Biomedical subjects

D M Bannerman

Publications and source records attributed to D M Bannerman.

36 records · Page 2Linked to original sources

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↗

PubMed2001

Selective cytotoxic lesions of the retrohippocampal region produce a mild deficit in social recognition memory.

Although a number of studies have implicated the hippocampal formation in social recognition memory in the rat, a recent study in this laboratory has demonstrated that selective cytotoxic lesions, confined to the hippocampus proper (encompassing the four CA subfields and the dentate gyrus), are without effect on this behaviour. This finding suggests that the hippocampus proper does not subserve social recognition memory in the rat, but does not preclude the possibility that other areas of the hippocampal formation, such as the entorhinal cortex or subiculum, could support this form of learning. The present study addressed this issue by examining the effects of selective cytotoxic retrohippocampal (RHR) lesions (including both the entorhinal cortex and subiculum) on social recognition memory in the rat. RHR lesions produced a mild social recognition memory impairment, although lesioned animals still displayed a reduction in investigation time between the first and second exposure to the juvenile. This result is consistent with other studies which have implicated the retrohippocampal or parahippocampal area in olfactory recognition memory processes. It also suggests, however, that other areas, out with the retrohippocampal region, are also likely to play an important role in social recognition memory.

Age Factors↗

PubMed2001

Faster is not surer--a comparison of C57BL/6J and 129S2/Sv mouse strains in the watermaze.

In recent years the use of genetic manipulations to investigate the molecular mechanisms underlying learning and memory has become a common approach. In a great many cases, the spatial learning ability of mutant mice has been assessed using the Morris watermaze task. The performance of these mice may, however, be strongly influenced by their genetic background and, therefore, the interpretation of their phenotype requires a preliminary characterization of the parental strains. The present study compared 129S2/Sv and C57/BL/6J inbred mouse strains, which have been widely used in deriving lines of genetically modified mice, on the hidden platform version of the watermaze task. During acquisition, the C57 mice displayed shorter escape latencies to find the platform than the 129S2s. Further analysis revealed, however, that the C57 mice also swam faster than the 129S2s. The analysis of path lengths was thus a more reliable measure of spatial learning, and revealed an equal level of performance in the two strains. This conclusion was confirmed during the two probe trials with both strains showing a similar spatial preference for the training site. These results suggest that the 129S2 substrain is no less proficient than the C57 substrain in terms of spatial learning in the watermaze, and also demonstrates the importance of not relying solely on escape latency as a measure of watermaze performance.

Animals↗

PubMed2001

Cytotoxic lesions of the hippocampus increase social investigation but do not impair social-recognition memory.

A number of studies have implicated the hippocampal formation in social-recognition memory in the rat. The present study addressed this issue directly by assessing the effects of cytotoxic lesions confined to the hippocampus proper, encompassing the four CA subfields and the dentate gyrus, on this behavioural task. Ibotenate-induced hippocampal lesions led to locomotor hyperactivity and a marked spatial working-memory impairment on the elevated T-maze. In addition, they also led to increased social investigation. However, despite these clear effects, there was no effect of the lesions on social-recognition memory. These results suggest that the hippocampus proper does not subserve social-recognition memory; but does not, however, preclude the possibility that other areas of the hippocampal formation (e.g. entorhinal cortex or subiculum) may support this memory process.

Animals↗

PubMed2001

The time course of the hyperactivity that follows lesions or temporary inactivation of the fimbria-fornix.

Lesions of the hippocampus or the fimbria-fornix produce a pronounced hyperactivity in rats. This effect is thought to be due to the loss of glutamatergic hippocampal inputs to the nucleus accumbens, although the mechanisms involved remain unclear. It has been suggested that the hyperactivity is due to changes in accumbens dopamine receptors, possibly involving the gradual development of denervation supersensitivity. Consistent with this possibility, the present study found that fimbria-fornix transection produced hyperactivity which, although undetectable immediately after surgery, gradually became apparent and then continued to increase over the course of several days. This does not, however, preclude the possibility that there is an immediate increase in activity which is masked by the after effects of surgery. To address this issue, local anaesthetic was infused into the fimbria-fornix via chronic indwelling cannulae, in order to silence the hippocampal inputs to the nucleus accumbens. This procedure impaired spatial working memory on the elevated T-maze and resulted in immediate hyperactivity, suggesting that there may be at least two components to fornix lesion-induced hyperactivity, and that the immediate effects of mechanical fornix lesions on activity levels may be masked by the after effects of surgery per se.

