Search PubMed⌕ Search

Biomedical subjects

O Steward

Publications and source records attributed to O Steward.

At least 19 recordsLinked to original sources
PubMed1992

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.

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.

Animals↗
PubMed1992

Signals that induce sprouting in the central nervous system: sprouting is delayed in a strain of mouse exhibiting delayed axonal degeneration.

This study evaluates whether CNS sprouting is initiated by signals related to the degeneration of presynaptic axons. We evaluate the time course of sprouting of cholinergic septohippocampal fibers after unilateral entorhinal cortex (EC) lesions in a substrain of mice carrying a mutation which leads to a substantial delay in the onset of Wallerian degeneration. We first verified that axonal degeneration resulting from EC lesions was delayed in mutant mice using silver-staining techniques (the Fink-Heimer method). Cholinergic sprouting was then evaluated using a histochemical technique for acetylcholinesterase (AChE) in mutant mice and normal controls. In normal control mice, both axonal degeneration and cholinergic sprouting occurred with a time course that was comparable to that described in rats. Argyrophilic degeneration debris was prominent by 4 days postlesion, and increases in AChE staining in the molecular layer of the dentate gyrus were well developed by 10 days. In mice carrying the "Ola" mutation, however, argyrophilic degeneration debris was not detectable at 4 or 6 days postlesion, began to appear in the dentate gyrus by 8 days postlesion, but did not become prominent until 12 days. Increases in AChE staining in the molecular layer of the dentate gyrus were not detectable even at 12 days postlesion, but developed gradually after 14 days. These results demonstrate that the signals which initiate at least one form of CNS sprouting are related to the degeneration of presynaptic axons.

Acetylcholinesterase↗
PubMed1992

Getting the message from the gene to the synapse: sorting and intracellular transport of RNA in neurons.

A key question in cellular neurobiology is how neurons target molecules to cellular microdomains at a distance from the nucleus. Of special importance are the thousands of postsynaptic sites that form the basis for synaptic communication. Recent evidence suggests that an important aspect of molecular trafficking involves differential sorting, selective intracellular transport, and docking of particular mRNA molecules and associated protein synthetic machinery at postsynaptic sites. This offers the potential for local regulation of the production of key proteins in response to conditions at individual synapses. This article reviews what is known about the mechanisms of mRNA trafficking in neurons and in other cells ranging from oocytes to oligodendrocytes, and considers the possible role that mRNA trafficking and the resulting local synthesis of particular proteins may play in cellular function.

Animals↗
PubMed1992

Temperature-dependent blockade of nucleocytoplasmic transport of newly synthesized RNA in neurons.

This study evaluates the temperature sensitivity of transport of recently synthesized RNA from the nucleus to the cytoplasm (nucleocytoplasmic transport) in CNS neurons. Rat hippocampal slices were incubated with [3H]uridine for 1 h to label recently synthesized RNA. Slices were then fixed immediately or maintained at 27 degrees C or 37 degrees C for chase intervals of 3, 4.5, and 6 h to allow for nucleocytoplasmic transport of recently synthesized RNA. The time-dependent translocation of recently synthesized RNA was evaluated autoradiographically. At the end of the 1 h pulse at either 27 degrees C or 37 degrees C, the label was localized exclusively over nuclei. In slices maintained at 37 degrees C, labeling expanded to cover the cell body and proximal dendrites. However, in slices that were labeled and maintained at room temperature, labeling remained confined to the nucleus. In slices that were pulse-labeled at room temperature, and then transferred to 37 degrees C medium, cytoplasmic labeling increased as a function of time. Nucleocytoplasmic transport of RNA in cultured rat hippocampal neurons showed a comparable temperature sensitivity. The inhibition of nucleocytoplasmic transport of RNA at room temperature provides an opportunity to evaluate neuronal function when no new RNA molecules can reach the cytoplasm.

Animals↗
PubMed1992

Seizures and the regulation of astroglial gene expression.

Seizures are known to induce dramatic alterations in neuronal gene expression. These changes may play a role in the genesis of an epileptic state. The present report describes another consequence of seizures-a dramatic induction of glial fibrillary acidic protein (GFAP) expression in astrocytes. Using a hippocampal kindling model, we demonstrate that kindled seizures lead to many fold increases in mRNA for GFAP in structures which experience electrographic seizures. The increases can be detected 1 day following a single seizure. If seizures are induced repetitively (every other day for many days), levels of GFAP mRNA remain elevated. However, when kindled seizures are not induced, levels of GFAP mRNA return to near control levels within a few days. The increases in GFAP mRNA levels are not in response to decreases in neuronal activity (as a result of postictal depression), because GFAP mRNA levels are unaffected when neuronal activity is decreased by blocking afferent drive (with tetrodotoxin). The induction of GFAP expression by seizures may reflect the first step in a process in which seizures induce astrocytic hypertrophy. The changes in astrocytes could in turn modify the way in which astrocytes maintain homeostasis in the extracellular microenvironment in ways that could contribute to the development of an epileptic state.

