Biomedical subjects

J N P Rawlins

Publications and source records attributed to J N P Rawlins.

At least 19 recordsLinked to original sources

PubMed2006

The drugs don't work-or do they? Pharmacological and transgenic studies of the contribution of NMDA and GluR-A-containing AMPA receptors to hippocampal-dependent memory.

OBJECTIVE: The aim of this article is to provide a review of studies using N-methyl-D-aspartate (NMDA) receptor antagonists to assess the hippocampal long-term potentiation (LTP)/learning hypothesis. DISCUSSION: In particular, we will re-examine the validity of both (1) the original hippocampal LTP/spatial learning hypothesis of Morris and (2) the sensorimotor account put forward by Cain, among others, both from the point of view of the pharmacological studies on which they were based and with regard to recent studies with genetically modified mice. More specifically, we will review the pharmacological studies in the light of recent work on the glutamate receptor A (GluR-A or GluR1) L-alpha-amino-3-hydroxy-5-methyl-4-isoxazelopropionate (AMPA) receptor sub-unit knockout mouse. We will argue that neither the original hippocampal LTP/spatial learning hypothesis nor a sensorimotor account can adequately explain all of the available data. We argue instead that hippocampal synaptic plasticity, which requires NMDA receptors for its induction and GluR-A-containing AMPA receptors for its continued expression, contributes to a process whereby appropriate behavioural responses are selected rapidly on the basis of conditional information provided by the context. These contextual cues could include not only the spatial context (i.e. the 'where') and the temporal context (the 'when'), but also other aspects of context, such as internal state cues (hunger and fear state), and can be used to rapidly and flexibly alter valences of specific response options. RECOMMENDATIONS: We also suggest that there is a separate, distinct, NMDA/GluR-A-independent mechanism through which the context can gradually (incrementally or decrementally) alter the valence of a particular response option.

2-Amino-5-phosphonovalerate↗

PubMed2005

Restoration of spatial working memory by genetic rescue of GluR-A-deficient mice.

Gene-targeted mice lacking the AMPA receptor subunit GluR-A (also called GluR1 encoded by the gene Gria1,) have deficits in hippocampal CA3-CA1 long-term potentiation (LTP) and have profoundly impaired hippocampus-dependent spatial working memory (SWM) tasks, although their spatial reference memory remains normal. Here we show that forebrain-localized expression of GFP-tagged GluR-A subunits in GluR-A-deficient mice rescues SWM, paralleling its rescue of CA3-CA1 LTP. This provides powerful new evidence linking hippocampal GluR-A-dependent synaptic plasticity to rapid, flexible memory processing.

Analysis of Variance↗

PubMed2005

Neuropathologically distinct prion strains give rise to similar temporal profiles of behavioral deficits.

Mouse-adapted scrapie strains have been characterized by vacuolation profiles and incubation times, but the behavioral consequences have not been well studied. Here, we compared behavioral impairments produced by ME7, 79A, 22L, and 22A strains in C57BL/6J mice. We show that early impairments on burrowing, glucose consumption, nesting and open field activity, and late stage motor impairments show a very similar temporal sequence in ME7, 79A, and 22L. The long incubation time of the 22A strain produces much later impairments. However, the strains show clear late stage neuropathological differences. All strains showed clear microglial activation and synaptic loss in the hippocampus, but only ME7 and 79A showed significant CA1 neuronal death. Conversely, 22L and 22A showed significant cerebellar Purkinje neuron loss. All strains showed marked thalamic neuronal loss. These behavioral similarities coupled with clear pathological differences could serve to identify key circuits whose early dysfunction underlies the neurological effects of different prion strains.

Animals↗

PubMed2005

GluR-A-dependent synaptic plasticity is required for the temporal encoding of nonspatial information.

