fMRI Hippocampal Activity During a VirtualRadial Arm Maze

Numerous studies have shown that the hippocampus is critical for spatial memory. Within nonhuman research, a task often used to assess spatial memory is the radial arm maze. Because of the spatial nature of this task, this maze is often used to assess the function of the hippocampus. Our goal was to extrapolate this task to humans and examine whether healthy undergraduates utilize their hippocampus while performing a virtual reality version of the radial arm maze task. Thirteen undergraduates performed a virtual radial arm maze during functional magnetic resonance imaging. The brain maps of activity reveal bilateral hippocampal BOLD signal changes during the performance of this task. However, paradoxically, this BOLD signal change decreases during the spatial memory component of the task. Additionally, we note frontal cortex activity reflective of working memory circuits. These data reveal that, as predicted by the rodent literature, the hippocampus is involved in performing the virtual radial arm maze in humans. Hence, this virtual reality version may be used to assess the integrity of hippocampus so as to predict risk or severity in a variety of psychiatric disorders.     

Inactivation of the Anterior Cingulate Reveals Enhanced Reliance on Cortical Networks for Remote Spatial Memory Retrieval after Sequential Memory Processing

One system consolidation model suggests that as time passes, ensembles of cortical neurons form strong connections to represent remote memories. In this model, the anterior cingulate cortex (ACC) serves as a cortical region that represents remote memories. However, there is debate as to whether remote spatial memories go through this systems consolidation process and come to rely on the ACC. The present experiment examined whether increasing the processing demand on the hippocampus, by sequential training on two spatial tasks, would more fully engage the ACC during retrieval of a remote spatial memory. In this scenario, inactivation of the ACC at a remote time point was hypothesized to produce a severe memory deficit if rats had been trained on two, sequential spatial tasks. Rats were trained on a water maze (WM) task only or a WM task followed by a radial arm maze task. A WM probe test was given recently or remotely to all rats. Prior to the probe test, rats received an injection of saline or muscimol into the ACC. A subtle deficit in probe performance was found at the remote time point in the group trained on only one spatial task and treated with muscimol. In the group trained on two spatial tasks and treated with muscimol, a subtle deficit in probe performance was noted at the recent time point and a substantial deficit in probe performance was observed at the remote time point. c-Fos labeling in the hippocampus revealed more labeling in the CA1 region in all remotely tested groups than recently tested groups. Findings suggest that spatial remote memories come to rely more fully on the ACC when hippocampal processing requirements are increased. Results also suggest continued involvement of the hippocampus in spatial memory retrieval along with a progressive strengthening of cortical connections as time progresses.     

Intrusion of stereotyped responding in pigeon spatial memory tasks

Pigeons appear predisposed to respond in stereotyped manners in multi-item spatial memory tasks in which the items are simultaneously presented. We discovered this when we attempted to study primacy and recency serial position effects using a delayed matching of key location task (Experiment 1) and when we attempted to develop a keypack analog of the radial-arm maze task (Experiment 4). In Experiment 1 matching accuracy for first-pecked sample was above chance, approximately chance for the second-pecked sample, and below chance for the third-pecked sample. Experiments 2 and 3 showed that the results of Experiment 1 were due to “superstitious” stereotyped responding: When pigeons were allowed to respond to two or three keys in any order and then respond to the same keys again, they responded in the same order on the second occasion. In Experiment 4, the pigeons successfully avoided pecking previously-pecked keys but did so by pecking the keys in a fixed sequence.     

