Biomedical subjects

S M O'Mara

Publications and source records attributed to S M O'Mara.

At least 19 recordsLinked to original sources

PubMed2005

Combining exercise and cyclooxygenase-2 inhibition does not ameliorate learning deficits after brain insult, despite an increase in BDNF levels.

Neurodegeneration can produce behavioral impairments. Previously, we have found that inhibition of cyclooxygenase-2 activity or physical activity was neuroprotective during kainic-acid-induced neural loss. Here, we investigated the combined effect of exercise pre-insult and cyclooxygenase inhibitor treatment post-kainate-induced brain damage. However, in spite of an increase in BDNF levels, the combination did not improve behavioral performance in Morris watermaze and object exploration tasks.

Analysis of Variance↗

PubMed2005

Hippocampal contributions to neurocognitive mapping in humans: a new model.

The ability of an organism to develop, maintain, and act upon an abstracted internal representation of spatially extensive environments can provide an increased chance in ensuring that organism's survival. Here, we propose a neurocognitive model of spatial representation describing how several different processes interact and segregate the differing types of information used to produce a unified cognitive map. This model proposes that view-based egocentric and vestibulomotor translational information are functionally and anatomically separate, and that these parallel systems result in independent, but interacting, models within a neurocognitive map of space. In this context, we selectively review relevant portions of the large literature, addressing the establishment and operation of such spatial constructs in humans and the brain systems that underpin them, with particular reference to the hippocampal formation (HF). We present a reinterpretation of the types of knowledge used in the formation of this spatial construct, the processes that act upon this information, the nature of the final spatial representation, and describe how these universal concepts relate to the proposed model of spatial processing. The relevant experimental paradigms used to examine the neural basis of spatial representation and the main findings from previous research are also briefly presented. Finally, we detail a series of testable theoretical, behavioral, and anatomical predictions made by the model.

Brain Mapping↗

PubMed2004

Exercise, but not environmental enrichment, improves learning after kainic acid-induced hippocampal neurodegeneration in association with an increase in brain-derived neurotrophic factor.

Previous studies have suggested that exercise in a running wheel can be neuroprotective, perhaps due to, among others, gene-expression changes after exercise, increases in trophic proteins and/or enhanced cardiovascular responsivity. Here we ask whether physical exercise or environmental enrichment provide protection after brain damage, especially in terms of recovery of cognitive function. To evaluate the neuroprotective effect of these conditions, we used the kainic acid (KA) model of neuronal injury. Systemically-administered KA induces excitotoxicity by overstimulation of glutamate receptors, resulting in neuronal death by necrosis and apoptosis. Our results show that exercise, but not enriched environment, prior to KA-induced brain damage, improved behavioural performance in both Morris watermaze and object exploration tasks. However, prior exercise did not decrease to control levels the hyperactivity normally seen in KA-treated animals, as measured by ambulation in the open field. Furthermore, both exercise and enriched environment did not protect against neuron loss in CA1, CA2 and CA3 areas of the hippocampus, despite a substantial increase in brain-derived neutrophic factor (BDNF) levels in dentate gyrus of the exercise and KA-treated animals.

Analysis of Variance↗

PubMed2004

Impact of enriched-environment housing on brain-derived neurotrophic factor and on cognitive performance after a transient global ischemia.

Environmental enrichment promotes structural and functional changes in the brain, including enhanced learning and memory performance in rodents. Transient global cerebral ischemia (15 min) causes specific damage to dorsal hippocampal area CA1 pyramidal cells of the rat concomitantly with cognitive deficits. Thus, we investigated if environmental enrichment can protect rats against the cognitive and neurological consequences of transient ischemia. We evaluated the impairment of learning and memory with three tasks: odour discrimination, object exploration and spatial learning. Contrary to expectation, we found that the enriched environment improved performances for both ischemic and sham rats in odour discrimination and object exploration tasks compared with standard condition housed rats. After exposure to an enriched environment, ischemic rats performed better in the water maze than those in the standard housing conditions. However, exposure to an enriched environment does not protect against actual loss of CA1 pyramidal cells. Brain-derived neurotrophic factor (BDNF) levels were increased in environmental enrichment animals compared to those housed in standard conditions. We conclude that environmental enrichment has positive effects that are independent of the effects of ischemic brain lesions.

