcitable hippocampus by these seizures. The results demonstrated that prolonged experimental febrile seizures did not result in appreciable loss of any vulnerable hippocampal cell population, though causing strikingly enhanced sensitivity to hippocampal excitants later in life. In addition, experimental febrile seizures on postnatal day 10 did not enhance proliferation of granule cells, whereas seizures generated by kainic acid during the same developmental age increased neurogenesis in the immature hippocampus. However, prolonged febrile seizures resulted in long-term axonal reorganization in the immature hippocampal formation: Mossy fiber densities in granule cell- and molecular layers were significantly increased by 3 months (but not 10 days) after the seizures. Thus, the data indicate that prolonged febrile seizures influence connectivity of the immature hippocampus long-term, and this process requires neither significant neuronal loss nor altered neurogenesis. In addition, the temporal course of the augmented mossy fiber invasion of the granule cell and molecular layers suggests that it is a consequence, rather than the cause, of the hyperexcitable hippocampal network resulting from these seizures.

Dynamically detuned oscillations account for the coupled rate and temporal code of place cell firing.

Abstract: Firing of place cells in the exploring rat conveys doubly coded spatial information: both the rate of spikes and their timing relative to the phase of the ongoing field theta oscillation are correlated with the location of the animal. Specifically, the firing rate of a place cell waxes and wanes, while the timing of spikes precesses monotonically as the animal traverses the portion of the environment preferred by the cell. We propose a mechanism for the generation of this firing pattern that can be applied for place cells in all three hippocampal subfields and that encodes spatial information in the output of the cell without relying on topographical connections or topographical input. A single pyramidal cell was modeled so that the cell received rhythmic inhibition in phase with theta field potential oscillation on the soma and was excited on the dendrite with input depending on the speed of the rat. The dendrite sustained an intrinsic membrane potential oscillation, frequency modulated by its input. Firing probability of the cell was determined jointly by somatic and dendritic oscillations. Results were obtained on different levels of abstraction: a purely analytical derivation was arrived at, corroborated by numerical simulations of rate neurons, and an extension of these simulations to spiking neurons was also performed. Realistic patterns of rate and temporal coding emerged and were found to be inseparable. These results may have implications on the robustness of information coding in place cell firing and on the ways information is processed in structures downstream to the hippocampus.

Retrograde and anterograde object recognition in rats with hippocampal lesions

Abstract: Retrograde and anterograde object-recognition memory was assessed in rats with cytotoxic lesions of the hippocampal formation (HPC), using a paradigm based on the natural tendency of rats to spend more time exploring novel objects than familiar objects. The rats were allowed to explore a sample object for 5 min/day on 5 consecutive days, either 5 weeks or 1 week before surgery. After surgery, retrograde rec- ognition was assessed by comparing the amount of time spent exploring the sample versus a novel object in a free-choice situation. Control rats spent more time exploring the novel object than the sample objects from both presurgery time periods, whereas rats with HPC lesions did not discriminate between the novel objects and sample objects from either presurgery time period. Despite their deficits on the retrograde recogni- tion test, the rats with HPC lesions performed like control rats on antero- grade recognition tests, displaying a strong exploratory preference for novel objects over sample objects, with retention delays of either 15 min or 24 h. The findings suggest that extrahippocampal circuitry is capable of supporting object recognition, but only if the HPC does not participate in encoding the original encounter with the object. © 2003 Wiley-Liss, Inc.

Dorsal hippocampus and classical fear conditioning to tone and context in rats: effects of local NMDA-receptor blockade and stimulation.

