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Biomedical subjects

C A Barnes

Publications and source records attributed to C A Barnes.

At least 19 recordsLinked to original sources
PubMed1998

Dynamic regulation of RGS2 suggests a novel mechanism in G-protein signaling and neuronal plasticity.

Long-term neuronal plasticity is known to be dependent on rapid de novo synthesis of mRNA and protein, and recent studies provide insight into the molecules involved in this response. Here, we demonstrate that mRNA encoding a member of the regulator of G-protein signaling (RGS) family, RGS2, is rapidly induced in neurons of the hippocampus, cortex, and striatum in response to stimuli that evoke plasticity. Although several members of the RGS family are expressed in brain with discrete neuronal localizations, RGS2 appears unique in that its expression is dynamically responsive to neuronal activity. In biochemical assays, RGS2 stimulates the GTPase activity of the alpha subunit of Gq and Gi1. The effect on Gi1 was observed only after reconstitution of the protein in phospholipid vesicles containing M2 muscarinic acetylcholine receptors. RGS2 also inhibits both Gq- and Gi-dependent responses in transfected cells. These studies suggest a novel mechanism linking neuronal activity and signal transduction.

Animals↗
PubMed1998

Upf1 and Upf2 proteins mediate normal yeast mRNA degradation when translation initiation is limited.

mRNA degradation is coupled with the process of mRNA translation. For example, an mRNA molecule, on which translation is prematurely terminated because of a nonsense codon, may be rapidly degraded. This nonsense-mediated mRNA decay in the yeast Saccharomyces cerevisiae is mediated by the Upf1 and Upf2 proteins. Yeast mRNAs can also be selectively destabilized by limiting the rate of translation initiation. Two such destabilized mRNAs, from the SSA1 and SSA2 genes, have been identified using temperature-sensitive mutations affecting the Prt1 component of eukaryotic initiation factor 3. For SSA1 and SSA2 mRNAs, and for structurally modified SSA mRNA derivatives, I show here that degradation is triggered when translation initiation is limited but ongoing. This initiation-dependent mRNA degradation is limited to a subset of mRNAs that includes at least those from the SSA1 and SSA2 genes, and occurs through Upf1- and Upf2-mediated processes, although sequence elements characteristic of nonsense-mediated decay are not evident in these mRNAs.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Reactivation of neuronal ensembles in hippocampal dentate gyrus during sleep after spatial experience.

Patterns of neuronal activity recorded in CA1 of the hippocampus and in neocortex during waking-behavior, are reactivated during subsequent slow-wave sleep (SWS). It has been suggested that this reactivation may originate in the hippocampal CA3 region, where modifiable excitatory recurrent connections are abundant and where sharp-waves in which the reactivation is most robust, appear to arise. The present experiment investigated whether ensemble firing patterns of granule cells in the fascia dentata (FD), an area 'upstream' from CA3, are also reactivated during sleep. Populations of FD granule cells were recorded from during spatial behavior and during prior and subsequent SWS. firing rate correlations between cell-pairs with overlapping place fields were significantly enhanced during post behavioral sleep compared to pre behavioral sleep. Correlations between cells with non-overlapping place fields or which were silent during maze behavior, were not changed. Thus reactivation of experience-specific correlation states also occurs in granule cells during sleep. Because these cells do not have excitatory interconnections, but form a major input to CA3 pyramidal cells, current models predicted that sleep reactivation would appear first in CA3. There are, however, both extensive polysynaptic excitatory interactions among granule cells and feedback from CA3 pyramidal cells. Granule cells also receive indirect input from neocortical regions known to undergo trace reactivation. Although a simple model for a CA3 origin of the reactivation phenomenon cannot be confirmed, the present results extend our understanding of the generality of this phenomenon.

Animals↗
PubMed1997

Memory reprocessing in corticocortical and hippocampocortical neuronal ensembles.

