bluuebunny/crossref_metadata_2025 huggingface dataset:
The mechanism of cerebral hypoxic‐ischemic damage
Authors: Schurr Avital , Rigor Benjamin M.
Published: May 2005

The four most prominent hypotheses on the cellular processes leading to hypoxic‐ischemic neuronal damage or death are (1) the lactacidosis hypothesis, (2) the calcium overload hypothesis, (3) the excitotoxic hypothesis, and (4) the oxygen‐free radical hypothesis. The authors comment on the evidence in favor of and against each in an attempt to select the one hypothesis that best explains the mechanism of cerebral hypoxic‐ischemic damage while withstanding the scrutiny of scientific testing. A major part of this inquiry is derived from in vitro studies that are suited to mechanistic exploration. They conclude that the calcium overload hypothesis is the best qualified in this respect. It is important to note, however, that some of the other hypothetical mechanisms may play a secondary role in exacerbating neuronal damage by accelerating calcium influx and overload.
Lesion‐induced synapse reorganization in the hippocampus of cats: Sprouting of entorhinal, commissural/associational, and mossy fiber projections after unilateral entorhinal cortex lesions, with comments on the normal organization of these pathways
Authors: Steward Oswald
Published: May 2005

This study evaluates whether three forms of sprouting occur in the hippocampus of the cat following unilateral entorhinal cortex (EC) lesions: (1) sprouting of projections from the EC contralateral to the lesion; (2) sprouting of the commissural/associational system; and (3) sprouting of mossy fibers.

Tract tracing techniques were used to define the normal organization of the entorhinal cortical projection system, the commissural/associational (C/A) systems, and the mossy fiber projections in normal cats. The same techniques were then used to evaluate whether there were changes in these projections in animals with long‐standing unilateral EC lesions. The projections from the entorhinal cortex were evaluated autoradiographically following injections of 3H proline into the entorhinal area. The projections of the C/A system were traced using the Fink‐Heimer technique after lesions of the hippocampal commissures, and by using autoradiographic techniques after injections of 3H proline into the hippocampus. The distribution of mossy fibers was evaluated using the Timm's stain.

The results reveal that unilateral lesions of the EC in cats lead to the same sorts of sprouting that have been described in rats. There is: (1) an increase in the density of the crossed projection from the surviving EC to the contralateral dentate gyrus that had been deprived of its normal EC inputs; (2) an expansion of the terminal field of the C/A projection system into portions of the molecular layer of the dentate gyrus normally occupied by EC projections; and (3) an increase in supragranular mossy fibers in some animals. The mossy fiber sprouting was especially prominent when the lesions encroached upon the hippocampus. The studies also reveal additional details about the normal organization of hippocampal pathways in cats. The most important points are: (1) there is a crossed projection from the entorhinal cortex to the contralateral dentate gyrus; and (2) there is a complex laminar organization of the commissural and associational terminal fields in the molecular layer of the dentate gyrus that appears to be related to the point of origin of the projections along the septotemporal axis of the hippocampus. This heretofore unrecognized aspect of the laminar organization of C/A terminations has important implications for the temporal competition hypothesis, which has been advanced to account for the development of these afferent systems.
Autoradiographic localization of proline uptake in excitatory hippocampal pathways
Authors: Nadler J. Victor , Bray Sherrilynn D. , Evenson Debra A.
Published: May 2005

An autoradiographic method was developed to localize sites of high‐affinity, Na+‐dependent proline uptake in the rat hippocampal formation. Hippocampal slices were incubated with [3H]proline, fixed with a glutaraldehyde/carbodiimide mixture, and cut into frozen sections. The sections were coated with photographic emulsion and autoradiograms were prepared. Autoradiographic grain densities were highest over the inner and outer thirds of the dentate molecular layer, followed by stratum lacunosum‐moleculare of area CA3. Stratum oriens and stratum radiatum of area CA1 and CA3 were fairly intensely labeled. The pyramidal and granule cell body layers, stratum lucidum of area CA3, and middle third of the dentate molecular layer were lightly labeled. Effects of surgical and kainic acid lesions suggested that the lateral perforant path, associational‐commissural fibers in the fascia dentata, and Schaffer collateral‐commissural‐ipsilateral stratum oriens fibers have considerable proline uptake capacity. In contrast, the medial perforant path and the mossy fibers appear to accumulate little or no proline.

These results suggest that high‐affinity, Na+‐dependent uptake of proline is expressed by a subset of hippocampal glutamate pathways. The relative capacities of glutamate terminal populations to transport glutamate and proline varies widely. Proline was previously shown to possess neuroexcitatory and excitotoxic properties in the rat hippocampal formation. Taken together, these findings argue that proline plays a role in excitatory transmission. In elucidating this role, comparisons between medial and lateral divisions of the perforant path may prove especially advantageous.
Development of synapsin I and synapsin II in intraocular hippocampal transplants
Authors: Bergman Hanna , Browning Michael , Granholm Ann‐Charlotte
Published: May 2005

