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Biomedical subjects

M B Moser

Publications and source records attributed to M B Moser.

At least 19 recordsLinked to original sources
PubMed2001

Impaired recognition of the goal location during spatial navigation in rats with hippocampal lesions.

Converging evidence suggests that the hippocampus is essential for goal-directed spatial navigation. Successful navigation requires not only the ability to compute an appropriate path toward the target but is also guided by recognition of places along the trajectory between start and goal. To determine whether the hippocampus contributes to place recognition, we trained rats with hippocampal lesions in an annular water maze with a remotely controlled escape platform at a constant location in the corridor. The platform remained submerged and unavailable until the rat had swum at least one full lap. Probe trials with the platform unavailable for 60 sec were inserted at regular intervals. In these trials, the rat would swim over the platform several times, regardless of its navigational abilities. After a few training sessions, all sham-operated control animals reduced their swim velocity when they approached the platform, indicating that they recognized the target location. Rats with hippocampal lesions, in contrast, swam at the same velocity as elsewhere in the corridor. Preoperative training or prolonged postoperative training did not alleviate the deficit. Rats with hippocampal lesions were able to learn a cued version of the task, which implies that the failure to slow down was not attributable to motor inflexibility. Thus, hippocampal lesions caused a severe but selective deficit in the identification of a location, suggesting that the hippocampus may be essential for image recognition during spatial navigation.

Analysis of Variance↗
PubMed2001

Accumulation of hippocampal place fields at the goal location in an annular watermaze task.

To explore the plastic representation of information in spatially selective hippocampal pyramidal neurons, we made multiple single-unit recordings in rats trained to find a hidden platform at a constant location in a hippocampal-dependent annular watermaze task. Hippocampal pyramidal cells exhibited place-related firing in the watermaze. Place fields tended to accumulate near the platform, even in probe trials without immediate escape. The percentage of cells with peak activity around the hidden platform was more than twice the percentage firing in equally large areas elsewhere in the arena. The effect was independent of the actual position of the platform in the room frame. It was dissociable from ongoing motor behavior and was not related to linear or angular speed, swim direction, or variation in hippocampal theta activity. There was no accumulation of firing in any particular region in rats that were trained with a variable platform location. These training-dependent effects suggest that regions of particular behavioral significance may be over-represented in the hippocampal spatial map, even when these regions are completely unmarked.

Action Potentials↗
PubMed2001

Retrograde amnesia for spatial memory induced by NMDA receptor-mediated long-term potentiation.

If information is stored as distributed patterns of synaptic weights in the hippocampal formation, retention should be vulnerable to electrically induced long-term potentiation (LTP) of hippocampal synapses after learning. This prediction was tested by training animals in a spatial water maze task and then delivering bursts of high-frequency (HF) or control stimulation to the perforant path in the angular bundle. High-frequency stimulation induced LTP in the dentate gyrus and probably also at other hippocampal termination sites. Retention in a later probe test was disrupted. When the competitive NMDA receptor antagonist 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) was administered before the high-frequency stimulation, water maze retention was unimpaired. CPP administration blocked the induction of LTP. Thus, high-frequency stimulation of hippocampal afferents disrupts memory retention only when it induces a change in the spatial pattern of synaptic weights. The NMDA receptor dependency of this retrograde amnesia is consistent with the synaptic plasticity and memory hypothesis.

Afferent Pathways↗
PubMed2001

Place fields of rat hippocampal pyramidal cells and spatial learning in the watermaze.

To provide a background for studying place-related activity in hippocampal neurons during spatial learning, we compared the activity of hippocampal place cells in an annular watermaze and an analogous land-based task. Complex-spike cells had robust place correlates in both conditions, and a significant proportion of the cells had place fields at the same locations. However, the in-field firing rates were slightly higher in the wet condition. Elevated firing was observed also in an open water task. There was no enhancement when the platform location was varied randomly or when there was no platform at all. Second, the place fields were under stronger directional modulation during swimming. In the annular task, directional sensitivity appeared regardless of whether the animals were trained to find a platform or not. There were directionally modulated units also in the open watermaze, but the number was smaller than in the corridor. Altogether, these observations suggest that place fields in the watermaze are largely controlled by the same factors as on dry land, in spite of the differences in kinaesthetic and vestibular input. Differences in firing rate and directional control may depend on the geometric and cognitive structure of the task rather than the medium on which the rats are moving.

Animals↗
PubMed1999

Pretraining prevents spatial learning impairment after saturation of hippocampal long-term potentiation.

Spatial learning is impaired by NMDA receptor antagonists at doses that block hippocampal long-term potentiation (LTP). The deficit is not observed in animals that have received spatial or nonspatial pretraining in a different water maze. To determine whether this conditional impairment reflects debilitating sensorimotor effects of NMDA receptor antagonists in na¿ve animals, we compared spatial learning in na¿ve and pretrained animals in which induction of LTP was blocked by a saturation procedure with no obvious effects on sensorimotor functions. Rats with unilateral hippocampal lesions were implanted with multiple bipolar stimulation electrodes in the angular bundle and a recording electrode in the dentate gyrus of the intact hemisphere. Half of the rats were pretrained to find a hidden platform in a water maze. A week later, pretrained and na¿ve rats received either high-frequency (HF) or low-frequency (LF) stimulation at 2 hr intervals, until no further LTP could be induced. The stimulation did not interefere with performance on a balance task or a visual platform task. After stimulation, all rats were trained in a second water maze. Whereas na¿ve HF animals were impaired, pretrained HF animals acquired the new task rapidly and searched as extensively around the platform as LF control animals. These results suggest that pretraining prevents disruption of spatial learning after saturation of LTP in the absence of sensorimotor impairment, that hippocampal LTP might not be crucial for spatial representation per se, and that LTP may be involved only when spatial and contextual or procedural learning take place simultaneously.