Hippocampal cells that fire together during behaviour exhibit enhanced activity correlations during subsequent sleep, with some preservation of temporal order information. Thus, information reflecting experiences during behaviour is re-expressed in hippocampal circuits during subsequent 'offline' periods, as postulated by some theories of memory consolidation. If the hippocampus orchestrates the reinstatement of experience-specific activity patterns in the neocortex, as also postulated by such theories, then correlation patterns both within the neocortex and between hippocampus and neocortex should also re-emerge during sleep. Ensemble recordings were made in the posterior parietal neocortex, in CA1, and simultaneously in both areas, in seven rats. Each session involved an initial sleep episode (S1), behaviour on a simple maze (M), and subsequent sleep (S2). The ensemble activity-correlation structure within and between areas during S2 resembled that of M more closely than did the correlation pattern of S1. Temporal order (i.e. the asymmetry of the cross-correlogram) was also preserved within, but not between, structures. Thus, traces of recent experience are re-expressed in both hippocampal and neocortical circuits during sleep, and the representations in the two areas tend to correspond to the same experience. The poorer preservation of temporal firing biases between neurons in the different regions may reflect the less direct synaptic coupling between regions than within them. Alternatively, it could result from a shift, between behavioural states, in the relative dominance relations in the corticohippocampal dialogue. Between-structure order will be disrupted, for example, if, during behaviour, neocortical patterns tend to drive corresponding hippocampal patterns, whereas during sleep the reverse occurs. This possibility remains to be investigated.

Animals↗
PubMed1997

The effect of aging on experience-dependent plasticity of hippocampal place cells.

The firing characteristics of 1437 CA1 pyramidal neurons were studied in relation to both spatial location and the phase of the theta rhythm in healthy young and old rats performing a simple spatial task on a rectangular track. The old rats had previously been found to be deficient on the Morris spatial learning task. Age effects on the theta rhythm per se were minimal. Theta amplitude and frequency during rapid eye movement sleep were virtually identical. During behavior, theta frequency was slightly reduced with age. In both groups, cell firing occurred at progressively earlier phases of the theta rhythm as the rat traversed the place field of the cell (i. e., there was "phase precession," as reported by others). The net phase shift did not differ between age groups. The main finding of the study was a loss of experience-dependent plasticity in the place fields of old rats. During the first lap around the track on each day, the initial sizes of the place fields were the same between ages; however, place fields of young rats, but not old, expanded significantly during the first few laps around the track in a given recording session. As the place fields expanded, the rate of change of firing with phase slowed accordingly, so that the net phase change remained constant. Thus changes in field size and phase precession are coupled. A deficit in plasticity of place fields in old rats may lead to a less accurate population code for spatial location.

Action Potentials↗
PubMed1997

Experience-dependent, asymmetric expansion of hippocampal place fields.

Theories of sequence learning based on temporally asymmetric, Hebbian long-term potentiation predict that during route learning the spatial firing distributions of hippocampal neurons should enlarge in a direction opposite to the animal's movement. On a route AB, increased synaptic drive from cells representing A would cause cells representing B to fire earlier and more robustly. These effects appeared within a few laps in rats running on closed tracks. This provides indirect evidence for Hebbian synaptic plasticity and a functional explanation for why place cells become directionally selective during route following, namely, to preserve the synaptic asymmetry necessary to encode the sequence direction.

Animals↗
PubMed1997

Multistability of cognitive maps in the hippocampus of old rats.

Hippocampal neurons provide a population code for location. In young rats, environments are reliably 'mapped' by groups of neurons that have firing locations ('place fields') that can be stable for several months. Old animals exhibit deficits in spatial memory, raising the question of whether the quality or stability of their hippocampal 'cognitive maps' is altered. By recording from large groups of neurons, we observed the hippocampal spatial code to be multistable. In young rats, the place field maps were reliable both within and between episodes in a familiar environment. In old rats, place field maps were accurate and stable during an episode, but frequently exhibited complete rearrangements between episodes. In a spatial memory task, both young and old rats exhibited bimodal performance, consistent with map multistability early in training. However, the performance of young rats became almost unimodal with further training, whereas that of old rats remained markedly bimodal. The multistability of the hippocampal map provides an insight into the dynamics of neural coding in high-level cortical structures and their changes during ageing, and may provide an explanation for the frequent failure of place recognition in elderly humans.