Previous studies have indicated that the appearance of synaptic vesicle‐associated proteins known as the synapsins is one indicator of synapse formation. In this study, the levels and morphological distribution of synapsin I and synapsin IIa and IIb were studied in intraocular hippocampal transplants and in situ in the intact hippocampus. No detectable levels of either synapsin I or synapsin II were found in the fetal brain. The in situ levels of the synapsins exhibited parallel increases rapidly after birth, reaching peak levels at 8 weeks, after which a slight decline was noted in synapsin I and synapsin IIb. In hippocampal transplants, a comparable increase in the synapsins was seen during the first 8 weeks in oculo. It is likely that the synapse formation in the hippocampal transplants represents synapses from neurons within the transplant, as well as from various peripheral ganglia that send collaterals into the graft. Peripheral and central synapses express different synapsin I: synapsin IIa and IIb ratios. When the ratios of the synapsin proteins in hippocampal transplants were examined ratios essentially identical to those seen in the normal hippocampus were found, despite the numerous peripheral neurites innervating the grafts. Immunohistochemical studies supported the immunoblot data, showing no detectable immunofluorescence with synapsin antibodies in fetal or newborn hippocampal formation. The density of immunoreactive profiles increased substantially both in transplants and in the hippocampal formation in situ during the first 2 postnatal months.

In conclusion, the present data demonstrate that hippocampal transplants in oculo can develop significant levels of the synapsins and that there is no time lag in development in these levels compared to the hippocampal formation in situ.
Amygdala kindling‐induced seizures selectively impair spatial memory. 2. Effects on hippocampal neuronal and glial muscarinic acetylcholine receptor
Authors: Beldhuis Hans J. A. , Everts Henk G. J. , Van der Zee Eddy A. , Luiten Paul G. M. , Bohus Béla
Published: May 2005

The muscarinic acetylcholine receptor is linked via hydrolysis of phosphoinositides to the protein kinase C pathway. In a preceding paper (Beldhuis, H. J. A., H. G. J. Everts, E. A. Vander Zee, P. G. M. Luiten, and B. Bohus (1992) Amygdala kindling‐induced seizures selectively impair spatial memory. 1. Behavioral characteristics and effects on hippocampal neuronal protein kinase C isoforms. Hippocampus 2:397–410), the role of different isoforms of protein kinase C in neurobiological processes associated with plasticity was studied using both a spatial learning paradigm and amygdala kindling in the rat. This study extended the findings on protein kinase C activity to the level of the muscarinic acetylcholine receptor. Rats were trained in a spatial learning paradigm and kindled simultaneously in the amygdala to develop generalized motor convulsions. Control rats were trained only in the spatial learning paradigm to acquire stable working and reference memory performance. Alteration in the expression of the muscarinic acetylcholine receptor was investigated using a monoclonal antibody to muscarinic acetylcholine receptor proteins. Trained control rats that were exposed repeatedly to the spatial learning paradigm showed an increase in immunoreactivity for the muscarinic acetylcholine receptor located in the same hippocampal regions in which the protein kinase C activity was increased. In fully kindled rats, however, this increase located in principal neurons was absent, whereas expression of muscarinic acetylcholine receptor proteins was increased in hippocampal astrocytes. Moreover, fully kindled rats showed an impairment in reference memory performance as compared to trained control rats. It is argued that concomitant alterations at the level of receptor (muscarinic acetylcholine) and second messenger (protein kinase C) reflect an optimal state for neuronal plasticity. Kindling results in a disturbance of this effector system.
Region‐specific age effects on AMPA sensitivity: Electrophysiological evidence for loss of synaptic contacts in hippocampal field CA1
Authors: Barnes C. A. , Rao G. , Foster T. C. , McNaughton B. L.
Published: May 2005

The effects of aging on the responsiveness of hippocampal neurons to iontophoretic application of L‐glutamate and AMPA were studied in vitro. There were no effects of age on neuronal responses to L‐glutamate; however, CA1 pyramidal cells of old rats, but not granule cells in the fascia dentata, showed both a smaller reduction in extracellularly‐recorded synaptic responses following application of AMPA (presumably mediated by depolarization), and smaller extracellular “DC” fields (measured by subtracting the DC potentials at the dendrite and soma following AMPA application in the dendrites). To examine the cellular bases of this age‐related alteration in AMPA sensitivity, two additional electrophysiological approaches were used: (1) measurement of the amplitude ratios of extracellular EPSP and fiber potential components of the Schaffer collateral‐CA1 response; (2) measurement of intracellularly recorded unitary EPSPs and quantal analysis of their fluctuations. The interpretations that would be placed on four hypothetical possible outcomes of such experiments are outlined and assessed in relation to the experimental data. The pattern of results obtained in the present experiments supports the following conclusions: In old rats, individual Schaffer collateral synapses do not appear to have altered AMPA receptor properties, as neither the mean size of the unitary synaptic response nor the apparent quantal size differs between age groups; however, the data do support the conclusion that there are fewer synapses per Schaffer collateral branch in old versus young CA1 pyramidal cells.
Hippocampal plasticity induced by primed burst, but not long‐term potentiation, stimulation is impaired in area CA1 of aged fischer 344 rats
Authors: Moore Christopher I. , Browning Michael D. , Rose Gregory M.
Published: May 2005