Animals↗
PubMed1999

Making more synapses: a way to store information?

Although information may be stored in the brain is changes in the strength of existing synapses, formation of new synapses has long been thought of as an additional substrate for memory storage. The identification of subcellular structural changes following learning in mammals poses a serious 'needle-in-the-haystack' problem. In most attempts to demonstrate structural plasticity during learning, animals have been exposed for prolonged periods to complex environments, where they are confronted with a variety of sensory, motor- and spatial challenges throughout the exposure period. These environments are thought to promote several forms of learning. Repeated exposure to such environments has been shown to increase the density of spines and dendritic complexity in relevant brain structures. The number of neurons has also been reported to increase in some areas. It is not clear, however, whether the new synapses emerging from these forms of plasticity mediate specific information storage, or whether they reflect a more general sophistication of the excited parts of the network.

Animals↗
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↗
PubMed1997

Spatial training in a complex environment and isolation alter the spine distribution differently in rat CA1 pyramidal cells.

The hippocampus is critically involved in spatial learning. Spatial training in adult rats, which improved their spatial learning ability, increased the number of excitatory hippocampal CA1 spine synapses on basal dendrites as compared with either isolated or standardly housed animals (Moser et al. [1994] Proc. Natl. Acad. Sci. USA 91:12673-12675). In this article, we report that spine synapses on oblique apical dendritic branches do not increase in density or number after the same type of training. When examining the variability of the spine density on basal CA1 dendrites by using variance component analysis, the variance associated with the cells was twice as large in all three groups as that coupled to the rats. Analysis of the spine density plots shows that the enhanced spine density after spatial training is found in most cells recorded from the trained group but that a small subset of CA1 neurones are particularly well supplied with spines. The trained group had a significant right-skewed tail of the spine distribution, i.e., training caused high spine density to occur in a small subset of dendritic segments. Conversely, the isolated group had a significant left-skewed spine distribution, indicating that some of the dendritic segments were undersupplied with spines, whereas the paired group displayed no asymmetry.

Animals↗
PubMed1996

Cellular correlates to spatial learning in the rat hippocampus.

Learning through exploration gives increased synaptic field potentials in the perforant path/dentate synapses, largely due to an activity-dependent brain temperature increase. After temperature compensation, spatial learning was associated with small, but significant, STP-like changes of the field potential lasting 20-30 min. A group of spatially trained adult rats showed faster spatial learning and about 10% higher basal dendritic spine density (LY-filled) compared to two control groups. With unchanged dendritic length and branching pattern, the results suggest the formation of new synapses.

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↗
PubMed1994

An increase in dendritic spine density on hippocampal CA1 pyramidal cells following spatial learning in adult rats suggests the formation of new synapses.

The search for cellular correlates of learning is a major challenge in neurobiology. The hippocampal formation is important for learning spatial relations. A possible long-lasting consequence of such spatial learning is alteration of the size, shape, or number of excitatory synapses. The dendritic spine density is a good index for the number of hippocampal excitatory synapses. By using laser-scanning confocal microscopy, we observed a significantly increased spine density in CA1 basal dendrites of spatially trained rats when compared to nontrained controls. With unchanged dendritic length, the higher spine density reflects an increased number of excitatory synapses per neuron associated with spatial learning.

Animals↗
PubMed1993

Synaptic potentiation in the rat dentate gyrus during exploratory learning.

To investigate whether hippocampal synaptic transmission is enhanced during learning, we recorded synaptic field potentials in the dentate gyrus in response to stimulation of the perforant path in rats exploring a novel environment. Because these signals rapidly grow during brain temperature elevation, caused by any motor activity, the potentials were compared with signals sampled at similar brain temperatures after passive warming. Both the field excitatory postsynaptic potential (f-EPSP) and the population spike increased significantly early in the exploration, relative to temperature-matched control potentials. The effect decayed within 15-30 minutes. This is the first demonstration of a temperature-independent synaptic potentiation in the hippocampus during learning about the environment. The time course is similar to that of short-term potentiation.

Animals↗
PubMed1993

Spatial learning impairment parallels the magnitude of dorsal hippocampal lesions, but is hardly present following ventral lesions.

The hippocampus plays an essential role in spatial learning. To investigate whether the whole structure is equally important, we compared the effects of variously sized and localized hippocampal aspiration lesions on spatial learning in a Morris water maze. The volume of all hippocampal lesions was determined. Dorsal hippocampal lesions consistently impaired spatial learning more than equally large ventral lesions. The dorsal lesions had to be larger than 20% of the total hippocampal volume to prolong final escape latencies. The acquisition rate and precision on a probe test without platform were sensitive to even smaller dorsal lesions. The degree of impairment correlated with the lesion volume. In contrast, the lesions of the ventral half of the hippocampus spared both the rate and the precision of learning unless nearly all of the ventral half was removed. There was no significant effect of the location (dorsal or ventral) of damage to the overlying neocortex only. In conclusion, the dorsal half of the hippocampus appears more important for spatial learning than the ventral half. The spatial learning ability seems related to the amount of damaged dorsal hippocampal tissue, with a threshold at about 20% of the total hippocampal volume, under which normal learning can occur.

Animals↗
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↗