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Biomedical subjects

E I Moser

Publications and source records attributed to E I Moser.

14 recordsLinked to original sources
PubMed1999

Is learning blocked by saturation of synaptic weights in the hippocampus?

Long-term potentiation (LTP) has become a leading candidate mechanism for memory formation. The proposed link between LTP and memory rests primarily on a single type of behavioural evidence: disruption of learning by interventions that block critical steps in the induction of LTP. As such blockade may disrupt non-mnemonic functions also, the LTP-learning question should be approached with multiple strategies. One alternative approach is to determine whether hippocampus-dependent learning is blocked by saturation of hippocampal LTP before training. Early investigations found that spatial learning was impaired after cumulative LTP in dentate perforant-path synapses. Several groups failed to replicate these findings, but it is now clear that hippocampus-dependent spatial learning is disrupted only if LTP is saturated throughout the terminal field of the tetanized pathway. Moreover, to prevent compensatory modifications in the hippocampal network, a massed tetanization and training protocol may be required. The blockade of learning by repetition of the very same stimulus that induces LTP suggests that LTP-like modifications are necessary for memory encoding in the hippocampus.

Animals↗
PubMed1998

Impaired spatial learning after saturation of long-term potentiation.

If information is stored as activity-driven increases in synaptic weights in the hippocampal formation, saturation of hippocampal long-term potentiation (LTP) should impair learning. Here, rats in which one hippocampus had been lesioned were implanted with a multielectrode stimulating array across and into the angular bundle afferent to the other hippocampus. Repeated cross-bundle tetanization caused cumulative potentiation. Residual synaptic plasticity was assessed by tetanizing a naïve test electrode in the center of the bundle. Spatial learning was disrupted in animals with no residual LTP (<10 percent) but not in animals that were capable of further potentiation. Thus, saturation of hippocampal LTP impairs spatial learning.

Animals↗
PubMed1998

Distributed encoding and retrieval of spatial memory in the hippocampus.

To determine whether memory is processed in a localized or distributed manner by the hippocampus, we inactivated small regions of the structure in pretrained rats before a retention test. Ibotenic acid-induced lesions removing 40% of the hippocampal tissue disrupted retrieval of spatial memory in a water maze but failed to affect new learning or retrieval of a task that was acquired postoperatively. Partial inactivation of the hippocampus by local intrahippocampal 5-aminomethyl-3-hydroxyisoxazole muscimol infusion also impaired retrieval but not new learning. This impairment was temporary; infusions had no effect on retrieval of predrug performance when the test was conducted 48 hr after the infusion. Systematic variation of the volume of dorsal and ventral hippocampal lesions showed that successful retrieval required the integrity of the entire dorsal 70% of the hippocampus. Our data suggest that although spatial tasks can be acquired with local ensembles of hippocampal neurons when other parts of the hippocampus are inactivated, spatial memory is normally both encoded and retrieved by a widely distributed hippocampal network.

Animals↗
PubMed1998

Functional differentiation in the hippocampus.

The hippocampus is critically involved in certain kinds of memory. During memory formation, it may operate as an integrated unit, or isolated parts may be responsible for different functions. Recent evidence suggests that the hippocampus is functionally differentiated along its dorsoventral (septotemporal) axis. The cortical and subcortical connections of the dorsal and ventral hippocampus are different, with information derived from the sensory cortices entering mainly in the dorsal two-thirds or three-quarters of the dentate gyrus. Rats can acquire a spatial navigation task if small tissue blocks are spared within this region, but equally large blocks at the ventral end are not capable of supporting spatial learning. In primates, the posterior hippocampus (corresponding to the dorsal hippocampus of rodents) appears to be more important than anterior areas for encoding of spatial memory and certain forms of nonspatial memory. The ventral (or anterior) hippocampal formation is to some extent disconnected from the rest of the structure both in terms of intrahippocampal and extrahippocampal connections and may be performing functions that are qualitatively different from, and independent of, those of the dorsal hippocampal formation.

Animals↗
PubMed1998

A model of hippocampal memory encoding and retrieval: GABAergic control of synaptic plasticity.

The current view of the role of GABAergic interneurones in cortical-network function has shifted from one of merely dampening neuronal activity to that of an active role in information processing. In this review, we explore a potential role of hippocampal GABAergic interneurones in providing spatial and temporal conditions for modifications of synaptic weights during hippocampus-dependent memory processes. We argue that knowledge of spatiotemporal activity patterns in distinct classes of interneurone is essential to understanding the cellular mechanisms underlying learning and memory.

Electroencephalography↗
PubMed1996

Relationship between neuronal activity and brain temperature in rats.