The effect of two types of electrical stimulation designed to induce long‐lasting plasticity of the Schaffer/commissural inputs to CA1 pyramidal neurons was investigated using in vitro hippocampal slices made from young (3–6 month) and old (24–27 month) Fischer 344 rats. The first stimulation paradigm, primed burst (PB) stimulation, consisted of a total of five physiologically patterned stimuli: a single priming pulse followed 170 ms later by a burst of four pulses at 200 Hz. The second stimulation paradigm, long‐term potentiation (LTP) stimulation, consisted of a 200 Hz/1 second train (a total of 200 stimuli). Primed burst and LTP stimulation were equally effective at inducing a lasting increase in the population spike recorded from slices made from young rats. However, the enhancement of population spike amplitude produced by PB, but not LTP, stimulation was significantly less in slices made from old rats. These results suggest that the capacity of the hippocampus to demonstrate long‐lasting synaptic plasticity is not altered with age, but that engaging plasticity‐inducing mechanisms becomes more difficult. Furthermore, these data suggest that physiologically patterned paradigms for inducing long‐lasting synaptic plasticity may more accurately assess the functional status of hippocampal memory encoding mechanisms than does conventional LTP stimulation.
On the sites of presynaptic inhibition by neuropeptide y in rat hippocampus in vitro
Authors: Klapstein Gloria J. , Colmers William F.
Published: May 2005

Neuropeptide Y (NPY) reduces excitatory synaptic transmission between stratum radiatum and CA1 pyramidal cells in rat hippocampal slice in vitro by a presynaptic action. To understand NPY's role in the control of excitability in hippocampus, its actions on excitatory and inhibitory synaptic transmission were examined, using intracellular, sharp microelectrode, and tight‐seal, whole cell recordings from principal neurons in areas CA1, CA3, and dentate. Bath application of 1 μM NPY reversibly inhibited excitatory postsynaptic potentials (EPSPs) evoked in CA1 pyramidal cells from either stratum radiatum or stratum oriens by about 50%. Neuropeptide Y also inhibited EPSPs at mossy fiber‐CA3, stratum oriens‐CA3, and CA3‐CA3 synapses by between 45% and 55%. As in CA1, the action of NPY was presynaptic. By contrast, NPY did not inhibit EPSPs evoked in dentate granule cells from either perforant path or commissural inputs. Neuropeptide Y did not alter postsynaptic membrane properties in any cell type. Although NPY attenuated the orthodromically evoked (stratum radiatum) inhibitory postsynaptic potentials in CA1 pyramidal cells by about the same amount as it inhibited the EPSPs, it did not affect the IPSPs evoked in the same cells by antidromic stimulation from alveus. Inhibitory postsynaptic potentials evoked in pharmacological isolation in CA1, CA3, or dentate were also not significantly affected by NPY. The evidence supports the hypothesis that NPY acts at feedforward excitatory synapses to presynaptically reduce the amplitude of excitation as it travels through hippocampal circuits. By contrast, synaptically mediated inhibition is not directly affected by NPY. Neuropeptide Y is the only known endogenous substance that selectively reduces feedforward excitatory transmission without causing changes in other properties of the hippocampal circuitry.
Cumulative long‐term potentiation in the rat dentate gyrus correlates with, but does not modify, performance in the water maze
Authors: Jeffery Kathryn J. , Morris Richard G. M.
Published: May 2005

The electrically induced increase in hippocampal synaptic strength known as long‐term potentiation (LTP) is thought to involve some of the same mechanisms as those mediating information storage during spatial learning. Physiological saturation of synaptic weights might therefore be expected to occlude spatial learning. In support of this, Castro et al. (Castro CA, Silbert LH, McNaughton BL, Barnes CA, 1989, Nature 342:545–548) reported that repeated induction of LTP to asymptotic levels, over a 14‐day period, blocked the ability of rats to learn the position of a hidden platform in a water maze shortly afterwards. The authors have attempted to replicate this finding in two experiments. In Experiment I, rats were given either 400 Hz stimulation as 50 trains/day over a 5‐day period, to induce LTP, or were given the same number of stimulus pulses at 1 Hz. Two hours after the last stimulation session they underwent eight spatial learning trials, occurring at 2‐hour intervals. In Experiment 2, the procedure of Castro et al. was followed exactly, with LTP induced by 10 trains of 400 Hz stimulation daily for 14 days. Spatial learning trials began 10 minutes after the last stimulation session and consisted of 12 trials with alternating 30‐second and 2‐minute intervals. In neither experiment was a significant impairment of spatial learning observed. However, there was a strong positive correlation, in both experiments, between the final level of LTP and subsequent performance in the water maze.
Differential effects of kindling and kindled seizures on place learning in the morris water maze
Authors: McNamara Robert K. , Kirkby R. Duncan , dePape Gregory E. , Skelton Ronald W. , Corcoran Michael E.
Published: May 2005

There is some controversy about the role of long‐term potentiation (LTP) in spatial learning. The authors have found that triggering generalized kindled seizures with stimulation of the perforant path disrupts spatial learning in the Morris water maze but that kindling per se does not affect spatial learning. It is suggested that abnormal electrical activity induced by high‐frequency stimulation of the perforant path may have been responsible for the disruption of spatial learning previously attributed to LTP saturation.
Effects of glucocorticoids on hippocampal long‐term potentiation
Authors: Pavlides Constantine , Watanabe Yoshifumi , McEwen Bruce S.
Published: May 2005