Animals↗
PubMed1979

Functional effects of lesion-induced plasticity: long term potentiation in formal and lesion-induced temporodentate connections.

The crossed temporodentate pathway from the entorhinal cortex of one hemisphere which proliferates in response to a contralateral entorhinal lesion in adult rats was analyzed for its ability to exhibit long term potentiation of synaptic efficacy similar to that which occurs in the normal ipsilateral temporodentate pathway. It was found that while the small synaptic response evoked by contralateral entorhinal cortical stimulation in normal rats does not undergo long term potentiation, after unilateral entorhinal lesions and proliferation of the crossed temporodentate pathway, the crossed pathway acquires a capacity for potentiation of synaptic action which qualitatively resembles that of the normal ipsilateral temporodentate circuit. However, despite the potentiation of synaptic drive, no long term enhancement of cell discharge was observed in the re-innervated dentate gyrus even through potentiation of this parameter was very prominent in the ipsilateral pathway. Mechanisms are discussed by which a previously non-potentiating pathway may acquire, as a consequence of lesion-induced sprouting, an ability to undergo long term potentiation of synaptic efficacy in a fasion similar to the ablated pathway. Reasons for the failure to observe potentiation of cell firing are also considered.

Acetylcholinesterase↗
PubMed1979

Synapses as associative memory elements in the hippocampal formation.

This report analyzes long term potentiation (LTP) and associative interactions between synapses of the ipsilateral and crossed entorhinal cortical (EC) pathways to the dentate gyrus (DG). In the anesthetized rat, conditioning stimulation to one EC-DG pathway reliably elicits LTP at the ipsilateral synapses, while the synapses of the collateral, crossed pathway to the contralateral DG do not exhibit LTP. Furthermore, in the DG ipsilateral to the conditioning stimulation the convergent crossed pathway from the contralateral side, which had not been itself conditioned, failed to exhibit heterosynaptic LTP. These results are consistent with a specific 'synaptic' localization of the changes responsible for LTP, and suggest that some critical number of synapses must be activated in order to observe LTP. While the crossed EC-DG projection never exhibited LTP when conditioned alone, the crossed input could be potentiated under certain circumstances. Specifically, paired conditioning of ipsi- and contralateral inputs by nearly simultaneous conditioning stimulation of the EC bilaterally results in LTP in the crossed system. Furthermore, this associatively induced LTP of the crossed system can be reversed by subsequent conditioning of the ipsilateral system alone. Successive potentiating and depotentiating sequences are possible using paired and non-paired stimulation procedures even after lesions which prevent neural loops through the EC. The results are interpreted as evidence for a 'Hebb' type synapse which has the capability for erasure. This synaptic type is not appropriate for classical conditioning without appendant circuitry, but is suited for other forms of associative learning.

Animals↗
PubMed1979

Analysis of the habituation-like changes in transmission in the temporodentate pathway of the rat.

Habituation-like decrements in extracellular measures of synaptic activation (population EPSP) and cell discharge (population spike) were analyzed in the dentate gyrus of the rat following repetitive low-frequency stimulation of the medial and lateral entorhinal cortex. Stimulation of either subdivision of the entorhinal projection system resulted in comparable habituation-like response decrements with similar stimulation regimens. However, habituating stimulation of one subdivision did not result in decreased responsiveness to stimulation of the other. Repetitive low-frequency stimulation or even a single pulse delivered to either subdivision did, however, result in a potentiation of granule cell discharge in response to stimulation of the other subdivision (a form of heterosynaptic potentiation). This heterosynaptic potentiation of granule cell discharge was not accompanied by any increase in the extracellular EPSP. Comparisons of the relationship between the population EPSP and population spike before and during habituating stimulation revealed changes in cell discharge in response to the habituating stimulus which could not be accounted for by changes in synaptic activation alone. The results suggest that repetitive activation of the temporodentate pathway alters granule cell output as a result of two processes, a habituation-like decrement in synaptic activation, and a potentiation of granule cell discharge as a consequence of prior activation.