Anesthetics, Local↗

PubMed2001

The role of the entorhinal cortex in two forms of spatial learning and memory.

It is generally acknowledged that the rodent hippocampus plays an important role in spatial learning and memory. The importance of the entorhinal cortex (ERC), an area that is closely interconnected anatomically with the hippocampus, in these forms of learning is less clear cut. Recent studies using selective, fibre-sparing cytotoxic lesions have generated conflicting results, with some studies showing that spatial learning can proceed normally without the ERC, suggesting that this area is not required for normal hippocampal function. The present study compared cytotoxic and aspiration ERC lesions with both fimbria fornix (FFX) lesions and sham-operated controls on two spatial learning tasks which have repeatedly been shown to depend on the hippocampus. Both groups of ERC lesions were impaired during non-matching-to-place testing (rewarded alternation) on the elevated T-maze. However, neither of these lesions subsequently had any effect on the acquisition of a standard spatial reference memory task in the water maze. FFX lesions produced a robust and reliable impairment on both of these tasks. A second experiment confirmed that cytotoxic ERC lesions spared water maze learning but disrupted rewarded alternation on the T-maze, when the order of behavioural testing was reversed. These results confirm previous reports that ERC-lesioned animals are capable of spatial navigation in the water maze, suggesting that the ERC is not a prerequisite for normal hippocampal function in this task. The present demonstration that ERC lesions disrupt non-matching-to-place performance may, however, be consistent with the possibility that ERC lesions affect attentional mechanisms, for example, by increasing the sensitivity to recent reward history.

Animals↗

PubMed2001

Contextual fear conditioning is disrupted by lesions of the subcortical, but not entorhinal, connections to the hippocampus.

Recent studies have questioned the importance of the entorhinal cortex (ERC) for normal hippocampal function. For example, fibre-sparing ERC lesions have been found to have no effect on spatial learning in the watermaze. There is also doubt as to the importance of the ERC for contextual fear conditioning, with previous studies having yielded conflicting results. In an attempt to resolve this issue, the present study compared aspiration and cytotoxic ERC lesioned rats, along with fimbria-fornix (FFX) lesioned animals and sham operated controls, on an unsignalled contextual fear conditioning paradigm. The results of the present study show that whereas lesions of the FFX disrupted contextual freezing, neither aspiration nor cytotoxic ERC lesions had any effect on this behaviour. Aspiration ERC lesioned rats, however, like FFX lesioned animals, did display hyperactivity prior to the delivery of footshock. These results suggest that whereas projections between the hippocampus and subcortical structures are important for normal levels of contextual freezing, projections from the entorhinal cortex are not essential.

Animals↗

PubMed2001

Rats' processing of visual scenes: effects of lesions to fornix, anterior thalamus, mamillary nuclei or the retrohippocampal region.

We analysed the effects of lesions of hippocampal-diencephalic projections -- fornix (FX) mamillary bodies (MB) and anterior thalamic nuclei (AT) -- and retrohippocampal (RH) lesions including entorhinal cortex and ventral subiculum, upon scene processing. All lesions except FX were neurotoxic. Rats learned to discriminate among computer-generated visual displays ("scenes") each comprising three different shapes ("objects"). The paradigm was constant-negative; one constant scene (unrewarded) appeared on every trial together with a trial-unique variable scene (rewarded). Four types of variable scene were intermingled: (1) unfamiliar objects in different positions from those of the constant (type O+P), (2) unfamiliar objects in same positions as in the constant (type O), (3) same objects as the constant in different positions (type P), (4) same objects and positions as the constant but recombined (type X). Group RH performed like controls while groups FX, AT and MB showed (surprisingly) enhanced performance on types X and O. One explanation is that normal rats attempt to process all objects in a scene concurrently, while hippocampal-projection lesions disrupt this tendency, producing a narrower attention, which paradoxically aids performance with some variable types. The results confirm that the entorhinal cortex has a different function from other components of the hippocampal system.