Abstract: Consistent with the importance of the hippocampus in learning more complex stimulus relations, but not in simple associative learning, the dorsal hippocampus has commonly been implicated in classical fear conditioning to context, but not to discrete stimuli, such as a tone. In particular, a specific and central role in contextual fear conditioning has been attributed to mechanisms mediated by dorsal hippocampal N-methyl-D-aspartate (NMDA)-type glutamate receptors. The present study characterized the effects of blockade or tonic stimulation of dorsal hippocampal NMDA receptors by bilateral local infusion of the noncompetitive NMDA receptor antagonist MK-801 (dizocilpine maleate; 6.25 microg/side) or of NMDA (0.7 microg/side), respectively, on classical fear conditioning to tone and context in Wistar rats. Freezing was used to measure conditioned fear. Regardless of whether conditioning was conducted with tone-shock pairings or unsignaled footshocks (background or foreground contextual conditioning), both NMDA and MK-801 infusion before conditioning resulted in reduced freezing during subsequent exposure to the conditioning context. Freezing during subsequent tone presentation in a new context, normally resulting from conditioning with tone-shock pairings, was not impaired by MK-801 but was strongly reduced by NMDA infusion before conditioning; this freezing was also reduced by NMDA infusion before tone presentation (in an experiment involving NMDA infusions before conditioning and subsequent tone presentation to assess the role of state-dependent learning). It was assessed whether unspecific infusion effects (altered sensorimotor functions, state dependency) or infusion-induced dorsal hippocampal damage contributed to the observed reductions in conditioned freezing. Our data suggest that formation of fear conditioning to context, but not tone, requires NMDA receptor-mediated mechanisms in the dorsal hippocampus. As indicated by the effects of NMDA, some dorsal hippocampal processes may also contribute to fear conditioning to tone. The role of the dorsal hippocampus and local NMDA receptor-mediated processes in fear conditioning to tone and context is discussed in comparison with ventral hippocampal processes.

Morphological and numerical analysis of synaptic interactions between neurons in deep and superficial layers of the entorhinal cortex of the rat

Abstract: Neurons providing connections between the deep and superficial layers of the entorhinal cortex (EC) constitute a pivotal link in the network underlying reverberation and gating of neuronal activity in the entorhinal-hippocampal system. To learn more of these deep-to-superficial neurons and their targets, we applied the tracer Neurobiotin pericellularly in layer V of the medial EC of 12 rats. Labeled axons in the superficial layers were studied with light and electron microscopy, and their synaptic organization recorded. Neurobiotin-labeled layer V neurons displayed "Golgi-like" staining. Two major cell types were distinguished among these neurons: (1) pyramidal neurons with apical spiny dendrites traversing all layers and ramifying in layer I, and (2) horizontal neurons with dendrites confined to the deep layers. Labeled axons ramified profusely in layer III, superficially in layer II and deep in layer I. Analysis of labeled axon terminals in layers I-II and III showed that most synapses (95%) were asymmetrical. Of these synapses, 56% occurred with spines (presumably belonging to principal neurons) and 44% with dendritic shafts (presumably interneurons). A small fraction of the synapses (5%) was of the symmetrical type. Such synapses were mainly seen on dendritic shafts. We found in two sections a symmetrical synapse on a spine. These findings suggest that the deep to superficial projection is mainly excitatory in nature, and that these fibers subserve both excitation and feed-forward inhibition. There is an additional, much weaker, inhibitory component in this projection, which may have a disinhibitory effect on the entorhinal network in the superficial layers.

Sustained calpain activation associated with lysosomal rupture executes necrosis of the postischemic CA1 neurons in primates

Abstract: Because of the paucity of primate experimental models, the precise molecular mechanism of ischemic neuronal death remains unknown in humans. This study focused on nonhuman primates to determine which cascade necrosis or apoptosis is predominantly involved in the development of delayed (day 5) neuronal death in the hippocampal CA1 sector undergoing 20 min ischemia. We investigated expression, activation, and/or translocation of micro-calpain, lysosome-associated membrane protein-1 (LAMP-1), caspase-3, and caspase-activated DNase (CAD), as well as morphology of the postischemic CA1 neurons and DNA electrophoresis pattern. Immunoblotting showed sustained (immediately after ischemia until day 5) and maximal (day 3) activation of micro-calpain. The immunoreactivity of activated micro-calpain became remarkable as coarse granules at lysosomes on day 2, while it translocated throughout the perikarya on day 3. The immunoreactivity of LAMP-1 also showed a dynamic and concomitant translocation that was maximal on days 2-3, indicating calpain-mediated disruption of the lysosomal membrane after ischemia. In contrast, immunoblotting demonstrated essentially no increase in the activated caspase-3 at any time points after ischemia, despite upregulation of pro-caspase-3. Although expression of CAD was slightly upregulated on day 1 or 2, or both, it was much less compared with lymph node or intestine tissues. Furthermore, light and electron microscopy showed eosinophilic coagulation necrosis and membrane disruption without apoptotic body formation, while DNA electrophoresis did not show a ladder pattern, but rather a smear pattern. Sustained calpain activation and the resultant lysosomal rupture, rather than CAD-mediated apoptosis, may cause ischemic neuronal necrosis in primates.