Tool Use Specific Adult Neurogenesis and Synaptogenesis in Rodent (Octodon degus) Hippocampus

We previously demonstrated that degus (Octodon degus), which are a species of small caviomorph rodents, could be trained to use a T-shaped rake as a hand tool to expand accessible spaces. To elucidate the neurobiological underpinnings of this higher brain function, we compared this tool use learning task with a simple spatial (radial maze) memory task and investigated the changes that were induced in the hippocampal neural circuits known to subserve spatial perception and learning. With the exposure to an enriched environment in home cage, adult neurogenesis in the dentate gyrus of the hippocampus was augmented by tool use learning, but not radial maze learning, when compared to control conditions. Furthermore, the proportion of new synapses formed in the CA3 region of the hippocampus, the target area for projections of mossy fiber axons emanating from newborn neurons, was specifically increased by tool use learning. Thus, active tool use behavior by rodents, learned through multiple training sessions, requires the hippocampus to generate more novel neurons and synapses than spatial information processing in radial maze learning.     

Impaired learning with enhanced hippocampal long-term potentiation in PTPdelta-deficient mice

Protein tyrosine phosphatase delta (PTPdelta) is a receptor-type PTP expressed in the specialized regions of the brain including the hippocampal CA2 and CA3, B lymphocytes and thymic medulla. To elucidate the physiological roles of PTPdelta, PTPdelta-deficient mice were produced by gene targeting. It was found that PTPdelta-deficient mice were semi-lethal due to insufficient food intake. They also exhibited learning impairment in the Morris water maze, reinforced T-maze and radial arm maze tasks. Interestingly, although the histology of the hippocampus appeared normal, the magnitudes of long-term potentiation (LTP) induced at hippocampal CA1 and CA3 synapses were significantly enhanced in PTPdelta-deficient mice, with augmented paired-pulse facilitation in the CA1 region. Thus, it was shown that PTPdelta plays important roles in regulating hippocampal LTP and learning processes, and that hippocampal LTP does not necessarily positively correlate with spatial learning ability. To our knowledge, this is the first report of a specific PTP involved in the regulation of synaptic plasticity or in the processes regulating learning and memory.     

Stable panoramic views facilitate snap-shot like memories for spatial reorientation in homing pigeons

Following spatial disorientation, animals can reorient themselves by relying on geometric cues (metric and sense) specified both by the macroscopic surface layout of an enclosed space and prominent visual landmarks in arrays. Whether spatial reorientation in arrays of landmarks is based on explicit representation of the geometric cues is a matter of debate. Here we trained homing pigeons (Columba livia) to locate a food-reward in a rectangular array of four identical or differently coloured pipes provided with four openings, only one of which allowed the birds to have access to the reward. Pigeons were trained either with a stable or a variable position of the opening on pipes, so that they could view the array either from the same or a variable perspective. Explicit mapping of configural geometry would predict successful reorientation irrespective of access condition. In contrast, we found that a stable view of the array facilitated spatial learning in homing pigeons, likely through the formation of snapshot-like memories.     

Landscape complexity influences route-memory formation in navigating pigeons

Observations of the flight paths of pigeons navigating from familiar locations have shown that these birds are able to learn and subsequently follow habitual routes home. It has been suggested that navigation along these routes is based on the recognition of memorized visual landmarks. Previous research has identified the effect of landmarks on flight path structure, and thus the locations of potentially salient sites. Pigeons have also been observed to be particularly attracted to strong linear features in the landscape, such as roads and rivers. However, a more general understanding of the specific characteristics of the landscape that facilitate route learning has remained out of reach. In this study, we identify landscape complexity as a key predictor of the fidelity to the habitual route, and thus conclude that pigeons form route memories most strongly in regions where the landscape complexity is neither too great nor too low. Our results imply that pigeons process their visual environment on a characteristic spatial scale while navigating and can explain the different degrees of success in reproducing route learning in different geographical locations.     