Afferent Pathways↗
PubMed1978

Polysynaptic activation of the dentate gyrus of the hippocampal formation: an olfactory input via the lateral entorhinal cortex.

The possibility that olfactory input is transmitted to specific subregions of the hippocampal formation via the entorhinal cortex was investigated electrophysiologically by analyzing the laminar profiles of potentials evoked in the hippocampal formation by stimulation of the lateral olfactory tract (LOT). LOT stimulation resulted in long latency (14--20 ms) evoked responses in the dentate gyrus of the hippocampal formation ipsilateral to the stimulation. The variable long latency of these responses and their inability to follow stimulus rates of 40/s suggested that these potentials reflected polysynaptic activation. Analysis of the laminar profiles of the evoked potentials indicated that the responses originated from a synaptic field localized in the outer portion of the stratum moleculare of the dentate gyrus, a terminal distribution which overlaps that of the lateral entorhinal cortical (LEC) projection to the dentate gyrus. Lesions of the LEC eliminated the long latency responses in the dentate gyrus evoked by LOT stimulation. In addition, a conditioning pulse delivered either to the LOT or to the LEC produced paired pulse potentiation of the response elicited by subsequent stimulation of the other structure. No evidence was found to indicate that responses were generated in regio superior of the hippocampus proper following LOT stimulation. Taken together, these results suggest that stimulation of the LOT activates the dentate gyrus of the hippocampal formation by multisynaptic pathways which relay through the lateral portion of the entorhinal area. This finding is discussed with regard to entorhinal cortical organization and the known olfactory projections to the LEC.

Animals↗
PubMed1978

Identification of the cells of origin of a central pathway which sprouts following lesions in mature rats.

Following unilateral destruction of the entorhinal cortical region of the adult rat, the denervated granule cells of the dentate gyrus are reinnervated as a result of the proliferation of a pathway from the surviving contralateral entorhinal area. The present study investigates the cells of origin of this lesion-induced pathway. Following HRP injections into the reinnervated dentate gyrus, heavily labeled cells were evident in layers II and III of the contralateral entorhinal area, in marked contrast to the pattern of labeling in normal animals, where labeled cells are restricted almost entirely to layer III. The atypically labeled cells in the operated animals were found predominantly in the dorsal half of the entorhinal area, and were concentrated in the medial most portion of layer II. These atypically labeled cells in layer II of the operated animals were an average of 16% larger than their unlabeled neighbors in the same lamina. This was not related to the loading with HRP, however, since in normal animals, cells in layer II which are labeled with HRP were no different in size than unlabeled cells. The atypically labeled cells in layer II of operated animals could also be identified at the electron microscopic level, and could be distinguished from the cells in layer III which normally project to regio superior of the contralateral hippocampal formation. While labeled cells were evident in layers II and III following injections into the reinnervated dentate gyrus, no labeled cells were found in the presubiculum or parasubiculum. In combination, these results suggest (1) the pathway which reinnervates the dentate gyrus from the contralateral entorhinal area originates predominantly, if not exclusively, from the cells in layer II, (2) these cells in layer II have the same preferential distribution within the entorhinal area as the rare lightly labeled cells which can be found contralateral to an injection in normal animals and (3) cells which participate in the reinnervation are larger than their unlabeled neighbors which presumably do not give rise to fibers which reinnervate the contralateral dentate gyrus. Since the cells in layer II which sprout following lesions can be identified at both the light and elctron microscopic level, a potentially valuable model system is available in which to analyze cellular changes during sprouting.

Animals↗
PubMed1978

Histochemical evidence for a post-lesion reorganization of cholinergic afferents in the hippocampal formation of the mature cat.