Hippocampal damage equally impairs memory for single items and memory for conjunctions

Abstract: In a prior study of continuous recognition performance, data were reported in support of the hypothesis that the hippocampus is not needed to remember the individual components of a stimulus but is important for remembering associations between its components (Kroll et al. 1996. J Mem Lang 35:176-196). Patients with left hippocampal damage were able to endorse recently encountered words and to reject novel words, as well as disyllabic words in which one of the syllables had been previously encountered. However, they failed to reject words in which both syllables had been encountered independently in different words. We present data from five experiments designed to examine this finding in more detail. In each experiment, five patients with bilateral hippocampal damage and eight controls were tested using the same protocol as Kroll et al. (1996). On each trial, a two-component stimulus was presented. Stimuli could be entirely novel, novel with one previously encountered (repeated) component, novel but with both components repeated, or a true repetition. The first experiment was a direct replication using the same disyllabic words as Kroll et al. (1996). The second experiment used pseudo-words, constructed of two monosyllabic words (e.g., jambark). The third experiment used the same pairs of monosyllabic words, but presented separately on the screen to encourage participants to treat each component independently. The fourth experiment used pairs of objects, and the fifth experiment used face-house pairs. In all five experiments, patients with hippocampal damage exhibited impaired recognition memory. The impairment extended across all trial types with no evidence that hippocampal damage selectively (or disproportionately) impaired the associative or conjunctive component of memory. We discuss our findings in the light of the work by Kroll et al. (1996) and other recent neuropsychological, electrophysiological, and neuroimaging studies of hippocampal function and single-item and associative memory.

Longitudinal axis of the hippocampus: both septal and temporal poles of the hippocampus support water maze spatial learning depending on the training protocol.

Abstract: It has been suggested previously that 30% sparing of the hippocampus is enough to support spatial learning of a reference memory task in a water maze provided the spared tissue is located septally (Moser et al. 1995, Proc Natl Acad Sci USA 92:9697-9701). Therefore, the temporal hippocampus may not be involved in spatial memory. Place cells are also found in this part of the structure, and it has been suggested that these place cells have larger, less well-tuned place fields than are found in the septal hippocampus. We tested the possibility that the temporal hippocampus might be involved in spatial learning when the animals are required to distinguish between different contexts. Experiment 1 was a replication of the findings reported by Moser et al., using their protocol (8 trials/day, 6 days) and the groups with 20-40% hippocampus spared septally or temporally (volume assessed by quantitative volumetric techniques). In experiment 2, rats with also 20-40% sparing of the hippocampus either septally or temporally were trained in two water maze concurrently (four trials/day/water maze, 8 days). Rats with 20-40% hippocampus spared temporally were able to learn the two water maze tasks normally, and no difference was observed between rats with septal and temporal hippocampus spared across different measures of performance. In experiment 3, rats with 20-40% hippocampus spared septally or temporally were trained in one water maze as in experiment 1, but using a spaced training protocol similar to that of experiment 2 (four trials/day, 8 days). Rats with temporal hippocampus spared developed a preference for the training quadrant and acquired levels of performance indistinguishable from those of rats with septal hippocampus spared. The results suggest that the temporal hippocampus can support the learning of two, but also one, spatial water maze reference memory task, provided the training protocol is adequate.