Four related experiments studied operant performance of mice on differential reinforcement of low rates of responding (DRL) paradigms. Experiment 1 showed that excitotoxic hippocampal lesions impaired performance of a 10-s DRL schedule (DRL-10). Experiments 2 and 3 showed that GluR-A AMPA receptor subunit knockout mice, which are deficient in CA3-CA1 long-term potentiation (LTP), were markedly impaired at 15 s (DRL-15), but less impaired at DRL-10. Experiment 4 compared DRL-15 performance in mice from the 2 strains from which the GluR-A colony was derived and showed that they did not differ. The results show that GluR-A-containing AMPA receptors are required for normal performance on hippocampus-dependent, nonspatial working memory tasks, consistent with a role for GluR-A in the temporal encoding (what happened when) of nonspatial information.

Animals↗

PubMed2004

Spatial reference memory in GluR-A-deficient mice using a novel hippocampal-dependent paddling pool escape task.

Genetically modified mice lacking the L-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor subunit, GluR-A (GluR1), and deficient in hippocampal CA3-CA1 long-term potentiation (LTP), were assessed on a novel, hippocampal-dependent spatial reference memory, paddling pool escape task. The mice were required to use the extramaze cues around the laboratory to find a hidden escape tube that was in a constant location at one of 12 possible positions around the perimeter of the paddling pool, in order to escape from shallow water. The knockout mice performed well on this task. They displayed a small initial impairment (in terms of both escape latencies and choice errors), but they were soon as efficient as the wild-type mice in escaping from the water. This was further demonstrated by performance during a 20-s probe trial in which the exit tube was blocked. Both groups of mice spent most of the time searching in the quadrant of the pool in which the exit tube had previously been located. In a subsequent experiment, entirely normal spatial acquisition was observed in the knockout mice when the paddling pool was moved to a novel spatial environment. The GluR-A -/- mice were also unimpaired in a further reversal phase in which the correct exit location was moved by 180 degrees around the perimeter wall. These results are consistent with previous watermaze studies, providing further demonstration of intact hippocampus-dependent spatial reference memory in GluR-A knockout mice. They contrast strikingly with the profound deficits in hippocampus-dependent, short-term, flexible spatial working memory observed in these knockout mice. This study also demonstrates a novel behavioral task for assessing spatial memory in genetically modified mice. This task shares the behavioral profile of the well-established watermaze paradigm, but may have advantages for the study of genetically modified mice.

Animals↗

PubMed2004

Regional dissociations within the hippocampus--memory and anxiety.

The amnestic effects of hippocampal lesions are well documented, leading to numerous memory-based theories of hippocampal function. It is debatable, however, whether any one of these theories can satisfactorily account for all the consequences of hippocampal damage: Hippocampal lesions also result in behavioural disinhibition and reduced anxiety. A growing number of studies now suggest that these diverse behavioural effects may be associated with different hippocampal subregions. There is evidence for at least two distinct functional domains, although recent neuroanatomical studies suggest this may be an underestimate. Selective lesion studies show that the hippocampus is functionally subdivided along the septotemporal axis into dorsal and ventral regions, each associated with a distinct set of behaviours. Dorsal hippocampus has a preferential role in certain forms of learning and memory, notably spatial learning, but ventral hippocampus may have a preferential role in brain processes associated with anxiety-related behaviours. The latter's role in emotional processing is also distinct from that of the amygdala, which is associated specifically with fear. Gray and McNaughton's theory can in principle incorporate these apparently distinct hippocampal functions, and provides a plausible unitary account for the multiple facets of hippocampal function.

Animals↗

PubMed2004

Dissociation of function within the hippocampus: effects of dorsal, ventral and complete excitotoxic hippocampal lesions on spatial navigation.

