Showing papers by "Carol A. Barnes published in 1997"

Homer: a protein that selectively binds metabotropic glutamate receptors.

Abstract: 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.

Experience-dependent, asymmetric expansion of hippocampal place fields

Abstract: 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.

Multistability of cognitive maps in the hippocampus of old rats

Abstract: 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.

Memory reprocessing in corticocortical and hippocampocortical neuronal ensembles

Abstract: 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.

The Effect of Aging on Experience-Dependent Plasticity of Hippocampal Place Cells

Abstract: 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.

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

Abstract: 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

Selective Alteration of Long-Term Potentiation-Induced Transcriptional Response in Hippocampus of Aged, Memory- Impaired Rats

Abstract: 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.

Hippocampal glycogen metabolism, EEG, and behavior.

Abstract: 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.