Aging↗
PubMed1997

Selective alteration of long-term potentiation-induced transcriptional response in hippocampus of aged, memory-impaired rats.

Normal human aging is associated with selective changes in cognition that are attributable, in part, to dysfunction of hippocampal pathways. Rodents also exhibit age-dependent hippocampal dysfunction that results in spatial memory deficits and a correlated reduction in the maintenance of long-term potentiation (LTP). Although suprathreshold stimulus protocols result in normal LTP induction in aged rats, the ability to sustain this increase in synaptic efficacy is reduced in the old animals. The maintenance phase of LTP is known to be dependent on rapid, transcriptional events, and recent studies have identified signal transduction mechanisms that link glutamate-induced responses at the synapse with transcriptional responses at the nucleus. To examine the integrity of these signaling pathways in aged hippocampus, we monitored the induction of a panel of immediate early genes (IEGs) that are known to be transcriptionally activated after LTP-inducing stimuli, using a "reverse Northern" strategy. Here we report that a broad representation of IEGs are similarly induced in awake, behaving young adult and aged, memory-impaired rats. This indicates a general preservation of these presumptive signaling pathways during the aging process. Induced levels of c-fos mRNA, however, are significantly higher in the aged animals. These observations suggest that age-dependent hippocampal dysfunction may be associated with a selective change in the dynamic activity of signaling pathways upstream of c-fos, possibly involving calcium regulation.

Aging↗
PubMed1997

Homer: a protein that selectively binds metabotropic glutamate receptors.

Spatial localization and clustering of membrane proteins is critical to neuronal development and synaptic plasticity. Recent studies have identified a family of proteins, the PDZ proteins, that contain modular PDZ domains and interact with synaptic ionotropic glutamate receptors and ion channels. PDZ proteins are thought to have a role in defining the cellular distribution of the proteins that interact with them. Here we report a novel dendritic protein, Homer, that contains a single, PDZ-like domain and binds specifically to the carboxy terminus of phosphoinositide-linked metabotropic glutamate receptors. Homer is highly divergent from known PDZ proteins and seems to represent a novel family. The Homer gene is also distinct from members of the PDZ family in that its expression is regulated as an immediate early gene and is dynamically responsive to physiological synaptic activity, particularly during cortical development. This dynamic transcriptional control suggests that Homer mediates a novel cellular mechanism that regulates metabotropic glutamate signalling.

Animals↗
PubMed1997

Role of temporal summation in age-related long-term potentiation-induction deficits.

Hippocampal long-term potentiation (LTP) is reduced in aged relative to young F-344 rats when peri-threshold stimulation protocols (several stimulus pulses at 100-200 Hz) are used. The present study was designed to examine the possibility that this LTP-induction deficit is caused by a reduced overlap of Schaffer-collateral inputs onto CA1 pyramidal cells (input cooperativity). This reduced input cooperativity would decrease the levels of postsynaptic depolarization during LTP induction, which might account for the age-related LTP deficit. Both behavioral data (Morris Water Maze) and electrophysiological data (intracellular recordings from hippocampal slices) were collected from adult and aged F-344 rats. To counter the effects of reduced input cooperativity, stimulus intensities were adjusted to elicit baseline excitatory postsynaptic potentials (EPSPs) of equivalent amplitude in aged and young rats. Contrary to expectations, however, an age-related LTP-induction deficit was still observed. Further evaluation of the electrophysiological data revealed that temporal summation of multiple EPSPs during high-frequency stimulation was impaired in the aged rats. Thus, despite the equalization across age groups of the baseline EPSP amplitudes, the cells of aged rats were less depolarized during the LTP-inducing stimulation than were those of young rats. This reduced total depolarization was not an artifact of the higher stimulus intensity used on aged animals, nor was it caused by a failure of aged rats' CA1 afferents to follow high-frequency stimulation. The present data therefore suggest that there is a deficit in the ability of aged rats' synapses to provide the sustained depolarization necessary to active the LTP-induction cascade.