The present study was designed to assess the possibility that sub-total ventral hippocampal lesions might leave intact a mechanism for only highly accurate navigation, whereas sub-total dorsal hippocampal lesions might leave intact a mechanism only for less precise navigation. Animals with selective dorsal, ventral or complete hippocampal lesions were tested in a water maze, in which the target platform was moved from trial to trial, but always within a defined area, instead of being at a fixed location. Hence, an animal that searched at exactly the point where the platform had been found on a previous trial would be disadvantaged, in comparison with an animal that searched in the right general area. This might favor animals capable of less precise navigation over those with very precise navigational abilities. In subsequent phases of the experiment, we additionally assessed, for comparison, performance with a fixed platform location, reversal learning in the water-maze, and performance on an elevated T-maze. Our results revealed no sign of any qualitative difference between the effects of the selective sub-total lesions when the water maze hidden platform location was varied within the defined area, and the effects in subsequent more conventionally used tests. Ventral hippocampal damage never led to a performance deficit. Dorsal hippocampal damage led to significantly poorer performance in only some test phases, and never led to any sign of improved performance.

Animals↗

PubMed2004

Amygdala and ventral hippocampus contribute differentially to mechanisms of fear and anxiety.

Cytotoxic ventral hippocampal lesions produced anxiolytic effects on 4 ethologically based, unconditioned tests of anxiety in the rat (hyponeophagia, black/white 2-compartment box test, a successive alleys test that represents a modified version of the elevated plus-maze, and a social interaction test). Dorsal hippocampal lesions did not produce anxiolytic effects on these tests, suggesting a distinct specialization of function within the hippocampus. Furthermore, the effects of ventral hippocampal lesions were also distinct from those of amygdala lesions. This suggests that the effects of ventral hippocampal lesions are not simply due to direct or indirect effects on the amygdala, and that these 2 brain areas contribute differentially to a brain system (or systems) associated with the processing of fearful and/or anxiogenic stimuli.

Amygdala↗

PubMed2004

A comparison of GluR-A-deficient and wild-type mice on a test battery assessing sensorimotor, affective, and cognitive behaviors.

Previous studies have demonstrated a spatial working memory deficit in glutamate receptor (GluR)-A (GluR1) AMPA receptor subunit knockout mice. The present study evaluated male and female wild-type and GluR-A-/- mice on a test battery that assessed sensorimotor, affective, and cognitive behaviors. Results revealed a behavioral phenotype more extensive than previously described. GluR-A-/- mice were hyperactive, displayed a subtle lack of motor coordination, and were generally more anxious than wild-type controls. In addition, they showed a deficit in spontaneous alternation, consistent with previous reports of a role for GluR-A-dependent plasticity in hippocampus-dependent, spatial working memory. Although changes in motor coordination or anxiety cannot explain the dissociations already reported within the spatial memory domain, it is clear that they could significantly affect interpretation of results obtained in other kinds of behavioral tasks.

Affect↗

PubMed2004

Medial septal lesions mimic effects of both selective dorsal and ventral hippocampal lesions.

Electrolytic medial septal (MS) lesions, which depleted acetylcholinesterase staining in both dorsal and ventral hippocampus, produced a constellation of behaviors, combining aspects of both selective dorsal and ventral hippocampal lesion effects. MS lesions impaired spatial working memory on the T maze, thus resembling the effects of dorsal hippocampal lesions. In addition, MS lesions reduced anxiety during successive alleys (a modified form of the elevated plus-maze), social interaction, and hyponeophagia tests. MS lesions also reduced postshock freezing. These effects more closely resemble those of ventral hippocampal lesions. Therefore, the effects of electrolytic MS lesions derive from the resulting combined deafferentation of dorsal and ventral hippocampal regions, suggesting that previously reported effects of cytotoxic dorsal hippocampal lesions are unlikely to be due to a demyelination of fibers of passage coursing through the septal pole.

Animals↗

PubMed2003

The role of the septo-hippocampal cholinergic projection in T-maze rewarded alternation.

