Biomedical subjects

M W Brown

Publications and source records attributed to M W Brown.

At least 19 recordsLinked to original sources

PubMed2003

Galanin regulates spatial memory but not visual recognition memory or synaptic plasticity in perirhinal cortex.

It has previously been shown that the neuropeptide galanin plays a role in the age-dependent regulation of hippocampal synaptic plasticity and spatial memory. Here, we further extend these studies by demonstrating that galanin knockout mice also have deficits in an object-in-place spatial memory task. In contrast however, there is no deficit in single item object recognition memory, a memory that depends on perirhinal cortex. Furthermore, in perirhinal cortex slices there are no differences in activity-dependent long-term potentiation or depotentiation, nor in muscarinic receptor-dependent long-term depression between galanin knockout mice and wild-type litter-mates. Therefore, these results suggest that galanin has a differential role in hippocampal-dependent and perirhinal cortex-dependent memory.

Animals↗

PubMed2002

Evidence concerning how neurons of the perirhinal cortex may effect familiarity discrimination.

Many studies indicate that recognition memory involves at least two separable processes, familiarity discrimination and recollection. Aspects of what is known of potential neuronal substrates of familiarity discrimination are reviewed. Lesion studies have established that familiarity discrimination for individual visual stimuli is effected by a system centred on the perirhinal cortex of the temporal lobe. The fundamental change that encodes prior occurrence of such stimuli appears to be a reduction in the response of neurons in anterior inferior temporal (including perirhinal) cortex when a stimulus is repeated. The neuronal responses rapidly signal the presence of a novel stimulus, and are evidence of long-lasting learning after a single exposure. Computational modelling indicates that a neuronal network based on such a change in responsiveness is potentially highly efficient in information theoretic terms. Processes that occur in long-term depression within the perirhinal cortex provide candidate synaptic plastic mechanisms for that underlying the change, but such linkage remains to be experimentally established.

Animals↗

PubMed2002

Mechanisms and physiological role of enhancement of mGlu5 receptor function by group II mGlu receptor activation in rat perirhinal cortex.

In this study we have investigated mechanisms underlying enhancement by group II metabotropic glutamate (mGlu) receptors of group I mGlu receptor-induced calcium mobilization. Inhibition of protein kinase A (PKA) caused an enhancement of mGlu5 receptor-mediated calcium mobilization and occluded the enhancement by group II mGlu receptors. A peptide (Ht31) that prevents interaction between A-kinase anchoring protein (AKAP) and PKA also enhanced mGlu5-mediated calcium mobilization. Enhancement of mGlu5 function, by inhibition of PKA or by activation of group II mGlu receptors, was prevented by the protein phosphatase 2B (PP2B) inhibitor cyclosporin A. Furthermore, the enhancement by activation of group II mGlu receptors was prevented by raising intracellular cAMP. These results suggest that the regulation by PKA and PP2B of phosphorylation of a substrate on mGlu5 and/or on group II mGlu receptors is intimately involved in the mechanisms underlying interaction between group II mGlu and mGlu5 receptors. Long-term depression (LTD) in perirhinal cortex requires group I, group II and NMDA receptor activation at resting membrane potentials but does not require group II mGlu receptor activation at depolarized potentials. We previously suggested that interaction between group I and group II mGlu receptors is required for induction of LTD at resting potentials. In support of this, we demonstrate in perirhinal cortex slices that blocking mechanisms underlying mGlu receptor synergy (by raising intracellular cAMP or by inhibition of PP2B) selectively prevented LTD at resting membrane potentials. This study thus provides a potential explanation for the co-requirement in LTD of group I and group II mGlu receptor activation. Similar mechanisms of synergistic interaction may also be important in other physiological processes dependent on mGlu receptors.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed2001

An experimental test of the role of postsynaptic calcium levels in determining synaptic strength using perirhinal cortex of rat.