Aging↗
PubMed1997

Hippocampal glycogen metabolism, EEG, and behavior.

Glycogen phosphorylase a (GPa) is correlated with metabolic activation, suggesting its potential use as a marker for neuronal activity. In dentate gyrus, GPa patches are induced by glutamate infusion. Hippocampal electroencephalogram (EEG) and neuronal firing rates are modulated by behavioral state, and cell discharge is suppressed by restraint. In rats, under conditions of free exploration, passive movement under loose or secure restraint, quiet wakefulness, and anesthesia, GPa activity and 6-10-Hz theta power were inversely related: The more active the animal, the stronger the theta rhythm and the lower the GPa activity. Thus, GPa was least under conditions in which the hippocampus processes external information, and at intermediate levels during restraint, when neuronal firing is lowest. This dissociation raises doubts about the use of metabolic activity as an indicator of changes in neuronal activity or of information processing per se.

Animals↗
PubMed1997

Distribution of HLA-A, B and DR genes and haplotypes in the Irish population.

The distribution of HLA phenotypes, genes and haplotypes in the normal population is of considerable importance in, for example, disease susceptibility studies, platelet transfusion support and transplantation. HLA population genetics studies have been carried out on numerous population samples, however, no major studies have been performed on Irish Caucasoids. We have analysed the HLA-A, B and DR phenotypes of 1,910 healthy unrelated Irish blood donors recruited onto the Irish Bone Marrow Donor Panel. HLA typing was performed by a combination of serology, the polymerase chain reaction with sequence-specific primers and reverse hybridisation. We calculated Hardy-Weinberg fit, phenotype and gene frequencies and two- and three-locus haplotype frequencies, linkage disequilibrium (LD) values and their significance levels and relative LD values. Compared to many other European populations, the Irish show a high frequency of HLA-A1, B7, B8 and DR2 and a reduced frequency of HLA-A9, A30, B15 and DR4. Two- and three-locus haplotypes and the combinations of alleles in positive LD were all typical of northern European populations. However, the Irish have especially high frequencies of the common HLA-A1/B8, A2/B44, A3/B7, HLA-B8/DR3, B7/DR2, B44/DR4 and B44/DR7 haplotypes, while the frequency of other relatively common haplotypes, e.g. HLA-A2/B15, is reduced. These frequencies are of particular value for estimating the likelihood of finding bone marrow donors in patients' extended families and unrelated donor panels.

Adolescent↗
PubMed1996

Theta phase precession in hippocampal neuronal populations and the compression of temporal sequences.

O'Keefe and Recce [1993] Hippocampus 3:317-330 described an interaction between the hippocampal theta rhythm and the spatial firing of pyramidal cells in the CA1 region of the rat hippocampus: they found that a cell's spike activity advances to earlier phases of the theta cycle as the rat passes through the cell's place field. The present study makes use of large-scale parallel recordings to clarify and extend this finding in several ways: 1) Most CA1 pyramidal cells show maximal activity at the same phase of the theta cycle. Although individual units exhibit deeper modulation, the depth of modulation of CA1 population activity is about 50%. The peak firing of inhibitory interneurons in CA1 occurs about 60 degrees in advance of the peak firing of pyramidal cells, but different interneurons vary widely in their peak phases. 2) The first spikes, as the rat enters a pyramidal cell's place field, come 90 degrees-120 degrees after the phase of maximal pyramidal cell population activity, near the phase where inhibition is least. 3) The phase advance is typically an accelerating, rather than linear, function of position within the place field. 4) These phenomena occur both on linear tracks and in two-dimensional environments where locomotion is not constrained to specific paths. 5) In two-dimensional environments, place-related firing is more spatially specific during the early part of the theta cycle than during the late part. This is also true, to a lesser extent, on a linear track. Thus, spatial selectivity waxes and wanes over the theta cycle. 6) Granule cells of the fascia dentata are also modulated by theta. The depth of modulation for the granule cell population approaches 100%, and the peak activity of the granule cell population comes about 90 degrees earlier in the theta cycle than the peak firing of CA1 pyramidal cells. 7) Granule cells, like pyramidal cells, show robust phase precession. 8) Cross-correlation analysis shows that portions of the temporal sequence of CA1 pyramidal cell place fields are replicated repeatedly within individual theta cycles, in highly compressed form. The compression ratio can be as much as 10:1. These findings indicate that phase precession is a very robust effect, distributed across the entire hippocampal population, and that it is likely to be inherited from the fascia dentata or an earlier stage in the hippocampal circuit, rather than generated intrinsically within CA1. It is hypothesized that the compression of temporal sequences of place fields within individual theta cycles permits the use of long-term potentiation for learning of sequential structure, thereby giving a temporal dimension to hippocampal memory traces.