Animals↗

PubMed2001

The effect of cytotoxic lesions of the hippocampus on recognition memory in the rat: effects of stimulus size.

Rats with excitotoxic hippocampal lesions were trained on delayed nonmatching-to-sample (DNMS) with small goal boxes, containing complex objects, presented on a pseudo trial-unique schedule. A series of experiments then tested performance on repeated presentation of either the small object or large empty goal boxes. All rats acquired the nonmatching rule, but hippocampal-lesioned rats performed less well than controls on choice accuracy for the final 2 blocks of acquisition. In the study's main phase, the lesions impaired choice accuracy when the large empty boxes were used as stimuli. This deficit was ameliorated when the rats were tested with the small object boxes, although the performance of the hippocampal-lesioned rats was still below that of controls. These results extend previous reports of box size-dependent effects of hippocampal aspiration lesions on DNMS and suggest that selective damage to the hippocampus, not neuronal loss in adjacent structures or fiber tracts, is critical for the effect.

Animals↗

PubMed2001

Conditional discriminations based on external and internal cues in rats with cytotoxic hippocampal lesions.

Septal-hippocampal system lesions, mostly using aspiration techniques, have been reported to impair performance of conditional tasks. Rats with axon-sparing cytotoxic hippocampal lesions were therefore tested in a range of instrumental conditional paradigms. They did not differ from controls in their ability to choose the appropriate object in a conditional object discrimination cued by internal state (hunger or thirst) or on performance of conditional visuospatial object discriminations. Acquisition of a conditional visuospatial discrimination with black and white boxes as stimuli was also unimpaired. In contrast, lesioned rats were profoundly impaired on an open T-maze task when cued by either their internal state (reference memory task) or their previous response (working memory task). The results indicate that perception or use of spatial cues, rather than conditional responding per se, is impaired by cytotoxic hippocampal lesions.

Abortion, Habitual↗

PubMed2000

Rats with hippocampal lesions learn about allocentric place cues in a non-navigational task.

Hippocampal-lesioned rats (HPC) and sham controls (SH) learned constant-negative visual discriminations among scenes in a Y-maze. Any arm could be start arm for a trial. Two choice scenes ("constant" and "variable") were shown in the other arms. In Experiment 1, each problem had 2 constants. One or the other constant appeared on every trial, and the variable changed every trial; choosing the variable was rewarded. There were 4 problem types. Each constant might be always in a given direction from the start arm (added egocentric [Ego] cue), always in a given maze arm (added allocentric [Allo] cue), both, or neither. SH rats' visual learning was enhanced by Ego and by Allo cues. HPC rats' visual learning was enhanced by Ego cues, and by Allo cues, but only if there was no Ego cue. Experiment 2 confirmed that Allo cues helped HPC rats as much as SH, in the absence of Ego cues. Rats with HPC lesions can learn about allocentric place cues when navigation and idiothetic cue control are not required.

Animals↗

PubMed1999

Double dissociation of function within the hippocampus: a comparison of dorsal, ventral, and complete hippocampal cytotoxic lesions.

Rats with complete cytotoxic hippocampal lesions exhibited spatial memory impairments in both the water maze and elevated T maze. They were hyperactive in photocell cages; swam faster in the water maze; and were less efficient on a nonspatial, differential reinforcement of low rates (DRL) task. Performance on both spatial tasks was also impaired by selective dorsal but not ventral lesions; swim speed was increased by ventral but not dorsal lesions. Both partial lesions caused a comparable reduction in DRL efficiency, although these effects were smaller than those of complete lesions. Neither partial lesion induced hyperactivity when rats were tested in photocell cages, although both complete and ventral lesion groups showed increased activity after footshock in other studies (Richmond et al., 1999). These results demonstrate possible functional dissociations along the septotemporal axis of the hippocampus.

Analysis of Variance↗

PubMed1999

Dissociating context and space within the hippocampus: effects of complete, dorsal, and ventral excitotoxic hippocampal lesions on conditioned freezing and spatial learning.