1. We have investigated the prediction of a relationship between the magnitude of activity-dependent increases in postsynaptic calcium and both the magnitude and direction of synaptic plastic change in the central nervous system. 2. Activity-dependent increases in calcium were buffered to differing degrees using a range of concentrations of EGTA and the effects on synaptic plasticity were assessed. Activity-dependent synaptic plasticity was induced during whole-cell recording in rat perirhinal cortex in vitro. In control conditions (0.5 mM EGTA) low frequency stimulation (LFS; 200 stimuli) delivered to neurones held at -40 or -70 mV induced long-term depression (LTD) or, at -10 mV, induced long-term potentiation (LTP). 3. The relationship between EGTA concentration (0.2 to 10 mM) and the magnitude of LTD was examined. This relationship described a U-shaped curve, as predicted by models of synaptic plasticity. This provides strong evidence that the magnitude of LTD is determined by the magnitude of the increase in intracellular calcium concentration. 4. LFS paired with depolarisation to -10 mV induced LTD, no change or LTP as activity-dependent postsynaptic calcium levels were allowed to increase progressively by the use of progressively lower concentrations of buffer (10 to 0.2 mM EGTA). 5. We investigated if the lack of plasticity that occurs at the transition between LTD and LTP is due to induction of both of these processes with zero net change, or is due to neither LTD nor LTP being induced. These experiments were possible as LTP but not LTD was blocked by the protein kinase inhibitor staurosporine while LTD but not LTP was blocked by the mGlu receptor antagonist MCPG. At the transition between LTD and LTP, blocking LTP mechanisms did not uncover LTD whilst blocking LTD mechanisms did not uncover LTP. This suggests that the transition between LTD and LTP is due to the lack of induction of both of these processes and also suggests that these two processes are induced independently of one another.

Animals↗

PubMed2001

Tracking memory's trace.

There is strong converging evidence that the intermediate and medial part of the hyperstriatum ventrale of the chick brain is a memory store for information acquired through the learning process of imprinting. Neurons in this memory system come, through imprinting, to respond selectively to the imprinting stimulus (IS) neurons and so possess the properties of a memory trace. Therefore, the responses of the intermediate and medial part of the hyperstriatum ventrale neurons to a visual imprinting stimulus were determined before, during, and after training. Of the total recorded population, the proportions of IS neurons shortly after each of two 1-h training sessions were significantly higher (approximately 2 times) than the pretraining proportion. However, approximately 4.5 h later this proportion had fallen significantly and did not differ significantly from the pretraining proportion. Nevertheless, approximately 21.5 h after the end of training, the proportion of IS neurons was at its highest (approximately 3 times the pretraining level). No significant fluctuations occurred in the proportions of neurons responding to the alternative stimulus. In addition, nonmonotonic changes were found commonly in the activity of 230 of the neurons tracked individually from before training to shortly after the end of training. Thus the pattern of change in responsiveness both at the population level and at the level of individual neurons was highly nonmonotonic. Such a pattern of change is not consistent with simple models of memory based on synaptic strengthening to asymptote. A model is proposed that accounts for the changes in the population responses to the imprinting stimulus in terms of changes in the responses of individual neurons.

Analysis of Variance↗

PubMed2001

Recognition memory: what are the roles of the perirhinal cortex and hippocampus?

The hallmark of medial temporal lobe amnesia is a loss of episodic memory such that patients fail to remember new events that are set in an autobiographical context (an episode). A further symptom is a loss of recognition memory. The relationship between these two features has recently become contentious. Here, we focus on the central issue in this dispute--the relative contributions of the hippocampus and the perirhinal cortex to recognition memory. A resolution is vital not only for uncovering the neural substrates of these key aspects of memory, but also for understanding the processes disrupted in medial temporal lobe amnesia and the validity of animal models of this syndrome.

Amnesia↗

PubMed2001

Fos imaging reveals differential neuronal activation of areas of rat temporal cortex by novel and familiar sounds.