Animals↗
PubMed1996

How much of the hippocampus can be explained by functional constraints?

In the spirit of Marr, we discuss an information-theoretic approach that derives, from the role of the hippocampus in memory, constraints on its anatomical and physiological structure. The observed structure is consistent with such constraints, and, further, we relate the quantitative arguments developed in earlier analytical studies to experimental measures extracted from neuronal recordings in the behaving rat.

Animals↗
PubMed1996

Contribution of single-unit spike waveform changes to temperature-induced alterations in hippocampal population spikes.

Brain temperature changes accompany exploratory behavior and profoundly affect field potential amplitudes recorded in hippocampus. The waveform alterations in fascia dentata include a reduction in population spike area, which might be explained by fewer granule cells firing in response to a given stimulus or by an alteration in the size or shape of the individual action potentials. This study was designed to assess these alternate possibilities. In experiment 1, changes in the shape and firing rates of single cells recorded in the fascia dentata of awake rats were compared with changes in the population spike before and after a bout of activity. Single-unit amplitudes were significantly reduced following exploration, and there was a small (< 3%) change in unit spike-width. These changes, however, were insufficient to account, in a linear fashion, for the entire decline in the population spike. In experiment 2, radiant heat was used to manipulate brain temperature in anesthetized rats. As in the first experiment, the magnitude of change in the extracellular units was much smaller than the change in population spike amplitude. The spontaneous firing rates of the cells were also modified by brain temperature changes. In experiment 3, the polysynaptic, contralateral commissural response (which covaries with changes in the ipsilateral population spike at a fixed temperature) was measured as a function of either exploratory behavior or radiant heat. The relationship between the ipsilateral population spike and corresponding polysynaptic commissural response was altered following exploration and passive warming in a manner consistent with a reduction in net granule cell output, reduced transmission efficacy through the polysynaptic circuit, or a combination of these. Taken together these data suggest that at least two factors contribute to temperature-dependent changes in the perforant path-evoked population spikes recorded in the fascia dentata: changes in the size of individual action potentials and alterations in discharge of action potentials in response to a given stimulus.

Action Potentials↗
PubMed1996

Differential effects of selective immunotoxic lesions of medial septal cholinergic cells on spatial working and reference memory.

The effect of injection into the medial septum of a toxin selective for cholinergic neurons, 192 IgG-saporin, was examined in rats trained to perform 2 versions of the radial 8-arm maze task. Rats were first trained to perform a task with varying delays (0, 1, 2 min) imposed between the 4th correct arm choice and access to all 8 arms. Lesioned rats made significantly more errors in the first 4 choices compared with controls and significantly more errors after delays; however, this effect was not delay dependent. Rats were then trained on a different version of this 8-arm maze task in which they learned to avoid 2 arms that were never baited. There was no treatment effect on acquisition of this task. These data are consistent with the hypothesis that the cholinergic projection to the hippocampus facilitates the acquisition of information into the system responsible for short-term memory for locations visited (spatial working memory) but is not involved in retention of this information. It also appears to play no role in either the acquisition or retention of place-nonreward associations (spatial reference memory).

Animals↗