Comparison of computational models of familiarity discrimination in the perirhinal cortex

Abstract: This study compares the efficiency and plausibility of published computational models of familiarity discrimination in the perirhinal cortex. Substantial evidence indicates that the perirhinal cortex is involved in both the familiarity discrimination aspect of recognition memory and in perceptual functions involved with representations of complete stimuli (i.e., object identification). Published models of how the perirhinal cortex may perform familiarity discrimination can be divided into two groups. The first group assumes that a proportion of perirhinal neurons form a network specialised just for familiarity discrimination (these models may be based on Hebbian or anti-Hebbian synaptic plasticity). In contrast, the second group assumes that both familiarity discrimination and learning representations of complete stimuli are performed within a single combined network. This study establishes that when the responses of neurons that provide input to the familiarity discrimination network are correlated (as indicated by experimental data), specialised networks based on anti-Hebbian learning may recognise the previous occurrence of many more stimuli (i.e., have a capacity up to thousands of times larger) than specialised networks based on Hebbian learning. The currently published combined models do not learn an optimal stimulus representation (they do not fully extract statistically independent features), and hence their capacities are even lower than those of the specialised models based on Hebbian learning. Hence, the combined models published thus far are critically less efficient than the specialised models based on anti-Hebbian learning. This study also compares the consistency of the models with experimental observations concerning what is known of synaptic plasticity in the perirhinal cortex and the responses of its neurons. Many theoretically important parameters remain undetermined, and experiments are suggested to provide information critical for refining and distinguishing between the various models. However, the above theoretical arguments and currently published data favour the existence of a separate network specialised for familiarity discrimination.

Downregulation of the alpha5 subunit of the GABA(A) receptor in the pilocarpine model of temporal lobe epilepsy.

Abstract: Specific subunits of γ-aminobutyric acid (GABA)A receptors may be regulated differentially in animal models of temporal lobe epilepsy during the chronic stage. Although several subunits may be upregulated, other subunits may be downregulated in the hippocampal formation. The α5 subunit is of particular interest because of its relatively selective localization in the hippocampus and its potential role in tonic inhibition. In normal rats, immunolabeling of the α5 subunit was high in the dendritic layers of CA1 and CA2 and moderate in these regions of CA3. In chronic pilocarpine-treated rats displaying recurrent seizures, α5 subunit-labeling was substantially decreased in CA1 and nearly absent in CA2. Only slight decreases in immunolabeling were evident in CA3. In situ hybridization studies demonstrated that the α5 subunit mRNA was also strongly decreased in stratum pyramidale of CA1 and CA2. Thus, the alterations in localization of the α5 subunit peptide and its mRNA were highly correlated. The large decreases in labeling of the α5 subunit did not appear to be related to loss of pyramidal neurons in CA1 or CA2 since these neurons were generally preserved in pilocarpine-treated animals. No comparable decreases in labeling of the α2 subunit of the GABAA receptor were detected. These findings indicate that the α5 subunit of the GABAA receptor is capable of substantial and prolonged downregulation in remaining pyramidal neurons in a model of temporal lobe epilepsy. The results raise the possibility that presumptive extrasynaptic GABAA receptor subunits, such as the α5 subunit, may be regulated differently than synaptically located subunits, such as the α2 subunit, within the same brain regions in some pathological conditions. Hippocampus 2003;13:633–645. © 2003 Wiley-Liss, Inc.

Preserved performance in a hippocampal-dependent spatial task despite complete place cell remapping.

Abstract: The spatially localized firing of hippocampal place cells is thought to underlie the navigational function of the, hippocampus. Performance on a spatial task learned using a particular place cell map should therefore deteriorate if the map is disrupted. To test this prediction, we trained rats on a hippocampal-dependent spatial task in a black box and tested them in a white box. Although the change from black to white induced remapping of most place cells, navigational performance remained essentially intact. Furthermore, place cell activity was also unrelated to specific aspects of the task such as tone onset, response, or goal location. Together, these results imply that the spatial information needed to solve this navigation task is represented outside the hippocampus and suggest that the place cells encode some other aspect, such as the spatial context. (C) 2003 Wiley-Liss, Inc.