Rats with complete excitotoxic hippocampal lesions or selective damage to the dorsal or ventral hippocampus were compared with controls on measures of contextually conditioned freezing in a signaled shock procedure and on a spatial water-maze task. Complete and ventral lesions produced equivalent, significant anterograde deficits in conditioned freezing relative to both dorsal lesions and controls. Complete hippocampal lesions impaired water-maze performance; in contrast, ventral lesions improved performance relative to the dorsal group, which was itself unexpectedly unimpaired relative to controls. Thus, the partial lesion effects seen in the 2 tasks never resembled each other. Anterograde impairments in contextual freezing and spatial learning do not share a common underlying neural basis; complete and ventral lesions may induce anterograde contextual freezing impairments by enhancing locomotor activity under conditions of mild stress.

Analysis of Variance↗

PubMed1997

Intracerebroventricular infusion of the NMDA receptor-associated glycine site antagonist 7-chlorokynurenate impairs water maze performance but fails to block hippocampal long-term potentiation in vivo.

Most previous studies investigating the relationship between N-methyl-D-aspartate receptor-dependent synaptic plasticity and learning have employed drugs that either compete with glutamate for access to the primary agonist binding site (e.g., D-2-amino-5-phosphopentanoic acid) or block the associated ion channel (e.g., dizocilpine). This study targeted the glycine receptor site located on the NMDA receptor complex. Chronic intracerebroventricular infusion of the glycine site antagonist 7-chlorokynurenate (7CK; 75 mM, 0.5 microliter/h, icv, for up to 14 days) impaired performance of male Lister hooded rats during acquisition of a spatial reference memory task in the water maze. In addition, however, these animals showed sensorimotor deficits, including a prolonged righting reflex, ataxia, and difficulty in staying on the escape platform. On completion of behavioral testing, the rats were anesthetized with urethane and an attempt was made to induce LTP in the hippocampus ipsilateral to the infusion cannula. Both control and 7CK-infused animals displayed equivalent long-term potentiation (LTP) 60 min posttetanus. A novel analytical technique for assaying drug tissue levels involving high-performance liquid chromotography with fluorescence detection revealed that tissue levels of 7CK in hippocampus were extremely low and unlikely to be sufficient to affect LTP, as observed. These findings neither support nor compromise the LTP/learning hypothesis, but they illustrate some of the problems of using drugs to elucidate the neurobiological mechanisms of learning and memory and the importance of a within-subjects design incorporating behavioral, physiological, and biochemical measures.

Animals↗

PubMed1995

Distinct components of spatial learning revealed by prior training and NMDA receptor blockade.

Synaptic plasticity dependent on N-methyl-D-aspartate (NMDA) receptors is thought to underlie certain types of learning and memory. In support of this, both hippocampal long-term potentiation and spatial learning in a watermaze are impaired by blocking NMDA receptors with a selective antagonist D(-)-2-amino-5-phosphonovaleric acid (AP5) or by a mutation in one of the receptor subunits. Here we report, however, that the AP5-induced learning deficit can be almost completely prevented if rats are pretrained in a different watermaze before administration of the drug. This is not because of stimulus generalization, and occurs despite learning of the second task remaining hippocampus dependent. An AP5-induced learning deficit is, however, still seen if the animals are pretrained using a non-spatial task. Thus, despite its procedural simplicity, the watermaze may involve multiple cognitive processes with distinct pharmacological properties; although required for some component of spatial learning, NMDA receptors may not be required for encoding the spatial representation of a specific environment.

2-Amino-5-phosphonovalerate↗

PubMed1994

Intracerebroventricular injection of a nitric oxide synthase inhibitor does not affect long-term slope potentiation in vivo.

Although there is evidence from in vitro studies to suggest that NO synthesis may be involved in the induction of hippocampal LTP, other in vitro studies and experiments conducted in vivo have provided conflicting results. In agreement with previous work conducted in this laboratory using an i.p. route of administration, this paper reports that i.c.v. injections of the NO synthase inhibitor, N omego-nitro-L-arginine methyl ester (L-NAME), at a dose sufficient to inhibit hippocampal NO synthase by 90-95%, failed to block the induction of LTP in the dentate gyrus in vivo (as measured by the change in the slope of the early rising phase of the field EPSP). The failure to block LTP occurred following both a strong and a weak tetanus. L-NAME injections did, however, result in a small but transient increase in the baseline slope of the field EPSP, a more prolonged enhancement of the baseline population spike, and a significant attenuation of spike potentiation induced by a strong tetanus. These results offer no support for the hypothesis that NO synthase is required for the induction of the synaptic component of LTP, but do suggest a role for NO in the control of cell excitability in the hippocampus.