To provide information about the possible regions involved in auditory recognition memory, this study employed an imaging technique that has proved valuable in the study of visual recognition memory. The technique was used to image populations of neurons that are differentially activated by novel and familiar auditory stimuli, thereby paralleling previous studies of visual familiarity discrimination. Differences evoked by novel and familiar sounds in the activation of neurons were measured in different parts of the rat auditory pathway by immunohistochemistry for the protein product (Fos) of the immediate early gene c-fos. Significantly higher counts of stained neuronal nuclei (266 +/- 21/mm2) were evoked by novel than by familiar sounds (192 +/- 17/mm2) in the auditory association cortex (area Te3; AudA). No such significant differences were found for the inferior colliculus, primary auditory cortex, postrhinal cortex, perirhinal cortex (PRH), entorhinal cortex, amygdala or hippocampus. These findings are discussed in relation to the results of lesion studies and what is known of areas involved in familiarity discrimination for visual stimuli. Differential activation is produced by novel and familiar individual stimuli in sensory association cortex for both auditory and visual stimuli, whereas the PRH is differentially activated by visual but not auditory stimuli. It is suggested that this latter difference is related to the nature of the particular auditory and visual stimuli used.

Acoustic Stimulation↗

PubMed2001

Activation of muscarinic receptors induces protein synthesis-dependent long-lasting depression in the perirhinal cortex.

There is strong evidence that decrements in neuronal activation in perirhinal cortex when a novel stimulus is repeated provide a neural substrate of visual recognition memory. There is also strong evidence that muscarinic acetylcholine (ACh) receptors are involved in learning and memory. However, the mechanisms underlying neuronal decrements in the perirhinal cortex and the basis of ACh involvement in learning and memory are not understood. In an in vitro preparation of rat perirhinal cortex we now demonstrate that activation of ACh receptors by carbachol (CCh) produces long-lasting depression (LLD) of synaptic transmission that is dependent on muscarinic M1 receptor activation. Crucially, the induction of this form of LLD requires neither N-methyl-D-aspartate receptor activation nor synaptic stimulation. CCh-induced LLD was not blocked by the protein kinase C inhibitors staurosporine or BIM, or by the protein phosphatase inhibitor okadaic acid. However, each of cyclopiazonic acid (an agent that depletes intracellular calcium stores) and anisomycin (an inhibitor of protein synthesis) significantly reduced the magnitude of CCh-induced LLD. These mechanisms triggered by muscarinic receptor activation could play a role in the induction and/or expression of certain forms of activity-dependent long-term depression in perirhinal cortex. An understanding of CCh-induced LLD may thus provide clues to the mechanisms underlying lasting neuronal decrements that occur in the perirhinal cortex and hence for neural substrates of visual recognition memory.

Acetylcholine↗

PubMed2000

Using fos imaging in the rat to reveal the anatomical extent of the disruptive effects of fornix lesions.

Activity of the immediate early gene c-fos was compared across hemispheres in rats with unilateral fornix lesions. To engage Fos production, rats first performed a radial arm maze task that is severely disrupted by bilateral fornix lesions. Using immunohistochemical techniques, Fos-positive cells were visualized and counted in 39 sites in both hemispheres. Fornix lesions led to a significant reduction in Fos in all ipsilateral hippocampal subfields, as well as the entorhinal cortex and most of the subicular complex. Other sites that showed reduced activity included the ipsilateral retrosplenial, anterior cingulate, and postrhinal cortices. Subcortical regions showing significant Fos decreases included the anterior thalamic nuclei, supramammillary nucleus, diagonal band of Broca, and lateral septum. Thus, the effects of fornix lesions extended beyond the hippocampal formation and included sites not directly innervated by the tract. These changes were nevertheless selective, as shown by the lack of hemispheric difference in any of the preselected control sites, the perirhinal cortex, or nucleus accumbens. Furthermore, there were no hemispheric differences in an additional group of animals with unilateral fornix lesions that were killed directly from the home cage. The location of Fos changes closely corresponded to those brain regions that when lesioned disrupt spatial working memory. Moreover, there was a correspondence between those brain regions that show increased Fos production in normal animals performing the radial arm maze task and those affected by fornix lesions. These results show that fornix transection has widespread, but selective, effects on a network of structures normally activated by spatial memory processes, with these effects extending beyond the hippocampal formation.