Analysis of Variance↗

PubMed2004

Post-treatment, but not pre-treatment, with the selective cyclooxygenase-2 inhibitor celecoxib markedly enhances functional recovery from kainic acid-induced neurodegeneration.

We have investigated the role of inflammation in the excitotoxicity induced by overstimulation of glutamate receptors using kainic acid, an important tool for studying functions related to excitatory amino acid transmission and for producing neuronal death, especially in areas CA1 and CA3 of the hippocampus. We hypothesised that by inhibiting one of the major components of the neuroinflammation response, after kainic acid injection, that there would be less inflammation and therefore a reduction in cell loss, an enhancement of cognitive function (using spatial learning and object exploration tasks) or both. We examined brain-derived neurotrophic factor levels, expecting that there would be a correlation between its level and subsequent recovery. Our results confirmed our hypothesis: the kainic acid injected-rats treated with celecoxib (after kainic injection) performed better in the spatial and non-spatial tasks than the kainic acid-treated group. However, there was not any improvement if celecoxib was given before kainic acid treatment, underlining also the importance of the production of prostaglandin at the beginning of inflammation.

Analysis of Variance↗

PubMed2002

Plasticity in the projection from the anterior thalamic nuclei to the anterior cingulate cortex in the rat in vivo: paired-pulse facilitation, long-term potentiation and short-term depression.

Several neurophysiological and computational theories of the rodent navigational system suggest that the differing cortices of the frontal lobe and thalamus share information and therefore undergo changes in synaptic strength. We examine here for the first time three forms of synaptic plasticity in the projection from the anterior thalamic nuclei to the anterior cingulate cortex: we demonstrate that this projection is capable of expressing paired-pulse facilitation, long-term potentiation, and short-term depression. Furthermore, input/output curves show that field excitatory post-synaptic potential amplitude increased at all stimulus intensities following high-frequency stimulation. These findings add important information to our understanding of synaptic plasticity in this important pathway, which has been widely hypothesized to play important roles in memory and spatial representation in the rodent.

Animals↗

PubMed2002

Long-term potentiation and spatial learning are associated with increased phosphorylation of TrkB and extracellular signal-regulated kinase (ERK) in the dentate gyrus: evidence for a role for brain-derived neurotrophic factor.

In this study, the authors investigate changes in the presynaptic terminal of the dentate gyrus that accompany 2 types of hippocampal-dependent plasticity: spatial learning and long-term potentiation (LTP). Parallel changes occurred in the dentate gyrus of rats that had undergone training in the Morris water maze and had sustained LTP. In both cases, KCl-induced brain-derived neurotrophic factor release was increased, and this was accompanied by increased phosphorylation of TrkB and the mitogen-activated protein kinase, ERK. Glutamate release was also enhanced, and the data suggest that this may be a consequence of increased activation of TrkB and ERK. Because the data indicate that similar cellular modifications are shared by these 2 forms of plasticity, they provide circumstantial evidence that LTP satisfies some of the requirements of a memory-inducing cellular substrate.

Animals↗

PubMed2001

Lipopolysaccharide causes deficits in spatial learning in the watermaze but not in BDNF expression in the rat dentate gyrus.