Warming of a brain area in a behaving rat may reflect a local increase in neuronal activity, or the heat may be supplied from peripheral organs (muscles) via the arterial blood. To investigate the role of neuronal activity, brain temperature was measured in the hippocampus of anaesthetized rats in response to intense and prolonged stimulation of the perforant path. Repetitive discharge induced by such stimulation failed to raise dorsal hippocampal temperature by more than 0.6 degree C, even if cells discharged throughout the train. The widespread neuronal activity during paradoxical sleep was equally ineffective (increases < 0.3 degree C). Thus, most of the heat producing an increase in brain temperature during behaviour probably arises from peripheral organs.

Animals↗
PubMed1996

Altered inhibition of dentate granule cells during spatial learning in an exploration task.

To investigate the extent to which inhibitory interneurons control impulse flow through the dentate gyrus during spatial learning in an exploration task, dentate field potentials were recorded in response to paired stimulation of the perforant path while rats rested or explored. Recurrent inhibition of the granule cells was measured as the reduction of the second waveform when a population spike was present in the first. Both the population spike and the field EPSP (fEPSP) were suppressed at interstimulus intervals shorter than approximately 40 msec. Consistent differences were observed between potentials recorded at equivalent brain temperature in the exploration and resting (reference) conditions. During exploration, the fEPSP of the second (test) waveform was reduced further compared with reference potentials with a similar response to the first (conditioning) stimulus. This reduction was observed only when the first pulse elicited a population spike. The population spike of the second waveform was facilitated compared with reference potentials with similar fEPSP slopes. These observations suggest that exploration is coupled to increased inhibition on the perforant-path terminals or the dendrites of the granule cells, whereas the inhibition on the somata is decreased. The two phenomena were not correlated and followed different time courses. The suppression of the fEPSP decayed gradually, although it was still present at 15 min, whereas the facilitation of the population spike was stable. Together, these changes, which likely involve different populations of interneurons, may focus and amplify incoming signals from the entorhinal cortex.

Animals↗
PubMed1995

Spatial learning with a minislab in the dorsal hippocampus.

We have determined the volume and location of hippocampal tissue required for normal acquisition of a spatial memory task. Ibotenic acid was used to make bilateral symmetric lesions of 20-100% of hippocampal volume. Even a small transverse block (minislab) of the hippocampus (down to 26% of the total) could support spatial learning in a water maze, provided it was at the septal (dorsal) pole of the hippocampus. Lesions of the septal pole, leaving 60% of the hippocampi intact, caused a learning deficit, although normal electrophysiological responses, synaptic plasticity, and preserved acetylcholinesterase staining argue for adequate function of the remaining tissue. Thus, with an otherwise normal brain, hippocampal-dependent spatial learning only requires a minislab of dorsal hippocampal tissue.

Acetylcholinesterase↗
PubMed1995

Brain temperature and hippocampal function.

Even though homeothermic animals regulate the body temperature, fluctuations up to 2-3 degrees C may occur during physiological conditions. In many species, including the rat, a similar variation can be measured in the brain temperature. Such changes are expressed throughout the brain with a preserved gradient between the warmer basal and cooler dorsal parts. In spite of these recordable physiological changes, spatial learning is quite robust, in that it occurs at brain temperatures between 30 and 39 degrees C. Even drastic cooling (to below 15 degrees C) fails to affect consolidation or storage of information when the animal is tested after rewarming. The physiological temperature fluctuations have significant consequences for electrophysiological responses in the brain. Various bioelectrical signals are more sensitive during warming, axonal conduction is speeded up, and stimulus-elicited transmitter release becomes faster and more synchronized. Action potentials have shorter rise and decay times in warm conditions, and the amplitude becomes slightly smaller. Population responses are differently affected by these changes. Dentate field potentials in response to stimulation of perforant-path fibers appear with shorter latency in warm conditions, and the rate of rise in the field EPSP is increased. Paradoxically, the amplitude of the population spike is reduced. This is due to a combination of reduced amplitude of individual action potentials and reduced efficiency of the summation of groups of action potentials. Due to the large effects of temperature on hippocampal field potentials, it is mandatory that brain temperature changes are monitored and/or controlled whenever such responses are recorded in freely moving and anesthetized animals.

Action Potentials↗
PubMed1995

Learning-related changes in hippocampal field potentials.

It is commonly believed that learning is based on modifications of synaptic strength. Much of the evidence for this comes from the observation that blockade of processes necessary for induction of long-term potentiation in the hippocampus also blocks certain forms of learning. As such correlations may have many causes, an understanding of the mechanisms for memory formation might also profit from direct recording of cellular activity in learning tasks. Field potential recording represents one such approach. Although changes in field potentials are unlikely to uncover modifications in synaptic strength related to the storage of memory, any general facilitation (or reduction) of synaptic transmission taking place in populations of neurons during the acquisition stage might be picked up by a field measure. One problem related to the approach is that field potentials are heavily affected by non-learning factors. It is shown that field potentials in the hippocampus are highly sensitive to changes in brain temperature and that a significant part of the increase in field excitatory postsynaptic potentials (f-EPSPs) during learning reflects warming of the brain. Temperature-related changes in synaptic transmission do not affect the efficiency of spatial learning, as the acquisition of a water-maze task is equally efficient at low (30-32 degrees C) and high (37-39 degrees C) brain temperatures. Subtraction of the temperature component of the field potential alterations during learning in an exploration task shows that exploration is accompanied by a temperature-independent synaptic potentiation as well. Both the f-EPSP and the population spike are increased, and both decay gradually within 15-20 min. It is important to find out whether this potentiation reflects learning-related processes and whether such a potentiation is useful to the brain given the apparent 'noise' caused by temperature-related physiological changes.