Animals↗

PubMed2000

Fos imaging reveals differential patterns of hippocampal and parahippocampal subfield activation in rats in response to different spatial memory tests.

We compared neuronal activation, as measured by Fos staining, during different spatial tasks in two experiments. The counts of Fos-stained neurons in the hippocampus increased as the spatial demands of the tasks increased, the tasks having been carefully matched for other factors. In Experiment 1, matched groups of rats either ran a standard eight-arm radial maze task or were trained to run up and down just one arm of the maze; the number of runs and rewards was identical in both conditions. In Experiment 2, rats were trained on the eight-arm maze but in different rooms. On the critical test day, both groups were run in the same room so that one group now performed with novel landmarks. All hippocampal subfields (dentate gyrus, CA3, CA1, dorsal, ventral, and caudal subiculum) showed a relative increases in c-fos activation in the eight-arm (Experiment 1) and novel room (Experiment 2) conditions, the sole exception being the ventral subiculum in Experiment 2. Although increased c-fos activation was found in both dorsal and ventral hippocampus, in Experiment 2 the relative increase was significantly greater in the dorsal hippocampus. Parahippocampal cortices responded heterogeneously: the perirhinal cortex failed to show increased activation in both experiments, in contrast to the entorhinal and postrhinal cortices. Subsequent comparisons confirmed that the perirhinal and postrhinal cortices responded in qualitatively different ways, the perirhinal cortex differing from the rest of the hippocampal formation. These experiments, which provide the first analysis of hippocampal Fos production during tests of allocentric spatial working memory, reveal that all components of the hippocampus are activated, but that under certain conditions the dorsal hippocampus is disproportionately involved.

Animals↗

PubMed2000

Fos expression in the rostral thalamic nuclei and associated cortical regions in response to different spatial memory tests.

Using the quantification of the Fos protein as an indicator of neuronal activation, we studied the involvement of the rostral thalamic nuclei and associated structures in different spatial memory tasks in two experiments. In both experiments, tasks were matched for sensorimotor factors but differed in their spatial and mnemonic demands. In Experiment 1, matched groups of rats either ran in a standard eight-arm radial maze or ran up and down just one arm of the maze while the number of runs and rewards were matched across pairs of rats. In Experiment 2, both groups were trained on the eight-arm radial maze but in different rooms. On the test day, one group was moved so that both groups now performed the same radial-maze task in the same room but for one group the extramaze cues were novel. There were significant increases in Fos in all three of the anterior thalamic nuclei (anterodorsal, anteroventral and anteromedial) as well as the adjacent nucleus reuniens and rostral reticular thalamic nucleus, in both the eight-arm versus one-arm condition (Experiment 1) and the novel room versus familiar room condition (Experiment 2). There were no significant differences in the mediodorsal thalamic nucleus in either experiment. The more spatially demanding task in each experiment also resulted in increased Fos expression in the subicular complex (postsubiculum, presubiculum and parasubiculum), as well as in the prelimbic cortex. Performing the standard radial-arm maze task also produced significant Fos increases in both rostral and caudal levels of the retrosplenial cortex when compared to rats running up and down a single arm in the same maze (Experiment 1); performing the task in a novel room did not, however, result in any further Fos increases in this region (Experiment 2). The specificity of the changes in levels of Fos was shown by a lack of any consistent difference in levels in six control sites.The present results reveal a group of anatomically related structures that work together in the intact rat brain during tasks that tax allocentric spatial working memory.

Animals↗

PubMed2000

A new form of long-term depression in the perirhinal cortex.