Administration of 192IgG-saporin, a cholinergic neurotoxin, to the medial septum destroys the cell bodies from which the septo-hippocampal cholinergic projection originates, leading to reductions in both hippocampal acetylcholinesterase (AChE) and choline acetyltransferase (ChAT). Despite reports that 192IgG-saporin-induced cholinergic loss leads to post-operative impairments in acquisition and performance of spatial memory tasks, a number of other reports have described intact spatial memory performance following these lesions. Factors that might account for these different outcomes include variations in toxin injection sites or volumes, and post-operative testing at times that might permit regeneration of damaged neuronal processes. We, therefore, assessed the effects of intraseptal microinjection of 192IgG-saporin, in rats, on the post-operative retention of pre-operatively acquired discrete-trial rewarded alternation in the T-maze. This design allowed us to assess the effects of the lesion 7 days post-surgery, at which point, at best, incomplete neuronal regeneration would have been expected to have occurred. The lesion led to a profound loss of hippocampal AChE staining, and a clear inflammatory response, as assessed by proliferation of OX42-stained macrophages in the medial septum and diagonal band nuclei, but there was no impairment in spatial working memory.

Acetylcholinesterase↗

PubMed2003

Ventral hippocampal lesions affect anxiety but not spatial learning.

Rats with cytotoxic ventral hippocampal lesions which removed approximately 50% of the hippocampus (including dentate gyrus) starting from the temporal pole, displayed a reduction in freezing behaviour following the delivery of an unsignalled footshock in an operant chamber. This was more plausibly a result of reduced susceptibility to fear than a result of a lesion-induced increase in general motor activity. There was no consistent difference between sham and lesioned animals in spontaneous locomotor activity, or locomotion following acute or chronic treatment with amphetamine. In contrast, ventral hippocampal lesioned animals were quicker to pass from the black to the white box during a modified version of the light/dark exploration test, and were quicker to begin eating during tests of hyponeophagia. Furthermore, rats with ventral hippocampal lesions defecated less than their sham counterparts both during open field testing and in extinction sessions following contextual conditioning. In contrast to these clear lesion effects, there were no signs of any spatial learning impairment either in the watermaze or on the elevated T-maze. Taken together these results suggest that the ventral hippocampus may play a role in a brain system (or systems) associated with fear and/or anxiety, and provide further evidence for a distinct specialisation of function along the septotemporal axis of the hippocampus.

Amphetamine↗

PubMed2003

Entorhinal cortex lesions disrupt the transition between the use of intra- and extramaze cues for navigation in the water maze.

This study with rats examined the effects of excitotoxic lesions to the entorhinal cortex (EC) and hippocampus (HPC) on using extramaze and intramaze cues to navigate to a hidden platform in a water maze. HPC lesions resulted in a disruption to the use of extramaze cues, but not intramaze cues, whereas EC lesions had no effect on the use of these cues when they were encountered for the first time. However, prior navigation training in which 1 type of cue was relevant disrupted navigation with the other type in rats with EC lesions. Results show that the EC contributes to the processing of spatial information, but that this contribution is most apparent when there is a conflict between 2 sources of navigational cues in the water maze.

Animals↗

PubMed2003

GluR-A-Deficient mice display normal acquisition of a hippocampus-dependent spatial reference memory task but are impaired during spatial reversal.

Acquisition and reversal of a spatial discrimination were assessed in an appetitive, elevated plus-maze task in 4 groups of mice: knockout mice lacking the AMPA receptor subunit GluR-A (GluR1), wild-type controls, mice with cytotoxic hippocampal lesions, and controls that had undergone sham surgery. In agreement with previous studies using tasks such as the water maze, GluR-A(-/-) mice were unimpaired during acquisition of the spatial discrimination task, whereas performance in the hippocampalgroup remained at chance levels. In contrast to their performance during acquisition, the GluR-A(-/-) mice displayed a mild deficit during reversal of the spatial discrimination and were profoundly impaired during discrete trial, rewarded-alternation testing on the elevated T maze. The latter result suggests a short-term, flexible spatial working memory impairment in GluR-A(-/-) mice, which might also underlie their mild deficit during spatial reversal.

Animals↗

PubMed2003

Synaptic changes characterize early behavioural signs in the ME7 model of murine prion disease.