Maturation of granule cell dendrites after mossy fiber arrival in hippocampal field CA3.

Abstract: Most granule neurons in the rat dentate gyrus are born over the course of the first 2 postnatal weeks The resulting heterogeneity has made it difficult to define the relationship between dendritic and axonal maturation and to delineate a time course for the morphological development of the oldest granule neurons By depositing crystals of the fluorescent label Dil in hippocampal field CA3, we retrogradely labeled granule neurons in fixed tissue slices from rats aged 2-9 days The results showed that all labeled granule cells, regardless of the age of the animal, exhibited apical dendrites On day 2, every labeled neuron had rudimentary apical dendrites, and a few dendrites on each cell displayed immature features such as growth cones, varicosities, and filopodia Some cells displayed basal dendrites By day 4, the most mature granule neurons had longer and more numerous apical branches, as well as various immature features Most had basal dendrites On days 5 and 6, the immature features and the basal dendrites had begun to regress on the oldest cells, and varying numbers of spines were present On day 7, the first few adult-like neurons were seen: immature features and basal dendrites had disappeared, all dendrites reached the top of the molecular layer, and the entire dendritic tree was covered with spines These data show that dendritic outgrowth occurs before, or concurrent with, axon arrival in the CA3 target region, and that adult-like granule neurons are present by the end of the first week

Temporal spacing of synaptic stimulation critically modulates the dependence of LTP on cyclic AMP‐dependent protein kinase

Abstract: Genetic and electrophysiological experiments have defined an important role for cAMP-dependent protein kinase (PKA) in certain forms of long-term potentiation (LTP). However, the characteristics of stimulation that are critical for regulating the PKA-dependence of LTP have not been clearly defined. In the present study, we have used PKA mutant mice (R(AB) transgenic mice), which have reduced PKA activity in neurons within the hippocampus, to explore the role of temporal spacing of synaptic stimulation in regulating the PKA-dependence of LTP. The time interval between successive bursts of electrical stimulation was varied while keeping constant the total number of stimulus pulses. LTP induced by temporally spaced tetraburst synaptic stimulation was impaired in the Schaeffer collateral pathway of hippocampal slices from R(AB) mutant mice. In contrast, LTP induced by temporally compressed tetraburst stimulation was normal in slices from R(AB) mutants, and its long-term maintenance was not significantly affected by bath application of KT-5720, an inhibitor of catalytic subunits of PKA. In slices from wildtype mice, LTP induced by spaced tetraburst stimulation was significantly attenuated by KT-5720. These genetic and pharmacological experiments show that LTP induced by these compressed patterns of stimulation does not require PKA activation. Thus, altering the temporal spacing of synaptic stimulation per se critically modulates the PKA-dependence of hippocampal LTP. PKA-dependent LTP is selectively recruited by temporally spaced, multiburst synaptic stimulation. Hippocampus 2003;13:293–300. © 2003 Wiley-Liss, Inc.

Electrophysiological and morphological diversity of neurons from the rat subicular complex in vitro

Abstract: We combined whole-cell recordings with Neurobiotin labeling to examine the electrophysiological and morphological properties of neurons from the ventral subicular complex in vitro (including the subicular, presubicular, and parasubicular areas). No a priori morphological sampling criteria were used to select cells. Cells were classified as bursting (IB), regular-spiking (RS), and fast-spiking (FS) according to their firing patterns in response to depolarizing current pulses. A number of cells remained unclassified. We found 54% RS, 26% IB, 11% FS, and 9% unclassified cells out of a total of 131 neurons examined. We also found cells showing intrinsic membrane potential oscillations (MPO) (6%), which represented a subgroup of the unclassified cells. We analyzed several electrophysiological parameters and found that RS and IB cells can be subclassified into two separate subgroups. RS cells were subclassified as tonic and adapting, according to the degree of firing adaptation. Both responded with single spikes to orthodromic stimulation. IB cells were subclassified in two subgroups according to their capacity to fire more than one burst, and showed different responses to orthodromic stimulation. We observed that bursting in these two subgroups appeared to involve both Ca2+ and persistent Na+ components. Both IB and RS cells, as well as MPO neurons, were projecting cells. FS cells were morphologically identified as local circuit interneurons. We also analyzed the spatial distribution of these cell types from the vicinity of CA1 to the parasubicular areas. We conclude that, in contrast to the commonly accepted idea of the subicular complex as a bursting structure, there is a wide electrophysiological variability even within a given cellular group.