The effects of chronic and acute corticosterone (CORT) administration were investigated on hippocampal long‐term potentiation (LTP) in the dentate gyrus granule cell layer of the rat. Electrophysiological experiments were performed in vivo under urethane anesthesia. Chronic CORT treatment (40 mg/kg/day) over 21 days decreased LTP compared to vehicle controls, even when LTP was measured 48 hours after cessation of CORT treatment, when serum CORT levels had returned to baseline. A single injection of CORT also decreased LTP compared to vehicle controls, but only when CORT levels were high, since at 48 hours after a single acute CORT injection LTP was not depressed. The decrements in LTP were seen both for the slope of the excitatory postsynaptic potential and for the population spike. Yet CORT had no effects on posttetanic potentiation or neuronal excitability. These findings are consistent with previous reports showing a reduction in LTP in the CAI field of animals exposed to stress or acute CORT administration.
GABA induces a unique rise of [CA]i in cultured rat hippocampal neurons
Authors: Segal Menahem
Published: May 2005

GABA evoked a reversible rise of free intracellular calcium concentration ([Ca]i) in cultured rat hippocampal neurons, detected with Fluo‐3 fluorescence in a confocal laser scanning microscope. The GABA‐evoked change of [Ca]i was mimicked by muscimol and not by baclofen, but was only minimally affected by picrotoxin or bicuculline, indicating that this effect of GABA is not likely to be mediated by activation of GABAB receptor or by a conventional chloride‐linked GABAA receptor. GABA‐evoked rise of [Ca]i expressed a marked desensitization; only 10–20 minutes after a previous exposure to GABA was the response to a subsequent application fully expressed. This desensitization was not seen in electrophysiological responses to GABA or in [Ca]i changes evoked by NMDA in the same neurons. The GABA response appeared to be developmentally regulated and was seen in 1–7‐day‐old more than in 21–28‐day‐old cells. It is suggested that GABA evokes a unique change of [Ca]i in young hippocampal neurons.
Structural synaptic correlate of long‐term potentiation: Formation of axospinous synapses with multiple, completely partitioned transmission zones
Authors: Geinisman Yuri , Detoledo‐Morrell Leyla , Morrell Frank , Heller Richard E. , Rossi Marvin , Parshall Robert F.
Published: May 2005

Synapses were analyzed in the middle molecular layer (MML) and inner molecular layer (IML) of the rat dentate gyrus following the induction of long‐term potentiation (LTP) by high‐frequency stimulation of the medial perforant path carried out on each of 4 consecutive days. Potentiated animals were sacrificed 1 hour after the fourth high frequency stimulation. Stimulated but not potentiated and implanted but not stimulated animals served as controls. Using the stereological disector technique, unbiased estimates of the number of synapses per postsynaptic neuron were differentially obtained for various subtypes of axospinous junctions: For atypical (giant) nonperforated synapses with a continuous postsynaptic density (PSD), and for perforated ones distinguished by (1) a fenestrated PSD and focal spine partition, (2) a horseshoe‐shaped PSD and sectional spine partition, (3) a segmented PSD and complete spine partition(s), and (4) a fenestrated, (5) horseshoe‐shaped, or (6) segmented PSD without a spine partition. The major finding of this study is that the induction of LTP in the rat dentate gyrus is followed by a significant and marked increase in the number of only those perforated axospinous synapses that have multiple, completely partitioned transmission zones. No other synaptic subtype exhibits such a change as a result of LTP induction. Moreover, this structural alteration is limited to the terminal synaptic field of activated axons (MML) and does not involve an immediately adjacent one (IML) that was not directly activated by potentiating stimulation. The observed highly selective modification of synaptic connectivity involving only one particular synaptic subtype in the potentiated synaptic field may represent a structural substrate of the long‐lasting enhancement of synaptic responses that characterizes LTP.
Early areal differentiation of the human cerebral cortex: Entorhinal area
Authors: Kostović Ivica , Petanjek Zdravko , Judaš Miloš
Published: May 2005

The early cytoarchitectonic specialization and area‐specific differentiation of the prospective entorhinal cortex were studied in the postmortem human fetal brains (9.5–13.5 postovulatory weeks). At 10 weeks, using the Golgi method, we saw the appearance of area‐specific large neurons (promoter neurons) with widely bifurcating apical dendrites situated at the outer margin of the cortical plate of the prospective entorhinal cortex. The analysis of the serial Nissl‐stained sections revealed the concomitant appearance of a one‐cell‐thick layer (monolayer) at the interface between the cortical plate and the marginal zone and multilaminated spread of the deep part of the cortical plate. This is the earliest sign of area‐specific cytoarchitectonic differentiation of all pallial regions characterized by the presence of the typical cortical plate. The first subareal differentiation within the entorhinal cortex begins at 13 postovulatory weeks with uneven development of fiber‐rich lamina dissecans, which separates two cellular laminae principales (externa and interna), and with the appearance of characteristic cell islands of the prospective layer II. At rostral levels, cell islands begin to develop in the rostromedial entorhinal area at the subpial depths where large promoter neurons reside. At intermediate levels, both lamina dissecans and lamina principalis interna are well delineated. At caudal levels, lamina principalis interna is continuous with the upper subplate zone of the adjacent neocortex. Both area‐specific neurons (promoters) and fiber‐rich (afferent) strata develop synchronously during the earliest areal differentiation of the cerebral cortex. The precocious lamination of the cortical plate is the crucial event in the histogenesis of the entorhinal cortex.
Transport of cytoskeletal proteins in axons of hippocampal pyramidal cells
Authors: Watson Danny F. , Fittro Kenneth P.
Published: May 2005