We demonstrate a form of long-term depression (LTD) in the perirhinal cortex that relies on interaction between different glutamate receptors. Group II metabotropic glutamate (mGlu) receptors facilitated group I mGlu receptor-mediated increases in intracellular calcium. This facilitation plus NMDA receptor activation may be necessary for induction of LTD at resting membrane potentials. However, depolarization enhanced NMDA receptor function and removed the requirement of synergy between group I and group II mGlu receptors: under these conditions, activation of only NMDA and group I mGlu receptors was required for LTD. Such glutamate receptor interactions potentially provide new rules for synaptic plasticity. These forms of LTD occur in the perirhinal cortex, where long-term decreases in neuronal responsiveness may mediate recognition memory.

2-Amino-5-phosphonovalerate↗

PubMed2000

World-wide genetic differentiation of Eubalaena: questioning the number of right whale species.

Few studies have examined systematic relationships of right whales (Eubalaena spp.) since the original species descriptions, even though they are one of the most endangered large whales. Little morphological evidence exists to support the current species designations for Eubalaena glacialis in the northern hemisphere and E. australis in the southern hemisphere. Differences in migratory behaviour or antitropical distribution between right whales in each hemisphere are considered a barrier to gene flow and maintain the current species distinctions and geographical populations. However, these distinctions between populations have remained controversial and no study has included an analysis of all right whales from the three major ocean basins. To address issues of genetic differentiation and relationships among right whales, we have compiled a database of mitochondrial DNA control region sequences from right whales representing populations in all three ocean basins that consist of: western North Atlantic E. glacialis, multiple geographically distributed populations of E. australis and the first molecular analysis of historical and recent samples of E. glacialis from the western and eastern North Pacific Ocean. Diagnostic characters, as well as phylogenetic and phylogeographic analyses, support the possibility that three distinct maternal lineages exist in right whales, with North Pacific E. glacialis being more closely related to E. australis than to North Atlantic E. glacialis. Our genetic results provide unequivocal character support for the two usually recognized species and a third distinct genetic lineage in the North Pacific under the Phylogenetic Species Concept, as well as levels of genetic diversity among right whales world-wide.

Animals↗

PubMed2000

GABAB receptors mediate frequency-dependent depression of excitatory potentials in rat perirhinal cortex in vitro.

Excitatory synaptic transmission in the perirhinal cortex exhibits marked homosynaptic paired pulse depression (PPD) at inter-pulse intervals between 100 and 1000 ms, being maximal at 200 ms. Additionally, there is greater PPD with stimulation of the pathway from the temporal cortex side than with stimulation of the pathway from the entorhinal cortex side. We establish that this frequency-dependent depression relies on the activation of GABAB (gamma-aminobutyric acid) receptors. PPD in both temporal and entorhinal pathways is abolished by either of the selective GABAB receptor antagonists, 3-N[1-(S)-(3, 4-dichlorophenyl)ethyl]amino-2-(S)-hydroxypropyl-p-benzyl-phosphinic acid (CGP55845A) or 3-amino-propyl(diethoxymethyl)phosphinic acid (CGP35348). Barium which blocks G-protein-coupled, inwardly rectifying potassium channels, does not block PPD. Heterosynaptic depression mediated by GABAB receptors was also observed. The depression of the entorhinal pathway by stimulation of the temporal pathway is greater than depression of the temporal pathway by stimulation of the entorhinal pathway. Moreover, PPD increases with stimulus strength and the depression is enhanced by short trains of stimuli, consistent with stronger stimulation resulting in more GABA reaching GABAB receptors on excitatory glutamatergic synapses. Synaptic activation of GABAB receptors may be important in regulating excitability in a frequency-dependent manner with maximal depression occurring at approximately 5 Hz, which approximates to the theta rhythm. That homosynaptic and heterosynaptic depression by stimulation of the temporal pathway is greater than by stimulation of the entorhinal pathway suggests that activation of temporal feedforward connections to the perirhinal cortex can dominate the GABAergic control of synaptic activity within the perirhinal cortex.

Animals↗

PubMed1999

Is neuronal encoding of subject-object distance dependent on learning?