Animals↗
PubMed1994

Conserved spatial learning in cooled rats in spite of slowing of dentate field potentials.

Behaviorally induced brain temperature changes have significant effects on field potentials recorded in the hippocampal formation. All components of the field potential are slowed during cooling. Field excitatory postsynaptic potentials (f-EPSPs) are often reduced, while the population spike is increased in this state. To investigate whether such synaptic alterations affect hippocampus-dependent learning, we have compared the effects of reduced brain temperature on dentate field potentials and spatial learning in a Morris water maze. Rats were implanted with thermistors in the brain. A subset of the rats received electrodes for field potential recording in the perforant path-granule cell synapses of the dentate gyrus. After recovery, the rats were cooled by swimming in a pool of water. This invariably led to a brain temperature reduction of several degrees centigrade and a delay of the extracellular response. In addition, the field potential changed as described above. The effect of these changes on spatial learning in a second pool, the water maze, was determined by first cooling and then reheating each rat to a given level of brain temperature prior to each spatial training session. In spite of marked changes in dentate field potentials, all rats trained at brain temperatures above 30 degrees C learned to find the submerged platform similarly well. The speed of acquisition and the final precision of search behavior were also similar in these rats. Only rats that had been cooled below 30 degrees C failed to locate the hidden target. These animals also showed clear evidence of motor impairment.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed1990

The spontaneously hypertensive rat as an animal model of attention-deficit hyperactivity disorder: effects of methylphenidate on exploratory behavior.

Spontaneously hypertensive rats (SHR) show a pervasive hyperactivity in several paradigms. Thus, these rats may be used as an animal model of childhood hyperactivity also called Attention-Deficit Hyperactivity Disorder. This disorder is frequently treated with psychomotor stimulant drugs, but little is known about the effects of such drugs on behavior. The present study investigated the behavioral effects of 1-24 mg/kg methylphenidate (Ritalin) on the exploratory behavior of male SHR and Wistar-Kyoto control rats (WKY) in a two-compartment free-exploration open field. Except following very high doses. SHR spent most of the session time in the field while WKY stayed in the home cage. Low and medium doses were followed by increased activity in the field for SHR and increased activity in the cage for WKY. The response-stimulatory effects of low to medium doses of methylphenidate are less in SHR than in WKY. Starting at medium doses, activity decreased and stereotyped behavior increased progressively by increasing dose. Locomotor activity in the field decreased following lower doses than locomotor activity in the cage, and vertical activity (rearing) was reduced by lower doses than horizontal activity (crossing). The following conclusions were drawn. (i) There is no "paradoxical" inhibition of SHR hyperactivity following methylphenidate. On the contrary, SHR activity is in fact stimulated, albeit to a lesser degree than that of WKY. (ii) The stimulatory effects of low to medium doses are, in general, most pronounced for the kind of exploratory behavior most frequently used by the rat during baseline conditions. (iii) Rearing might be more susceptible to adverse effects of methylphenidate than ambulation.

Animals↗
PubMedDate not supplied

Potentiation of dentate synapses initiated by exploratory learning in rats: dissociation from brain temperature, motor activity, and arousal.

Certain kinds of learning may be related to potentiation of transmission at specific hippocampal synapses. We investigated whether transmission across the perforant-path/granule-cell synapses of the dentate gyrus is facilitated when rats are learning about novel objects in an open field during exploration. Such studies are complicated by the sensitivity of hippocampal field potentials to brain temperature change. To control for this, we have recorded both brain temperature and field potentials and compared potentials sampled during exploration with potentials taken at corresponding brain temperature in a passive warming situation, with the animals at rest. Relative to these reference potentials, both the f-EPSP slope and the population spike were elevated while the rats explored. The potentiation reached its maximum within < 5 sec after the exploration began. During the first 2 min, the f-EPSP slope was enhanced by 6.5% relative to the control values. The potentiation then decayed, reaching the reference values after 20-30 min of exploration. Significant potentiation required exploration above a certain minimum intensity. Control experiments showed that the changes were neither mimicked by arousal in response to aversive stimuli nor by motor activity. It is suggested that the facilitated transmission across the perforant-path/dentate synapses may be involved in learning during exploration.

Animals↗