Axonal transport of cytoskeletal proteins has not yet been extensively studied in the brain proper, in contrast to the peripheral nerves and optic nerves. The authors have developed a means for the study of transport of cytoskeletal proteins in axons of hippocampal pyramidal cells. Proteins of intrinsic neurons of the dorsal hippocampus were labeled by microinjection of 35S methionine, and the subsequent transport of labeled proteins was characterized in the axons projecting into the fimbria‐fornix. A peak of labeled proteins was present in the fimbria‐fornix at 4–12 days after labeling, corresponding to transport rates 0.2–0.7 mm/day. The most abudant proteins at each time studied exhibited one‐dimensional electrophoretic mobilites of actin and tubulin; neurofilaments were less intensely labeled. The observed specializations of cytoskeletal transport, especially the paucity of tubulin transport at rates of 2–4 mm/day, may predispose hippocampal pyramidal cells to accumulate tubulin and microtubule‐associated proteins in their cell bodies in various disease states.
Pathway specificity of noradrenergic plasticity in the dentate gyrus
Authors: Pelletier Marc R. , Kirkby R. Duncan , Jones Sandra J. , Corcoran Michael E.
Published: May 2005

Previous experiments have described highly specific effects of noradrenergic agonists on synaptic transmission in the dentate gyrus (DG). For example, perfusion of hippocampal slices with the beta‐noradrenergic agonist isoproterenol induces a long‐lasting potentiation (LLP) of extracellularly recorded responses following stimulation of the medial perforant path (PP), and long‐lasting depression (LLD) of responses evoked by stimulation of the lateral PP (Dahl D, Sarvey JM, 1989, Proc Natl Acad Sci USA 86:4776–4780). To examine the possible interactions of LLP, LLD, and long‐term potentiation induced by tetanic stimulation (LTP), the authors recorded extracellular field potentials evoked in the DG by stimulation of the lateral or medial perforant path following LTP and LLP or LLD, invoked in different orders. After establishment of LLP or LLD by path application of isoproternol, subsequent tetanization of the respective afferents resulted in additional potentiation of the medial PP‐evoked response and return of the lateral PP‐evoked response to baseline levels. In other slices application of isoproterenol after establishment of LTP resulted in further potentiation of medial PP‐evoked responses but no change in the potentiated response evoked by lateral PP stimulation. Thus the pathway specificity was maintained irrespective of the history of previous potentiation or depression. Experiments using the specific beta1 antagonist metoprolol further confirmed pathway specificity. Perfusion with 20 μM of metoprolol appeared to reduce LTP evoked by stimulation of the medial but not lateral PP. In a subsequent experiment, metoprolol in the absence of tetanization produced LLD of the medial PP‐evoked response and LLP of the lateral PP‐evoked response, opposite to the effects of ISO. These results confirm the impressive extent of pathway specificity in the DG and reveal the persistent capacity for synaptic modification as exemplified by the processes of LLP, LLD, and LTP. © 1994 Wiley‐Liss, Inc.
Selective degeneration of CA1 pyramidal cells by chronic application of bismuth
Authors: Müller Michael , Rietschin Lotty , Grogg Franziska , Streit Peter , Gähwiler Beat H.
Published: May 2005

The heavy metal bismuth induces a new type of selective neuronal degeneration that shares some common aspects with that seen following hypoxia and ischemia. Continuous application of 3 μm bismuth to organotypic cultures of rat hippocampus resulted after 2–3 weeks in selective degeneration of CA1 pyramidal cells, while CA3 pyramidal cells, dentate granule cells, and subicular neurons were resistant. With 10 μm MK‐801, a noncompetitive NMDA‐antagonist, during the entire culturing period failed to prevent neuronal degeneration induced by 3 μm bismuth. GABA‐immunoreactive interneurons were also affected by bismuth, but were generally less sensitive than CA1 pyramidal cells. Acute application of up to 100 μm bismuth did not change the electrophysiological properties of CA1 pyramidal cells. © 1994 Wiley‐Liss, Inc.
Postmortem changes in the levels and localization of microtubule‐associated proteins (tau, MAP2 and MAP1B) in the rat and human hippocampus
Authors: Schwab Claudia , Bondada Vimala , Sparks D. Larry , Cahan Leslie D. , Geddes James W.
Published: May 2005

The neuronal cytoskeleton is disrupted in neurodegenerative disorders such as Alzheimer's disease. Due to the lack of suitable animal models, studies examining the events involved in the neurodegeneration have relied on postmortem human brain tissue obtained from individuals with the disease and from normal controls. However, it is uncertain if the neuronal cytoskeleton is stable during the postmortem interval. Immunohistochemistry and immunoblots were used to examine the microtubule–associated proteins tau, MAP2, and MAP1B in the rat hippocampus at various times after death. Shortly after death, tau immunoreactivity was lost from axons and accumulated in somatodendritic compartments. MAP2 and MAP1B also accumulated in neuronal cell bodies prior to a loss of immunostaining in some regions, notably subiculum. Immunoblots confirmed a loss of MAP2 and MAP1B within a few hours after death. Tau levels remained constant during the 8–hour postmortem interval examined, although the electrophoretic mobility of some tau bands was altered. Human brain tissue obtained at autopsy and at surgery demonstrated similar cytoskeletal alterations in postmortem tissue. These results demonstrate that microtubules and associated proteins are not stable postmortem. © 1994 Wiley‐Liss, Inc.
Principal cells are the postsynaptic targets of supramammillary afferents in the hippocampus of the rat
Authors: Maglóczky Zsófia , Acsády László , Freund Tamás F.
Published: May 2005