Amino Acid Oxidoreductases↗

PubMed1994

Inhibition of nitric oxide synthase does not impair spatial learning.

Nitric oxide (NO), a putative intercellular messenger in the CNS, may be involved in certain forms of synaptic plasticity and learning. This article reports a series of experiments investigating the effects of N omega-nitro-L-arginine methyl ester (L-NAME) upon various forms of learning and memory in the watermaze. L-NAME (75 mg/kg, i.p., sufficient to bring about > 90% inhibition of NO synthesis in brain) produced an apparent impairment in spatial learning when given to naive rats during acquisition (3 d, six training trials per day). This impairment was dose related, stereoselective, and attenuated by coadministration of L-arginine. A second study showed that L-NAME did not affect the retention of a previously learned spatial task. In addition, in a visual discrimination task, the rate at which criterion levels of performance were reached was unaffected by L-NAME. Thus, inhibition of NO synthase may cause a selective impairment of spatial learning without effect upon retention. However, analysis of the early training trials of the visual discrimination task revealed significantly elevated escape latencies in the L-NAME-treated rats, suggesting that inhibition of NO synthase may have more general effects. As normal rats learn the spatial task very rapidly, the possibility arises that the apparent deficit in learning is due to a disruption of some process other than learning per se. A further series of experiments investigated this possibility. L-NAME was found not to impair the learning of a new platform position in the same spatial environment. Surprisingly, L-NAME also had no effect on spatial learning in a second watermaze located in a novel spatial environment by rats well practiced with all aspects of watermaze training. Finally, L-NAME had no effect on spatial learning in naive rats trained with just one trial per day. Thus, systemic injection of an NO synthase inhibitor impairs behavioral performance in two tasks during their initial acquisition, but the basis of this functional disruption is unlikely to be due to any direct effect upon the mechanisms of spatial learning.

Amino Acid Oxidoreductases↗

PubMed1994

Inhibition of nitric oxide synthase does not prevent the induction of long-term potentiation in vivo.

Nitric oxide (NO), a putative intercellular messenger in the CNS, may be involved in certain forms of synaptic plasticity and learning. This article reports a series of experiments investigating whether an inhibitor of NO synthase, N omega-nitro-L-arginine methyl ester (L-NAME), affects long-term potentiation (LTP) in vivo, as the results of recent in vitro experiments would predict. L-NAME, given as an acute injection at a dose sufficient to inhibit hippocampal NO synthase (> 90%), had no effect on perforant path-dentate gyrus LTP induced by a strongly suprathreshold tetanus, but appeared to impair LTP induced by a weak near-threshold tetanus that may be more physiologically relevant. However, subsequent studies revealed that chronic L-NAME treatment (> 95% inhibition of NO synthase) had no effect upon LTP induction, and that acute (but not chronic) treatment resulted in a gradual but significant reduction in nontetanized baseline field potentials. The baseline shift appeared to be of a magnitude sufficient to account for the apparent impairment of weak tetanus-induced LTP. This possibility was further examined in a two-hemisphere experiment in which the time course of changes in the field EPSP of the nontetanized pathway served as the within-subject control for the tetanized pathway. No impairment of LTP induction was observed; indeed, if anything, there was a trend for greater potentiation with L-NAME. Because NO has also been implicated in the control of vasodilation, the effect of L-NAME on cerebrovascular function was also investigated. Peripheral blood pressure was significantly increased by L-NAME at the same dose that affected the field EPSP. Local cerebral glucose utilization was unchanged, while local cerebral blood flow decreased significantly in various brain regions, including the hippocampus, indicating an uncoupling of cerebral metabolism and blood flow. Thus, while NO synthase inhibition does not appear to limit the induction of LTP in vivo, it does reduce the size of baseline field EPSPs and affect local cerebrovascular function.

Amino Acid Oxidoreductases↗