We investigated the effects of a single injection and a daily injection of lipopolysaccharide (LPS) on spatial learning and brain-derived neurotrophic factor (BDNF) expression in the rat dentate gyrus. LPS is derived from the cell wall of Gram-negative bacteria and is a potent endotoxin that causes the release of cytokines such as interleukin-1 and tumour necrosis factor. LPS is thought to activate both the neuroimmune and neuroendocrine systems; it also blocks long-term potentiation in the hippocampus. Here, we examined the effects of LPS on a form of hippocampal-dependent learning-spatial learning in the water maze. Rats were injected with LPS intraperitoneally (100 microg/kg) and trained in the water maze. The first group of rats were injected on day 1 of training, 4 h prior to learning the water maze task. Groups 2 and 3 were injected daily, again 4 h prior to the water-maze task; group 2 with LPS and group 3 with saline. A number of behavioural variables were recorded by a computerised tracking system for each trial. The behavioural results showed a single injection of LPS (group 1) impaired escape latency in both the acquisition and retention phases of the study, whereas a daily injection of LPS did not significantly impair acquisition or retention. BDNF expression was analysed in the dentate gyrus of all animals. No significant differences in BDNF expression were found between the three groups.

Animals↗

PubMed2001

The subiculum: a review of form, physiology and function.

We review the neuroanatomical, neurophysiological and functional properties of the mammalian subiculum in this paper. The subiculum is a pivotal structure positioned between the hippocampus proper and entorhinal and other cortices, as well as a range of subcortical structures. It is an under-investigated region that plays a key role in the mediation of hippocampal-cortical interaction. We argue that on neuroanatomical, physiological and functional grounds, the subiculum is properly part of the hippocampal formation, given its pivotal role in the hippocampal circuit. We suggest that the term "subicular complex" embraces a heterogenous range of distinct structures and this phrase does not connote a functionally or anatomically meaningful grouping of structures. The subiculum has a range of electrophysiological and functional properties which are quite distinct from its input areas; given the widespread set of cortical and subcortical areas with which it interacts, it is able to influence activity in quite disparate brain regions. The rules which govern the plasticity of synaptic transmission are not well-specified; it shares some properties in common with the hippocampus proper, but behaves quite differently in other respects. Equally, its functional properties are not well-understood, it plays an important but ill-defined role both in spatial navigation and in mnemonic processing. The important challenges for the future revolve around the theoretical specification of its unique contribution to hippocampal formation processing on the one hand, and the experimental investigation of the many open questions (anatomical, physiological, pharmacological, functional) regarding its properties, on the other.

Action Potentials↗

PubMed2001

The effects of the bacterial endotoxin lipopolysaccharide on synaptic transmission and plasticity in the CA1-subiculum pathway in vivo.

Lipopolysaccharide is derived from the cell wall of gram-negative bacteria and is a potent endotoxin which causes the release of cytokines in the CNS. We examined the effect of lipopolysaccharide on synaptic transmission and synaptic plasticity in the hippocampal area CA1-subicular pathway in vivo. We found that lipopolysaccharide did not affect baseline synaptic transmission in this pathway; it did, however, reduce the magnitude of paired-pulse facilitation, a form of short-term plasticity thought to be primarily presynaptic in origin. We then examined the interaction between lipopolysaccharide and two common models for the biological basis of memory: high-frequency stimulation induced long-term potentiation and low-frequency stimulation induced long-term depression of synaptic transmission. We found that lipopolysaccharide blocked long-term potentiation following high-frequency stimulation and also induced potentiation of synaptic transmission after low-frequency stimulation. Lipolysaccharide blocked paired-pulse facilitation selectively at short rather than longer interstimulus intervals. Thus, lipopolysaccharide has different effects on synaptic transmission in this pathway depending on the frequency and length of stimulation. These results provide new insights into the action of lipopolysaccharide on various forms of plasticity in the hippocampus, an area known to play a vital role in learning and memory.

Animals↗

PubMed2000

Responses of rat subicular neurons to convergent stimulation of lateral entorhinal cortex and CA1 in vivo.

