Biomedical subjects

Robert U Muller

Publications and source records attributed to Robert U Muller.

13 recordsLinked to original sources

PubMed2005

Defective place cell activity in nociceptin receptor knockout mice with elevated NMDA receptor-dependent long-term potentiation.

There is growing evidence that NMDA receptor-dependent long-term potentiation (LTP) in the hippocampus mediates the synaptic plasticity that underlies spatial learning and memory. LTP deficiencies correlate well with spatial memory deficits and LTP enhancements may improve spatial memory. In addition, LTP deficiencies are associated with abnormal place cells as expected from the spatial mapping hypothesis of hippocampal function. In contrast, nothing is known on how enhanced NMDA receptor-dependent LTP affects place cells. To address this question we recorded place cells from mice lacking the nociceptin receptor (NOP1/ORL1/OP4) that have enhanced hippocampal LTP. We found that the enhanced LTP was mediated by NMDA receptors, did not require L-type calcium channels, and occurred only when high frequency tetanizing stimulus trains were used. Place cells in nociceptin receptor knockout mice were abnormal in several ways: they were less stable, had noisier positional firing patterns, larger firing fields and higher discharge rates inside and outside the firing fields. Our results suggest that excessive LTP can cause subnormal hippocampal place cell function. The effects of LTP enhancement on place cell function may therefore also depend on molecular details of synaptic plasticity, including the relationship between stimulus frequency and synaptic strength, and not merely on the magnitude of synaptic strength increases. The data have important clinical implications on development of strategies to improve cognitive function.

Action Potentials↗

PubMed2005

Deforming the hippocampal map.

To investigate conjoint stimulus control over place cells, Fenton et al. (J Gen Physiol 116:191-209, 2000a) recorded while rats foraged in a cylinder with 45 degrees black and white cue cards on the wall. Card centers were 135 degrees apart. In probe trials, the cards were rotated together or apart by 25 degrees . Firing field centers shifted during these trials, stretching and shrinking the cognitive map. Fenton et al. (2000b) described this deformation with an ad hoc vector field equation. We consider what sorts of neural network mechanisms might be capable of accounting for their observations. In an abstract, maximum likelihood formulation, the rat's location is estimated by a conjoint probability density function of landmark positions. In an attractor neural network model, recurrent connections produce a bump of activity over a two-dimensional array of cells; the bump's position is influenced by landmark features such as distances or bearings. If features are chosen with appropriate care, the attractor network and maximum likelihood models yield similar results, in accord with previous demonstrations that recurrent neural networks can efficiently implement maximum likelihood computations (Pouget et al. Neural Comput 10:373-401, 1998; Deneve et al. Nat Neurosci 4:826-831, 2001).

Action Potentials↗

PubMed2005

Impairment in long-term retention but not short-term performance on a water maze reversal task following hippocampal or mediodorsal striatal N-methyl-D-aspartate receptor blockade.

Male Long-Evans rats were injected with 32 ng/mul of the N-methyl-D-aspartate (NMDA) receptor antagonist 3-(2-carboxypiperazin-4-yl) propyl-1-phosphonic acid (CPP) or vehicle and trained to locate a hidden platform in a different location (reversal training) than used on the initial 4 days of training. Rats treated with vehicle or CPP into the dorsal hippocampus, basolateral amygdala, or mediodorsal striatum had similar latencies to locate the platform on the reversal day. Rats infused with CPP into the dorsal hippocampus or mediodorsal striatum failed to search preferentially in the novel location during a 24-hr, drug-free retention test, whereas all other groups searched preferentially in this location. Therefore, blocking dorsal hippocampal or mediodorsal striatal NMDA receptors selectively blocked long-term spatial retention without producing short-term performance deficits.

Analysis of Variance↗

PubMed2005

NMDA-receptor blockade by CPP impairs post-training consolidation of a rapidly acquired spatial representation in rat hippocampus.