Neurons of the supramammillary nucleus are known to fire phase‐locked to hippocampal theta rhythm. Stimulation of this area induces theta activity in the hippocampus via the medial septum and facilitates perforant pathway stimulation‐evoked population spikes in the dentate gyrus even if the medial septum is inactivated. This latter effect was suggested to be due to a direct inhibitory input from the supramammilary nucleus to hippocampal nonpyramidal cells resulting in disinhibition. In the present study, using anterograde tracing with Phaseolus vulgaris leucoagglutinin, we aimed to identify the types of neurons innervated by the supramammillary projection in the dentate gyrus and Ammons horn, with particular attention to the presumed postsynaptic inhibitory neurons, which may mediate the proposed disinhibitory action. Double‐immunostaining for the tracer and different neuropeptides (somatostatin, cholecystokinin, neuropeptide Y) or calcium binding proteins (calretinin, parvalbumin, calbindin D28k) present in different subpopulations of interneurons revealed no multiple contacts between supramammillary afferents and labeled inhibitory cells at the light microscopic level. Furthermore, postembedding immunostaining of electron microscopic sections for GABA demonstrated that none of the 68 PHAL‐labeled supramammillary boutons examined and none of their postsynaptic targets were immunoreactive for the inhibitory neurotransmitter. We conclude, therefore, that most if not all postsynaptic targets of the supramammillary projection are principal cells both in the dentate gyrus and in the CA2‐CA3a subfields. This suggests that a mechanism other than disinhibition is responsible for the facilitatory effect of this pathway on hippocampal evoked activity. © 1994 Wiley‐Liss, Inc.
Spatial information content and reliability of hippocampal CA1 neurons: Effects of visual input
Authors: Markus Etan J. , Barnes Carol A. , McNaughton Bruce L. , Gladden Victoria L. , Skaggs William E.
Published: May 2005

The effects of darkness on quantitative spatial firing characteristics of 235 hippocampal CA1 “complex spike” (CS) cells were studied in young and old Fischer‐344 rats during food‐motivated performance of a randomized, forced‐choice task on an eight‐arm radial maze. The room lights were turned on or off on alternate blocks of all eight arms.

In the dark, a lower proportion of CS cells had “place fields,” and the fields were less specific and less reliable than in the light. A small number of cells had place fields unique to the dark condition. Like CS cells, Theta cells showed a reduction in spatially related firing in the dark. The specificity and reliability of the place fields under both light and dark conditions were similar for both age groups. Increasing the salience of the environment, by increasing the light level and the number of visual cues in the light condition, did not affect the specificity or reliability of the place fields.

Even though all rats had substantial prior experience with the environment, and were placed on the maze center under normal illumination before the first dark trial, the correlation between the firing pattern in the light and dark increased after the rat first traversed the maze in the light. Thus, even after considerable experience with the environment over days, experiencing the illuminated environment from different locations on a given day was a significant factor affecting subsequent location and reliability of place fields in darkness.

While the task was simple and errors rare, rats that made fewer errors (i.e., re‐entries into the previously visited arm) also had more reliable place cells, but no such correlation was found with place cell specificity. Thus, the reliability of spatial firing in the hippocampus may be more important for spatial navigation than the size of the place fields per se. Alternatively, both spatial memory and place field reliability may be modulated by a common variable, such as attention. © 1994 Wiley‐Liss, Inc.
Ipsilateral associational pathway in the dentate gyrus: An excitatory feedback system that supports N‐methyl‐D‐aspartate—dependent long‐term potentiation
Authors: Hetherington Phil A. , Austin Kevin B. , Shapiro Matthew L.
Published: May 2005

Axons from granule cells in the dentate gyrus of the rat hippocampus project to cells in the hilar region, including mossy cells, which project along the longitudinal axis of the hippocampus and synapse in the inner (proximal) one‐third of the molecular layer of the dentate gyrus. To study this feedback system, multiple recording electrodes were located along the longitudinal (septo‐temporal) axis in the dorsal leaf of the dentate gyrus in urethane‐anesthetized rats. Single pulse electrical stimuli delivered to the hilar region evoked negative‐going, monosynaptic field potentials that were largest in the inner one‐third of the molecular layer (commissural zone). These evoked field potentials (EFPs) were recorded simultaneously at three to five locations. The latency to onset and peak amplitude of the EFP varied linearly with distance from point of stimulation, and EFPs were elicited in both directions along the longitudinal axis. The transmission speed was estimated to be 1.4 m/s. Tetanic stimulation of the hilar region potentiated the EFP slopes (mean= 26%). Potentiation lasted at least 2 hours and was specific to responses from the tetanized stimulating electrode; the responses to other stimulating electrodes in the hilus and the angular bundle of the perforant path changed less than 4%. Combined stimulation of the hilus and the medial perforant path increased the magnitude of recorded field potentials and population spikes, demonstrating that both pathways are excitatory. NMDA antagonist NPC‐17742 blocked potentiation of EFP slopes in both the medial perforant path and hilus pathways. The results suggest that the ipsilateral associational system of the dentate gyrus is excitatory and capable of supporting long‐lasting, NMDA‐dependent, synapse‐specific plasticity. © 1994 Wiley‐Liss, Inc.
Differential NPY mRNA expression in granule cells and interneurons of the rat dentate gyrus after kainic acid injection
Authors: Gruber Bernhard , Greber Susanne , Rupp Elke , Sperk Günther
Published: May 2005