Reelin‐expressing neurons in the postnatal and adult human hippocampal formation

Abstract: Reelin plays a major role in the development of laminated brain structures. In the developing neocortex and hippocampus, Reelin is secreted by Cajal-Retzius cells in the marginal zone. In the present report, we characterize Reelin-immunoreactive neurons in the perinatal and adult human hippocampal formation. Two main populations of cells are described: Cajal-Retzius cells and interneurons. Cajal-Retzius cells are defined as neurons that coexpress Reelin and p73, a nuclear protein of the p53 family. Colocalization experiments of p73 with calcium-binding proteins indicate that most Cajal-Retzius cells express calretinin, but not calbindin. Cajal-Retzius cell density decreases dramatically during the postnatal period, although a few Reelin/p73-positive neurons are still found in the adult. At birth, Reelin-positive, p73-negative neurons are present in all layers of the hippocampal formation. Their morphology and localization indicate that they belong to a heterogeneous population of interneurons. They are numerous in the strata lacunosum-moleculare and radiatum of CA1-CA3, in the hilus, and in the molecular layer of the dentate gyrus, but less common in stratum oriens and alveus, and rare in the principal cell layers. Subpopulations of Reelin-positive interneurons express calretinin or calbindin. The packing density of Reelin-positive cells decreases postnatally, which may be related to the disappearance of Cajal-Retzius cells and to the growth of the hippocampal formation. The presence of Reelin-immunoreactive cells in the adult hippocampal formation indicates that Reelin is not restricted to development but that it may have additional functions in adult life.

Encoding of novel picture pairs activates the perirhinal cortex: an fMRI study.

Abstract: It is well established in nonhuman primates that the medial temporal lobe (MTL) structures, the hippocampus and the entorhinal and perirhinal cortices, are necessary for declarative memory encoding In humans, the neuropathological and neuropsychological changes in early Alzheimer's disease (AD) further support a role for the rhinal cortex in the consolidation of new events into long-term memory Little is known, however, regarding the function of the rhinal cortex in humans in vivo To examine the participation of the interconnected MTL structures as well as the whole-brain network of activated brain areas in visual associative long-term memory, functional magnetic resonance imaging (fMRI) was used to determine the brain regions that are activated during encoding and retrieval of paired pictures in 12 young control subjects The most striking finding in the MTL activation pattern was the consistent activation of the perirhinal cortex in the encoding-baseline and encoding-retrieval comparisons with a strict statistical threshold (P < 000001) In contrast, no perirhinal cortex activation was detected in the retrieval-baseline or retrieval-encoding comparisons even with a low statistical threshold (P < 005) The location of the perirhinal activation area was in the transentorhinal part of the perirhinal cortex, in the medial bank of the collateral sulcus The hippocampus and the more posterior parahippocampal gyrus were activated in both encoding and retrieval conditions During the encoding processing, MTL activations were more consistent and the hippocampal activation area located more anteriorly than during retrieval The frontal, parietal, temporal, and occipital association cortices were also activated in the encoding-baseline and retrieval-baseline comparisons The data suggest that encoding, but not retrieval, of novel picture pairs activates the perirhinal cortex To our knowledge, this is the first fMRI study reporting encoding activation in this transentorhinal part of the perirhinal cortex, the site of the very earliest neuropathological changes in AD Hippocampus 2003;13:67–80 © 2003 Wiley-Liss, Inc

Temporal specific patterns of semaphorin gene expression in rat brain after kainic acid-induced status epilepticus.