Recent evidence suggests that N-methyl-D-aspartate (NMDA)-receptor mediated plasticity in hippocampus has a more subtle role in memory-based behaviours than originally thought. One idea is that NMDA-based plasticity is essential for the consolidation of post-training memory but not for the initial encoding or for short-term memory. To further test this idea we used a three-phase variant of the hidden goal water maze task. In the first phase, rats were pre-trained to an initial location. Next, intense, massed training was done in a 2-h interval to teach the rats to go to a new location after either an injection of the NMDA receptor antagonist (6)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) or of vehicle. Finally, under drug-free conditions 24 h after new location training, a competition test was done between the original and new locations. We find that N-methyl-D-aspartate (NMDA)-receptor blockade has little or no effect on new location training. In contrast, when tested 24 h later, the strength of the trace for the new location learned during NMDA-receptor blockade was much weaker compared with the trace for the new location learned after saline injection. Further experiments showed similar effects when NMDA-receptors were blocked immediately after the new location training, suggesting that this is a memory consolidation effect. Our results therefore reinforce the notion that hippocampal NMDA-receptors participate in post-training memory consolidation but are not essential for the processes necessary to learn or retain navigational information in the short term.

Animals↗

PubMed2004

The effects on place cells of local scopolamine dialysis are mimicked by a mixture of two specific muscarinic antagonists.

Using a dialysis probe near CA1 hippocampal recording electrodes, we infused nonspecific (scopolamine) and specific (methoctramine, pirenzepine) antagonists of muscarinic cholinergic transmission to determine their effects on the positional firing properties of place cells. Both low (0.5 mM) and high (2.0 or 3.0 mM) scopolamine significantly decreased in-field firing rate, increased the ratio of out-of-field to in-field rate, and reduced the smoothness of rate maps, while tending to increase out-of-field rate. Thus, local nonspecific muscarinic blockade mimicked the effects seen with intracerebroventricular application, suggesting that blockade of receptors local to the recorded cells plays an essential role. Unexpectedly, dialysis of scopolamine reduced locomotor activity, again duplicating the effects of intracerebroventricular administration. Most effects of methoctramine (1.0 mM), which blocks presynaptic m2 and m4 receptors, were initially strong but then diminished over hours. Methoctramine produced a significant increase only in out/in ratio and out-of-field rate, whereas it tended to increase in-field rate and monotonically decrease smoothness. Pirenzepine (3.0 mM), which blocks postsynaptic m1 receptors, produced a significant increase only in out/in ratio, whereas it tended to increase out-of-field rate and decrease in-field rate; all these effects were monotonic with respect to time. A mixture of methoctramine plus pirenzepine recapitulated the place-cell effects of scopolamine, although neither the mixture nor its separate components affected behavior. We conclude that the effects of scopolamine on place cells likely result from a combination of blockade of postsynaptic m1 receptors, leading to reduced excitability, with blockade of presynaptic m2 and m4 receptors, leading to increased out-of-field firing.

Action Potentials↗

PubMed2004

Passive movements of the head do not abolish anticipatory firing properties of head direction cells.

Neurons in the anterior dorsal thalamic nucleus (ADN) of the rat selectively discharge in relation to the animal's head direction (HD) in the horizontal plane. Temporal analyses of cell firing properties reveal that their discharge is optimally correlated with the animal's future directional heading by approximately 24 ms. Among the hypotheses proposed to explain this property is that ADN HD cells are informed of future head movement via motor efference copy signals. One prediction of this hypothesis is that when the rat's head is moved passively, the anticipatory time interval (ATI) will be attenuated because the motor efference signal reflects only the active contribution to the movement. The present study tested this hypothesis by loosely restraining the animal and passively rotating it through the cell's preferred direction. Contrary to our prediction, we found that ATI values did not decrease during passive movement but in fact increased significantly. HD cells in the postsubiculum did not show the same effect, suggesting independence between the two sites with respect to anticipatory firing. We conclude that it is unlikely that a motor efference copy signal alone is responsible for generating anticipatory firing in ADN HD cells.

Action Potentials↗

PubMed2004

Representation of objects in space by two classes of hippocampal pyramidal cells.