There has been little electrophysiological examination of the afferent projection from lateral entorhinal cortex to dorsal subiculum. Here we provide evidence that synaptic inputs from lateral entorhinal cortex and CA1 converge onto single dorsal subicular neurons in vivo. Subicular responses to CA1 stimulation consisted of excitation and/or long-duration inhibition. Neurons excited by CA1 activation usually showed inhibition to entorhinal stimulation. The latter inhibition was usually of short duration, however, long duration inhibition was seen in a significant proportion of responses. Entorhinal stimulation produced excitatory responses in four bursting cells and it was these cells that also tended to show the longest inhibition. Only bursting cells could be driven antidromically by entorhinal stimulation. Biocytin-filled multipolar and pyramidal cells displayed excitation-inhibition sequences to CA1 and inhibition to entorhinal stimulation. These data strongly suggest that subicular inhibitory neurons receive excitatory input from CA1 and display mutual inhibition. The source of entorhinal-evoked inhibition is less clear. The relative sparseness of observed entorhinal-evoked responses suggests that the input to dorsal subiculum from any one part of lateral entorhinal cortex is spatially restricted. These data show that excitation-inhibition sequences can be seen in subicular pyramidal and multipolar cells and that single subicular neurons receive convergent inputs from CA1 and entorhinal cortex. We show for the first time that bursting cells can be driven both orthodromically and antidromically by direct entorhinal stimulation. These data support the existence of a reciprocal excitatory connection between lateral entorhinal cortex and dorsal subiculum and suggest further that this connection may involve only bursting subicular neurons.

Action Potentials↗

PubMed2000

The effects of low frequency and two-pulse stimulation protocols on synaptic transmission in the CA1-subiculum pathway in the anaesthetized rat.

The downregulation of synaptic efficacy is referred to as long-term depression (LTD). Recent work has shown that a two-pulse stimulation (TPS) protocol is successful at inducing LTD in vivo in area CA1 of the hippocampus. Here, we examine the ability of two TPS protocols and two low-frequency stimulation (LFS) protocols to induce LTD in the projection from hippocampal area CA1 to the subiculum in the anaesthetized rat. We find no evidence of LTD induction with TPS or LFS protocols. Instead, with three of the protocols (both TPS protocols and 1 Hz LFS), a late-developing potentiation is observed.

Animals↗

PubMed2000

Synaptic plasticity in the hippocampal area CA1-subiculum projection: implications for theories of memory.

This paper reviews investigations of synaptic plasticity in the major, and underexplored, pathway from hippocampal area CA1 to the subiculum. This brain area is the major synaptic relay for the majority of hippocampal area CA1 neurons, making the subiculum the last relay of the hippocampal formation prior to the cortex. The subiculum thus has a very major role in mediating hippocampal-cortical interactions. We demonstrate that the projection from hippocampal area CA1 to the subiculum sustains plasticity on a number of levels. We show that this pathway is capable of undergoing both long-term potentiation (LTP) and paired-pulse facilitation (PPF, a short-term plastic effect). Although we failed to induce long-term depression (LTD) of this pathway with low-frequency stimulation (LFS) and two-pulse stimulation (TPS), both protocols can induce a "late-developing" potentiation of synaptic transmission. We further demonstrate that baseline synaptic transmission can be dissociated from paired-pulse stimulation of the same pathway; we also show that it is possible, using appropriate protocols, to change PPF to paired-pulse depression, thus revealing subtle and previously undescribed mechanisms which regulate short-term synaptic plasticity. Finally, we successfully recorded from individual subicular units in the freely-moving animal, and provide a description of the characteristics of such neurons in a pellet-chasing task. We discuss the implications of these findings in relation to theories of the biological consolidation of memory.

Animals↗

PubMed2000

Long-term potentiation and paired-pulse facilitation in the prelimbic cortex of the rat following stimulation in the contralateral hemisphere in vivo.

We demonstrate here for the first time that the afferent fibres to the prelimbic component of prefrontal cortex and/or their associated, recurrent collateral local-circuit axons are capable of expressing paired-pulse facilitation and long-term potentiation after stimulation of the prelimbic component in the contralateral hemisphere. Long-term potentiation resulted from both high- and low-frequency stimulation protocols. It was not possible to obtain either depotentiation of previously potentiated synapses or long-term depression with the protocol used. Input-output analyses revealed interactions between separate components of the evoked responses. Since neurophysiological and computational theories of the rodent navigational system include the prefrontal cortex, these findings add important information to theories of prefrontal function and spatial representation in the rodent.