Abstract: Mossy fiber sprouting and other forms of synaptic reorganization may form the basis for a recurrent excitatory network in epileptic foci. Four major classes of axon guidance molecules--the ephrins, netrins, slits, and semaphorins--provide targeting information to outgrowing axons along predetermined pathways during development. These molecules may also play a role in synaptic reorganization in the adult brain and thereby promote epileptogenesis. We studied semaphorin gene expression, as assessed by in situ hybridization, using riboprobes generated from rat cDNA in an adult model of synaptic reorganization, kainic acid (KA)-induced status epilepticus (SE). Within the first week after KA-induced SE, semaphorin 3C, a class III semaphorin, mRNA content is decreased in the CA1 area of the hippocampus and is increased in the upper layers of cerebral cortex. Another class III semaphorin, semaphorin 3F, is also decreased in CA1 and CA3 of hippocampus within the first week after KA-SE. These changes in gene expression are principally confined to neurons. By contrast, there was little change in the semaphorin 4C mRNA content of CA1 neurons at this time. No changes in expression of semaphorin 3A and 4C genes were detected 28 days after KA-induced SE. Regulation of semaphorin gene expression after KA-induced SE suggests that neurons may regulate the expression of axonal guidance molecules and thereby contribute to synaptic reorganization after injury of the mature brain. The anatomic locale of the altered semaphorin gene expression may serve as a marker for specific networks undergoing synaptic reorganization in the epileptic brain.

Hippocampal Spreading Depression Bilaterally Activates the Caudal Trigeminal Nucleus in Rodents

Abstract: Spreading depression (SD) and migraine aura involve transiently altered (i.e., increased followed by decreased) electrophysiological activity that propagates at the distinctive rate of millimeters per minute (mm/min), leading to the suggestion that they (and perhaps pain from migraine) are causally related via changes in the same brain structure. Neocortex is considered the anatomical zone associated with migraine aura and is the sole area known to induce caudal trigeminal nucleus (TNC) activation from SD in rodents. However, classical evidence of SD in human neocortex is reported only with severe brain disease, while migraine is a common and comparatively benign disorder. Because SD occurs in human hippocampus, and memory dysfunction referable to hippocampus is seen in migraineurs, we determined whether recurrent SD confined to hippocampus in rat could induce TNC activation. Our work shows that recurrent hippocampal SD evoked a significant (P < 0.05–0.001) increase in bilateral c-fos immunostaining within TNC superficial laminae compared with sham controls. Furthermore, hippocampal SD occurred with a correlated and transient change in spontaneous activity and blood flow in the ipsilateral neocortex without spread of SD to that area. Thus, hippocampal SD may be a previously unrecognized, potential trigger for nociceptive activation of TNC perhaps associated with migraine. © 2003 Wiley-Liss, Inc.

Stimulation-induced reset of hippocampal theta in the freely performing rat.

Abstract: Previous research has suggested that visual and auditory stimuli in a working memory task have the ability to reset hippocampal theta, perhaps allowing an organism to encode the incoming information optimally. The present study examined two possible neural pathways involved in theta resetting. Rats were trained on a visual discrimination task in an operant chamber. At the beginning of a trial, a light appeared over a centrally located lever that the rat was required to press to receive a water reward. There was a 30-s intertrial interval before the next light stimulus appeared. After learning the task, all rats received surgical implantation of stimulating electrodes in both the fornix and the perforant path and recording electrodes, bilaterally in the hippocampus. After surgery, theta was recorded before and after the light stimulus to determine whether resetting to the visual stimulus occurred. During the intertrial interval, rats received single-pulse electrical stimulation of either the fornix or perforant path. Theta was recorded both before and after the electrical stimulation to determine whether resetting occurred. In this experiment, hippocampal theta was reset after all three stimulus conditions (light, perforant path, and fornix stimulation), with the greatest degree of reset occurring after the fornix stimulation. The results suggest that activation of the perforant path and fornix may underlie theta reset and provide a mechanism by which the hippocampus may enhance cognitive processing. Hippocampus 2003;13:109–116. © 2003 Wiley-Liss, Inc.