Humans can recognize and navigate in a room when its contents have been rearranged. Rats also adapt rapidly to movements of objects in a familiar environment. We therefore set out to investigate the neural machinery that underlies this capacity by further investigating the place cell-based map of the surroundings found in the rat hippocampus. We recorded from single CA1 pyramidal cells as rats foraged for food in a cylindrical arena (the room) containing a tall barrier (the furniture). Our main finding is a new class of cells that signal proximity to the barrier. If the barrier is fixed in position, these cells appear to be ordinary place cells. When, however, the barrier is moved, their activity moves equally and thereby conveys information about the barrier's position relative to the arena. When the barrier is removed, such cells stop firing, further suggesting they represent the barrier. Finally, if the barrier is put into a different arena where place cell activity is changed beyond recognition ("remapping"), these cells continue to discharge at the barrier. We also saw, in addition to barrier cells and place cells, a small number of cells whose activity seemed to require the barrier to be in a specific place in the environment. We conclude that barrier cells represent the location of the barrier in an environment-specific, place cell framework. The combined place + barrier cell activity thus mimics the current arrangement of the environment in an unexpectedly realistic fashion.

Animals↗

PubMed2003

Seizure-induced changes in place cell physiology: relationship to spatial memory.

Status epilepticus (SE) is a frequent neurological emergency associated with a significant risk of morbidity in survivors. Impairment of hippocampal-specific memory is a common and serious deficit occurring in many of the survivors. However, the pathophysiological basis of cognitive deficits after SE is not clear. To directly address the cellular concomitants of spatial memory impairment, we recorded the activity of place cells from CA1 in freely moving rats subjected to SE during early development and compared this activity to that in control rats. Place cells discharge rapidly only when the rat's head is in a cell-specific part of the environment called the "firing field." This firing field remains stable over time. Normal place cell function seems to be essential for stable spatial memory for the environment. We, therefore, compared place cell firing patterns with visual-spatial memory in the water maze in SE and control rats. Compared with controls, place cells from the SE rats were less precise and less stable. Concordantly, the water maze performance was also impaired. There was a close relationship between precision and stability of place cells and water maze performance. In contrast, a single, acute, chemically induced seizure produced cessation of place cell activity and spatial memory impairment in water maze performance that reversed within 24 hr. These results strongly bolster the idea that there is a relationship between abnormal place cells and spatial memory. Our findings also suggest that the defects in place cell and spatial memory after SE and acute chemically induced seizures result from different processes.

Action Potentials↗

PubMed2002

Relationships between place cell firing fields and navigational decisions by rats.

This study examined the performance of spatial problems by rats when purely behavioral manipulations disturb the relationship between the place cell representation and the cues used to solve the problems. Place cells were recorded while rats performed a task in which they had to locate a goal in a gray cylinder. In the "far" task, the unmarked goal was displaced by a large fixed distance from a white card on the cylinder wall. In the "near" task, the unmarked goal was directly in front of the card. Finally, in the "cue" task the goal was marked by a black disk on the cylinder floor. Relationships between visible stimuli and place cell activity were manipulated by conducting either "hidden" (with the rat in its home cage) or "visible" (with the rat in the recording apparatus) rotations of the wall card and, when present, independent rotations of the black disk. Hidden card rotations generally caused equal firing field rotations, whereas visible card rotations often did not cause fields to move. In the far task, visible card rotations were associated with a strong decrease of correct responses in the card-referred goal area. Most rats tended to search the goal in the field-referred area. In the near task, visible card rotations were associated with a moderate decrease of performance, with rats searching the goal at the wall card. Finally, field placements had no effect on performance in the cue task. Thus, visible rotations tended to disrupt the relationship between firing fields and cues in all tasks but impaired performance only in the task that required map-based navigation. These results provide strong new evidence in favor of the spatial mapping theory of hippocampal function.

Animals↗

PubMed2002

Non-ionotropic cross-talk between AMPA and NMDA receptors in rodent hippocampal neurones.