Using in situ hybridization histochemistry neuropeptide Y (NPY) mRNA expression was investigated after intraperitoneal injection of kainic acid (KA) and after local application of KA or quinolinic acid into the dentate gyrus of the rat. Enhanced concentrations of NPY mRNA were observed in interneurons of the hilus, including presumptive fusiform neurons and pyramidal‐shaped basket cells already 4 hours after initiation of limbic seizures by KA (10 mg/kg, i.p.). IncreaseD NPY expression persisted in neurons resistant to seizure‐induced cell death (6–48 h after i.p. KA). Exceptionally high hybridization signals were found in interneurons of the hilus and the CA1 and CA3 sectors 8 months after KA‐induced limbic seizures. In the granule cell layer only a transient but pronounced increase in NPY mRNA was observed 12–24 h after injection. Only moderate changes were observed in this cell layer at later intervals. Anticonvulsant treatment with thiopental, after a brief period of generalized seizures, prevented the increase in NPY mRNA in granule cells but not in interneurons. No change in NPY message was found also in granule cells of rats which responded with mild “wet dog shake” behvior but not with motor seizures to KA injection.

Local injections of low doses of KA (0.05–0.2 nmol) or quinolinic acid (6.5–100 nmol) into the dentate gyrus of the hippocampus under deep thiopental anesthesia, after 24 h, resulted in increased concentrations of NPY message in interneurons of the ipsilateral, but not of the contralateral hilus and not in granule cells. Higher doses of the excitatory amino acid analogs caused partial neurodegeneration at the injection site, but enhanced NPY expression in interneurons of the contralateral dentate. Only the highest dose of quinolinic acid (100 nmol), resulting in general neuronal cell loss at the injection area, induced enhanced NPY mRNA expression also in granule cells of the contralateral dentate gyrus.

The experiments suggest different mechanisms for NPY mRNA expression in interneurons and in granule cells of the dentate gyrus. Whereas in the stratum granulosum NPY mRNA expression was only observed after generalized limbic seizures, in hilar interneurons it was augmented by only moderate neuronal stimulation or directly by KA. © 1994 Wiley‐Liss, Inc.
Severity of memory impairment in monkeys as a function of locus and extent of damage within the medial temporal lobe memory system
Authors: Zola‐Morgan Stuart , Squire Larry R. , Ramus Seth J.
Published: May 2005

During the past decade, work with monkeys has helped identify the structures in the medial temporal lobe that are important for memory: the hippocampal region (including the hippocampus proper, the dentate gyrus, and the subicular complex) and adjacent cortical areas that are anatomically linked to the hippocampus, i.e., the entorhinal, perirhinal, and parahippocampal cortices. One idea that has emerged from this work is that the severity of memory impairment might increase as more components of the medial temporal lobe are damaged. We have evaluated this idea directly by examining behavioral data from 30 monkeys (ten normal monkeys and 20 monkeys with bilateral lesions involving structures within the medial temporal lobe) that have completed testing on our standard memory battery during the last 10 years. The main finding was that the severity of memory impairment depended on the locus and extent of damage to the medial temporal lobe. Specifically, damage limited to the hippocampal region produced a mild memory impairment. More severe memory impairment was produced when the damage was increased to include the adjacent entorhinal and parahippocampal cortices (the H+ lesion). Finally, memory impairment was even more severe when the H+ lesion was extended forward to include the anterior entorhinal cortex and the perirhinal cortex (H++ lesion). Taken together, these findings suggest that, whereas damage to the hippocampal region produces measurable memory impairment, a substantial part of the severe memory impairment produced by large medial temporal lobe lesions in humans and monkeys can be attributed to damage to entorhinal, perirhinal, and parahippocampal cortices adjacent to the hippocampal region. © 1994 Wiley‐Liss, Inc.
Sprouting of central noradrenergic fibers in the dentate gyrus following combined lesions of its entorhinal and septal afferents
Authors: Peterson Gray M.
Published: May 2005