Prion diseases are fatal, chronic neurodegenerative diseases of mammals, characterized by amyloid deposition, astrogliosis, microglial activation, tissue vacuolation and neuronal loss. In the ME7 model of prion disease in the C57BL/6 J mouse, we have shown previously that these animals display behavioural changes that indicate the onset of neuronal dysfunction. The current study examines the neuropathological correlates of these early behavioural changes. After injection of ME7-infected homogenate into the dorsal hippocampus, we found statistically significant impairment of burrowing, nesting and glucose consumption, and increased open field activity at 13 weeks. At this time, microglia activation and PrPSc deposition was visible selectively throughout the limbic system, including the hippocampus, entorhinal cortex, medial and lateral septum, mamillary bodies, dorsal thalamus and, to a lesser degree, in regions of the brainstem. No increase in apoptosis or neuronal cell loss was detectable at this time, while in animals at 19 weeks postinjection there was 40% neuronal loss from CA1. There was a statistically significant reduction in synaptophysin staining in the stratum radiatum of the CA1 at 13 weeks indicating loss of presynaptic terminals. Damage to the dorsal hippocampus is known to disrupt burrowing and nesting behaviour. We have demonstrated a neuropathological correlate of an early behavioural deficit in prion disease and suggest that this should allow insights into the first steps of the neuropathogenesis of prion diseases.

Animals↗

PubMed2002

Effects of cytotoxic nucleus accumbens lesions on instrumental conditioning in rats.

In two experiments the involvement of the nucleus accumbens in instrumental conditioning was investigated using rats as subjects. In experiment 1, extensive bilateral cytotoxic lesions of the nucleus accumbens mildly suppressed instrumental responding reinforced with food, but had no detectable effect on the sensitivity of the rats' performance either to outcome devaluation or to degradation of the instrumental contingency. In experiment 2, restricted accumbens lesions reliably attenuated the excitatory effect of systemically administered d-amphetamine on lever pressing for a conditioned reinforcer, and completely abolished Pavlovian-instrumental transfer. Taken together these results give a picture of the involvement of the rat nucleus accumbens in instrumental conditioning. They support the widely held theory that the nucleus accumbens mediates the excitatory effects of appetitively conditioned Pavlovian signals on instrumental performance and refute the hypothesis that the nucleus accumbens is part of the neural circuitry by which incentive value is attached to the representations of instrumental outcomes.

Animals↗

PubMed2002

Double dissociation of function within the hippocampus: spatial memory and hyponeophagia.

Complete and dorsal hippocampal lesions impaired spatial performance on 2 working memory tasks: rewarded alternation on the T maze and matching to position in the water maze. In contrast, ventral hippocampal lesions had no effect on these tasks, even when task difficulty was increased by the introduction of delays. Ventral lesions did resemble complete lesions in reducing anxiety in 3 commonly used tests of anxiety (social interaction, plus-maze, and hyponeophagia). Dorsal lesions also appeared to be anxiolytic in the social interaction and plus-maze tests, but they did not affect hyponeophagia. Complete- and dorsal-lesioned rats displayed hyperactivity, whereas ventral-lesioned rats did not. These results show a double dissociation between dorsal and ventral hippocampal lesions (hyponeophagia vs. spatial memory), suggesting differentiation of function along the septotemporal axis of this structure.

Amphetamine↗

PubMed2002

Spatial memory dissociations in mice lacking GluR1.

Gene-targeted mice lacking the AMPA receptor subunit GluR1 (GluR-A) have deficits in hippocampal CA3-CA1 long-term potentiation. We now report that they showed normal spatial reference learning and memory, both on the hidden platform watermaze task and on an appetitively motivated Y-maze task. In contrast, they showed a specific spatial working memory impairment during tests of non-matching to place on both the Y-maze and an elevated T-maze. In addition, successful watermaze and Y-maze reference memory performance depended on hippocampal function in both wild-type and mutant mice; bilateral hippocampal lesions profoundly impaired performance on both tasks, to a similar extent in both groups. These results suggest that different forms of hippocampus-dependent spatial memory involve different aspects of neural processing within the hippocampus.

Animals↗