Animals↗

PubMed1999

The effects of single and multiple episodes of theta patterned or high frequency stimulation on synaptic transmission from hippocampal area CA1 to the subiculum in rats.

Long-term potentiation (LTP) is a popular model for the synaptic changes that may occur during learning and memory; it involves a strengthening of synaptic response and is readily induced in the hippocampus, an area of the brain implicated in learning and memory. Previous research on LTP has focused on 'early' components of the hippocampal circuitry, that is, the dentate gyrus and areas CA1 and CA3. This paper examines the plasticity of the CA1-subiculum pathway; we extend our previous work in this area demonstrating that the projection from area CA1 to subiculum sustains theta-patterned stimulus-induced LTP in vivo. We show that this pathway remains potentiated over a long period (3 h). Furthermore, once this projection is potentiated, it seems resistant to further episodes of high-frequency stimulation. We discuss the implications of these findings for theories of hippocampal-cortical interaction during the biological consolidation of memory.

Animals↗

PubMed1999

Heterogeneity of in vitro radiosensitivity in human bladder cancer cells.

Human bladder cancer is often heterogeneous containing biologically different populations. Radiotherapy plus chemotherapy is the most common treatment for invasive disease. However few studies have investigated the role of heterogeneity in determining radiosensitivity. The radiation sensitivities of a parent human bladder cancer cell line (UCRU-BL-17CL) and nine cloned cell lines derived from it were determined. These cloned cell lines were previously shown to exhibit different biological characteristics when grown in nude mice. Radiation sensitivity was determined using both MTT and clonogenic assays. The radiobiological parameters, alpha,beta, and surviving fractions at 2 Gy and 8 Gy from the linear-quadratic model, were used to assess radiation sensitivity in the statistical analyses. The nine clones differed in radiosensitivity by both assays. By MTT, but not by the clonogenic assay, their radiation sensitivities were relatively consistent within each of the three biological groups (non-tumorigenic, tumorigenic, invasive); invasive clones were more sensitive than those of the non-tumorigenic and the tumorigenic groups for all the three-test criteria. The heterogeneity exhibited by this cell line may explain some of the variations in the clinical responses seen in the radiation treatment of invasive bladder cancer.

Animals↗

PubMed1999

Metabotropic glutamate receptor activation and blockade: their role in long-term potentiation, learning and neurotoxicity.

Metabotropic glutamate receptors represent a fairly recent addition to the family of glutamate receptors. These receptors have the distinguishing feature of being coupled to G-proteins rather than ion channels and they appear to have a variety of functional characteristics. These receptors play a vital role, for example, in the induction and maintenance of long-term potentiation, the most popular current model of the biological correlates of learning and memory. Blockade of metabotropic glutamate receptors prevents long-term potentiation induction and learning in a variety of tasks in different species. Chronic metabotropic glutamate receptor activation is also associated with neurodegeneration and selective neuronal loss when agonists of these receptors are injected in high concentrations directly into the brain. Metabotropic glutamate receptors also play a role in the normal development of the nervous system and these sites within the central nervous system offer possible routes for drug therapies; selective receptor antagonists, for example, may prove to have the very desirable feature of endowing neuroprotection during ischaemic episodes whilst allowing normal excitatory neurotransmission to occur.

Animals↗

PubMed1999

Disorientation combined with bilateral parietal cortex lesions causes path integration deficits in the water maze.

The navigational abilities of rats were examined using the water maze after disorientation induced by rotation and/or swimming in darkness. Control and light-disoriented groups performed similarly, whereas the dark group and the dark-disoriented groups were initially much slower but improved to control levels. After receiving bilateral parietal lesions, multiple start position tests showed that both rotation groups were severely impaired in finding the hidden platform. The effects of disorientation induced by darkness and by rotation are therefore separable.

Analysis of Variance↗