Virtually all of the afferents to the hippocampal formation undergo collateral sprouting after removal of adjacent afferent systems. However, the central noradrenergic (NA) afferents, which demonstrate a remarkable propensity for regeneration and sprouting in other regions of the brain, have not been found to sprout in the denervated hippocampal formation. The present study was designed to determine if the pattern of innervation by NA fibers in the dentate gyrus of adult rats can be altered by interruption of the other major afferents. The innervation pattern of NA fibers was examined in the dentate gyrus 4 weeks after removal of the ipsilateral and/or contralateral entorhinal afferents and/or transection of the fimbria‐fornix and supracallosal stria. The noradrenergic identity of the fibers was indicated by immunoreactivity for dopamine beta hydroxylase (DBH) and peripheral sympathetic fibers were demonstrated by immunoreactivity for nerve growth factor receptor (NGFr), which did not stain cholinergic fibers in this application. In control brains, the noradrenergic innervation of the dentate molecular layer was light and uniform across the width of the layer. Transection of the perforant path (ipsilateral entorhinal afferents) or ventral hippocampal commissure (contralateral entorhinal afferents) resultd in a significant increase in innervation density in the outer half of the molecular layer, and the combination of these two lesions produced the greatest increase. In those brains with transection of the ipsilateral and contralateral entorhinal afferents, the denervated dentate gyrus had a nearly twofold increase in density of DBH‐immunoreactive fibers within the outer half of the molecular layer. These fibers tended to course parallel to the pial surface rather that perpendicular as in control sections. Transection of the fimbria‐fornix alone had no affect on the innervation pattern of DBH‐ir fibers in the molecular layer. When the fimbria‐fornix was transected in combination with both of the other lesions, an overall increase in innervation density occurred, but there was no further increase in the difference between the inner and outer halves of the molecular layer. No NGFr‐immunoreactive fibers were observed in the molecular layer in any of the brains, indicating that the DBH‐immunoreactive fibers in this region were not of peripheral origin. It is concluded that removal of the ipsi‐ and contralateral entorhinal afferents to the dentate gyrus results in the sprouting of central NA fibers in the outer half of the molecular layer. © 1994 Wiley‐Liss, Inc.
Extrinsic modulation of medial septal cell discharges by the ascending brainstem hippocampal synchronizing pathway
Authors: Bland Brain H. , Oddie Scott D. , Colom Luis V. , Vertes Robert P.
Published: May 2005

Single cells or simultaneously recorded cell pairs in the medial septum (MS) vertical limb of the diagonal band of Broca (vDBB) in the urethane‐anesthetized rat were initially classified as either theta‐on or non‐related according to the system of Colom and Bland (1987, Brain Res 422:277–286). Subgroups of these cells were then studied under various test conditions that included electrical stimulation of the nucleus pontis oralis (PO) or posterior hypothalamus (PH), microinfusion of carbachol into the PO or PH, and the microinfusion of atropine sulfate or procaine hydrochloride into the PH. Electrical stimulation of either the PO or PH induced theta (θ) activity in the hippocampal formation (HPC), and electrical stimulation of the PO resulted in a simultaneous increase in the discharge rate of all MS/vDBB θ‐on cells tested, compared to the rates recorded during HPC large‐amplitude irregular activity (LIA). Five of the MS/vDBB θ‐on cells were tested consecutively with electrical stimulation of the PO and PH, and were shown to be activated in a similar manner in either condition. Microinfusion of carbachol into either the PO or PH resulted in the induction of HPC θ field activity and the simultaneous intense activation of all MS/vDBB θ‐on cells tested. Following the microinfusion of either atropine sulfate or procaine into the PH, electrical stimulation of the PO failed to induce HPC θ field activity or the concomitant rhythmic discharges of all MS/vDBB phasic θ‐on cells tested. Microinfusing procaine into the PH also abolished the coupling between all MS/vDBB cell pairs during HPC θ field activity including that between two cell pairs that were coupled during HPC LIA. The data support the following conclusions: (1) The brainstem HPC synchronizing pathway originating in the pons region ascends to the medial septum via the midline posterior hypothalamic region; (2) the present results taken together with previous work suggest that a major component of the ascending synchronizing pathway, up to and including the hippocampal formation, is cholinergic, cholinoceptive, or both, and the receptors involved are primarily muscarinic; (3) the midline posterior hypothalamic region is an important source of inputs to the medial septum and their major contribution is to provide frequency‐coded inputs to the MS/vDBB for relay into the hippocampal formation. © 1994 Wiley‐Liss, Inc.
Hippocampal conjunctive encoding, storage, and recall: Avoiding a trade‐off
Authors: O'Reilly Randall C. , McClelland James L.
Published: May 2005

The hippocampus and related structures are thought to be capable of (1) representing cortical activity in a way that minimizes overlap of the representations assigned to different cortical patterns (pattern separation); and (2) modifying synaptic connections so that these representations can later be reinstated from partial or noisy versions of the cortical activity pattern that was present at the time of storage (pattern completion). We point out that there is a trade‐off between pattern separation and completion and propose that the unique anatomical and physiological properties of the hippocampus might serve to minimize this trade‐off. We use analytical methods to determine quantitative estimates of both separation and completion for specified parameterized models of the hippocampus. These estimates are then used to evaluate the role of various properties and of the hippocampus, such as the activity levels seen in different hippocampal regions, synaptic potentiation and depression, the multi‐layer connectivity of the system, and the relatively focused and strong mossy fiber projections. This analysis is focused on the feedforward pathways from the entorhinal cortex (EC) to the dentate gyrus (DG) and region CA3. Among our results are the following: (1) Hebbian synaptic modification (LTP) facilitates completion but reduces separation, unless the strengths of synapses from inactive presynaptic units to active postsynaptic units are reduced (LTD). (2) Multiple layers, as in EC to DG to CA3, allow the compounding of pattern separation, but not pattern completion. (3) The variance of the input signal carried by the mossy fibers is important for separation, not the raw strength, which may explain why the mossy fiber inputs are few and relatively strong, rather than many and relatively weak like the other hippocampal pathways. (4) The EC projects to CA3 both directly and indirectly via the DG, which suggests that the two‐stage pathway may dominate during pattern separation and the one‐stage pathway may dominate during completion; methods the hippocampus may use to enhance this effect are discussed. © 1994 Wiley‐Liss, Inc.