Recordings were made in the intermediate and medial part of the hyperstriatum ventrale of behaving domestic chicks which had been imprinted (trained) by being exposed to a training stimulus. Neurons were tested for responsiveness to the training stimulus and to an alternative stimulus at each of three distances (d = 0.5 m, 1 m, 2 m) from the chick. For responses to the training stimulus 24/78 (31%) responsive neurons were d-sensitive, i.e. responses changed with distance. For responses to the alternative stimulus, a similar proportion of neurons was d-sensitive (16/57, 28%). Six d-invariant neurons responded similarly at each distance: four to the training and two to the alternative stimulus. Thus no effect of learning on d-sensitive or d-invariant neuronal responsiveness was found.

Animals↗

PubMed1999

Thrombogenic factors and recurrent coronary events.

BACKGROUND: Thrombosis is a pivotal event in the pathogenesis of coronary disease. We hypothesized that the presence of blood factors that reflect enhanced thrombogenic activity would be associated with an increased risk of recurrent coronary events during long-term follow-up of patients who have recovered from myocardial infarction. METHODS AND RESULTS: We prospectively enrolled 1045 patients 2 months after an index myocardial infarction. Baseline thrombogenic blood tests included 6 hemostatic variables (D-dimer, fibrinogen, factor VII, factor VIIa, von Willebrand factor, and plasminogen activator inhibitor-1), 7 lipid factors [cholesterol, triglycerides, HDL cholesterol, LDL cholesterol, lipoprotein(a), apolipoprotein (apo)A-I, and apoB], and insulin. Patients were followed up for an average of 26 months, with the primary end point being coronary death or nonfatal myocardial infarction, whichever occurred first. The hemostatic, lipid, and insulin parameters were dichotomized into their top and the lower 3 risk quartiles and evaluated for entry into a Cox survivorship model. High levels of D-dimer (hazard ratio, 2.43; 95% CI, 1.49, 3.97) and apoB (hazard ratio, 1.82; 95% CI, 1.10, 3.00) and low levels of apoA-I (hazard ratio, 1.84; 95% CI, 1.10, 3.08) were independently associated with recurrent coronary events in the Cox model after adjustment for 6 relevant clinical covariates. CONCLUSIONS: Our findings indicate that a procoagulant state, as reflected in elevated levels of D-dimer, and disordered lipid transport, as indicated by low apoA-1 and high apoB levels, contribute independently to recurrent coronary events in postinfarction patients.

Adult↗

PubMed1999

Survival of Escherichia coli O157 in a soil protozoan: implications for disease.

Intra-protozoal growth of bacterial pathogens has been associated with increased environmental survival, virulence and resistance to biocides and antibiotics. Using laboratory microcosms we have shown that Escherichia coli O157 survives and replicates in a common environmental protozoan, Acanthamoeba polyphaga. As protozoa are widely distributed in soils and effluents, they may constitute an important environmental reservoir for transmission of E. coli O157 and other pathogens.

Acanthamoeba↗

PubMed1999

Different contributions of the hippocampus and perirhinal cortex to recognition memory.

Brain regions involved in visual recognition memory, including the hippocampus, have been investigated by measuring differential neuronal activation produced by novel and familiar pictures. Novel and familiar pictures were presented simultaneously, one to each eye, using a paired viewing procedure. Differential neuronal activation was determined using immunohistochemistry for the protein products of c-fos as an imaging technique. The results establish that the regions of the rat brain associated with discriminating the novelty or familiarity of an individual item (such as a single object) differ from those responding to a spatial array of items (such as a scene). Perirhinal cortex and area TE of the temporal lobe are activated significantly more by pictures of novel than of familiar individual objects, but the hippocampus is not differentially activated. In contrast, pictures of novel arrangements of familiar items produce significantly greater activation than familiar arrangements of these items in postrhinal cortex and subfield CA1 of the hippocampus but significantly less activation in the dentate gyrus and subiculum; perirhinal cortex and area TE are not differentially activated. Thus, the hippocampus is importantly involved in processing information essential to recognition memory concerning the relative familiarity of arrangements of items, as needed for episodic memory of scenes, whereas the perirhinal cortex processes such information for individual items.

Animals↗