We have utilized acetylcholinesterase (AChE) histochemistry to analyze possible post-lesion changes in the distribution of AChE containing afferents to the hippocampal formation of the cat following unilateral destruction of the entorhinal cortex. In the cat, the entorhinal area gives rise to a massive projection to the ipsilateral fascia dentata, and to regio inferior and regio superior of the hippocampus proper. Sixty days following unilateral entorhinal lesions, histochemical preparations for AChE indicate a dramatic increase in the density of the reaction product in the zones normally occupied by entorhinal afferents in the fascia dentata and regio inferior of the hippocampus proper, whereas little if any increase in the density of the reaction product was observed in the entorhinal terminal zone in regio superior. In addition to these increases in the density of the AChE reaction product, there was also evidence for a widening of an AChE free zone in the inner stratum moleculare of the fascia dentata denervated by the lesion. The time course of these changes in the pattern of AChE staining was analyzed by sacrificing animals 7, 10, 13, 14, 16, 17,, 19, and 20 days following entorhinal cortical lesions. The increase in the density of the AChE reaction product in the denervated zones was not apparent at seven days post-lesion, while at ten days post-lesion, a slight increase in the density of the AChE reaction product could be observed. By 13 days post-lesion, the differences between the denervated and normally innervated (contralateral) hippocampal formation were prominent, and by 16 days post-lesion, the pattern of staining appeared comparable to that which was observed at longer post-lesion intervals. The present experiments indicate that following entorhinal cortical lesions in mature cats the final post-lesion pattern of altered AChE staining is quite comparable to that which is observed following similar lesions in rats. In the rat, such changes in AChE staining have been interpreted as a reflection of a proliferation of cholinergic septal afferents within the denervated zones. If this interpretation is correct, the present results suggest a similar proliferation of cholinergic afferents following entorhinal lesions in cats. The time course of this apparent proliferation is considerably slower in the cat then in the rat, however, since the earliest changes are observed at approximately five days post-lesion in the rat, and ten days post-lesion in the cat.

Acetylcholinesterase↗
PubMed1977

Quantitative autoradiographic analysis of the time course of proliferation of contralateral entorhinal efferents in the dentate gyrus denervated by ipsilateral entorhinal lesions.

The time course of the post-lesion proliferation of contralateral entorhinal afferents which occurs in response to ipsilateral entorhinal lesions was quanititatively analyzed with autoradiographic techniques. The extent of the crossed projection to the dentate granule cells was quantified on the basis of a contralateral/ipsilateral (C/I) ratio of grain density in the entorhinal terminal zones at 6, 8, 10, 12, 14, and over 60 days post-lesion. C/I ratios of grain density indicate little if any change in the crossed projection at 6 days post-lesion. Between 8 and 12 days post-lesion, the extent of the crossed projection increases dramatically, on the basis of the C/I ratio of grain density. C/I ratios do not increase further between 12 and 14 days post-lesion, but are higher at 60 days post-lesion. These results suggest that the crossed pathway proliferates extensively within the denervated zones between 8 and 12 days post-lesion, and may continue to proliferate at a much slower rate after 12 days post-lesion.

Animals↗
PubMed1977

Synaptic replacement in the dentate gyrus after unilateral entorhinal lesion: electron microscopic analysis of the extent of replacement of synapses by the remaining entorhinal cortex.

In response to a unilateral entorhinal lesion the input from the contralateral entorhinal cortex to the dentate gyrus appears to increase. We have studied this crossed projection by electron microscopy in normal animals and in animals one year or more after a unilateral entorhinal lesion. In normal animals few degenerating boutons are found after a contralateral entorhinal lesion. However, when the contralateral lesion was made one year after an ipsilateral entorhinal lesion, degenerating boutons were readily identified. The boutons were relatively few in number, but formed an abnormally large number of synaptic contacts. These results support the previous conclusion that fibres from the contralateral entorhinal cortex form additional synapses when their ipsilateral homologues are removed. However, these new cortical synapses probably account for only a small portion of those formed in response to the lesion. Thus an anatomically homologous input does not, in this case, selectively capture most of the newly available synaptic sites.

Animals↗
PubMed1976

Potentiation of excitatory synaptic transmission in the normal and in the reinnervated dentate gyrus of the rat.

Following destruction of the ipsilateral temporo-ammonic tract, which originates in the entorhinal cortex, and terminates on the granule cells of the dentate gyrus, fibers from the surviving contralateral entorhinal area proliferate forming extensive new connections with the denervated dentate granule cells. Utlizing extracellular recording techniques, we have compared the characteristics of synaptic transmission in the lesion induced afferents with the characteristics of the normal ipsilateral afferents by analyzing the responses of dentate granule cells to paired pulse activation of temporo-dentate circuitry. In the dentate gyrus of the normal rat, and extracellularly recorded EPSP evoked by stimulation of the ipsilateral entorhinal cortex is enhanced by as much as 100% by a "conditioning" pulse to the same afferent system. This is called paired pulse potentiation. In the reinnervated dentate gyrus, the extracellular EPSP evoked by a test stimulus delivered to the contralateral entorhinal cortex is also potentiated by a conditioning pulse. Thepaired pulse potentiation in the reinnervated dentate gyrus has a time course which is comparable to that of the normal ipsilateral afferent system, but the magnitude of the potentiation is somewhat less, averaging approximately 140% of control...

Afferent Pathways↗