Many fast excitatory synapses in the hippocampus are enriched with both AMPARs (alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate receptors) and NMDARs (N-methyl-D-aspartate receptors). Their proximity allows them to be activated simultaneously by the same neurotransmitter, L-glutamate. Activation of AMPARs leads to influx of sodium and calcium ions, which can increase or decrease NMDAR activity through sodium concentration-dependent cascades or a calcium-calmodulin-dependent inactivation process, respectively. Here we provide evidence that the activation of AMPARs inhibits NMDARs through a non-ionotropic mechanism. NMDA-induced current in isolated rat CA1 hippocampal cells and nucleated patches of cultured mouse hippocampal neurones decreased when AMPARs were activated. Conversely, when AMPARs were blocked, the NMDA component of glutamate-induced current increased. The inhibitory action of AMPAR activation on NMDAR-mediated current depends upon the open state of AMPA channels and rapidly diminishes after deactivation of AMPARs. The inhibitory action was independent of membrane voltage, univalent cation fluxes and calcium influx. The AMPA-NMDA cross-inhibition also occurred in evoked synaptic current in CA1 neurones from intact mouse hippocampal slices. This cross-talk may play a role in preventing overexcitation during bursting activities in the hippocampus.

Animals↗

PubMed2002

Remapping of place cell firing patterns after maze rotations.

When place cells are recorded from rats running on an elevated T-maze inside a curtained enclosure that contains distinct, experimenter selected stimuli, rotations of the maze plus stimuli cause equal rotations of firing fields. Here, we examined the effects of conflicting rotations of a T-maze relative to a laboratory frame that contained a large number of fixed stimuli in the environment and asked whether positional firing patterns stayed in register with the maze or the room cues or were modified in some more complex way. After maze rotations of 90 degrees, 180 degrees or 270 degrees, firing fields were stable in the laboratory frame and thus shifted to a different maze arm. In contrast, rotations of 45 degrees or -45 degrees resulted in dramatic changes of positional firing patterns regardless of their initial position on the maze. Crucially, even cells whose fields were initially on the central platform underwent major firing pattern alterations although the view of the environment from the platform was unchanged by such rotations. Finally, we found that altering the visual appearance by removing without rotation one or two maze arms did not alter firing fields on the remaining part of the maze. Thus, the "remappings" caused by 45 degrees rotations could result from the disturbed relationship between all arms and the room cues or from the changes in the possible paths the animal can take in the environment. Taken together, our results provide an example of combinatorial coding by the hippocampus, in which the place cell representation of the environment was seen to be modified as a unit and not piecewise according to locally available stimuli.

Animals↗

PubMed2002

Place-cell impairment in glutamate receptor 2 mutant mice.

There is a strong correlation between Hebbian, NMDA receptor-dependent long-term potentiation (LTP), place-cell firing, and learning and memory. We made glutamate receptor 2 (GluR2) null mutant mice that show enhanced non-Hebbian LTP in hippocampal CA1 neurons and impaired performance in a spatial learning task. We concluded that in vivo hippocampal place cells of GluR2 mutant mice were functionally impaired because (1) only 22.6% of CA1 neurons showed place fields in GluR2 mutant mice, which was significantly lower than that (43.8%) in wild-type mice; (2) GluR2 mutant place fields were much less precise; and (3) GluR2 mutant place fields were extremely unstable. Our data suggest that place cells of GluR2 knock-out mice did not form robust place fields, and that enhanced non-Hebbian LTP might play a negative role in their formation.

Action Potentials↗

PubMed2002

Telemetry system for reliable recording of action potentials from freely moving rats.

Recording single cells from alert rats currently requires a cable to connect brain electrodes to the acquisition system. If no cable were necessary, a variety of interesting experiments would become possible, and the design of other experiments would be simplified. To eliminate the need for a cable we have developed a one-channel radiotelemetry system that is easily carried by a rat. This system transmits a signal that is reliable, highly accurate and can be detected over distances of > or = 20 m. The mobile part of the system has three components: (1) a headstage with built-in amplifiers that plugs into the connector for the electrode array on the rat's head; the headstage also incorporates a light-emitting diode (LED) used to track the rat's position; (2) a backpack that contains the transmitter and batteries (2 N cells); the backpack also provides additional amplification of the single cell signals; and (3) a short cable that connects the headstage to the backpack; the cable supplies power to the headstage amplifiers and the LED, and carries the physiological signals from the headstage to the backpack. By using a differential amplifier and recording between two brain microelectrodes the system can transmit action potential activity from two nearly independent sources. In a future improvement, two transmitters with different frequencies would be used telemeter signals from four microelectrodes simultaneously.

Action Potentials↗