Effects of the NMDA antagonist MK-801 on radial maze performance in histidine-deficient rats

We examined the effects of a histidine-deficient diet on brain histamine contents as well as on learning and memory using the eight-arm radial maze in rats. A significant decrease in histamine content in the hippocampus was observed after long-term feeding of rats with a histidine-deficient diet. At the same time, significant enhancement of the acquisition process in radial maze performance was also observed. Pyrilamine did not show a significant effect on radial maze performance in histidine-deficient rats. On the other hand, pyrilamine caused a significant spatial memory deficit in control rats. Scopolamine was effective in inhibiting spatial memory in both histidine-deficient and control rats. MK-801 caused spatial memory deficits more potently in histidine-deficient rats than in controls. Brain glycine contents showed a significant increase in the hippocampus in histidine-deficient rats. These results indicated that the spatial memory deficits induced by MK-801 in histidine-deficient rats are closely related to increased glycine levels and activation of NMDA receptors.     

Odours stimulate neuronal activity in the dorsolateral area of the hippocampal formation during path integration

The dorsolateral area of the hippocampal formation of birds is commonly assumed to play a central role in processing information needed for geographical positioning and homing. Previous work has interpreted odour-induced activity in this region as evidence for an ‘olfactory map’. Here, we show, using c-Fos expression as a marker, that neuronal activation in the dorsolateral area of the hippocampal formation of pigeons is primarily a response to odour novelty, not to the spatial distribution of odour sources that would be necessary for an olfactory map. Pigeons exposed to odours had significantly more neurons activated in this area of the brain than pigeons exposed to filtered air with odours removed. This increased activity was observed only in response to unfamiliar odours. No change in activity was observed when pigeons were exposed to home odours. These findings are consistent with non-home odours activating non-olfactory components of the pigeon''s navigation system. The pattern of neuronal activation in the triangular and dorsomedial areas of the hippocampal formation was, by contrast, consistent with the possibility that odours play a role in providing spatial information.     

Behavior and spatial learning in birds in radial maze

Studies of spatial learning and memory of birds in radial maze are reviewed. The radial maze variants (standard, giant and open-field analog) are described; procedural problems of bird testing are discussed. Radial maze task performance of birds is compared with that of laboratory rats as a well-studied standard. Specific features of spatial learning in various taxonomic avian groups (pigeon, tits, corvids, chickens and others) are considered. The results of spatial memory studies in closely-related species with different ecology (food storing behavior, degree of caching specialization) and experiments with migrant birds and homing pigeons are discussed.     

Impaired representation of geometric relationships in humans with damage to the hippocampal formation

The pivotal role of the hippocampus for spatial memory is well-established. However, while neurophysiological and imaging studies suggest a specialization of the hippocampus for viewpoint-independent or allocentric memory, results from human lesion studies have been less conclusive. It is currently unclear whether disproportionate impairment in allocentric memory tasks reflects impairment of cognitive functions that are not sufficiently supported by regions outside the medial temporal lobe or whether the deficits observed in some studies are due to experimental factors. Here, we have investigated whether hippocampal contributions to spatial memory depend on the spatial references that are available in a certain behavioral context. Patients with medial temporal lobe lesions affecting systematically the right hippocampal formation performed a series of three oculomotor tasks that required memory of a spatial cue either in retinal coordinates or relative to a single environmental reference across a delay of 5000 ms. Stimulus displays varied the availability of spatial references and contained no complex visuo-spatial associations. Patients showed a selective impairment in a condition that critically depended on memory of the geometric relationship between spatial cue and environmental reference. We infer that regions of the medial temporal lobe, most likely the hippocampal formation, contribute to behavior in conditions that exceed the potential of viewpoint-dependent or egocentric representations. Apparently, this already applies to short-term memory of simple geometric relationships and does not necessarily depend on task difficulty or integration of landmarks into more complex representations. Deficient memory of basic geometric relationships may represent a core deficit that contributes to impaired performance in allocentric spatial memory tasks.     

Protective effects of methanol extract of Acori graminei rhizoma and Uncariae Ramulus et Uncus on ischemia-induced neuronal death and cognitive impairments in the rat

Acori graminei rhizoma (AGR) and Uncariae Ramulus et Uncus (URE) have been widely used as herbal medicine against ischemia. In order to investigate whether AGR and URE influenced cerebral ischemia-induced neuronal and cognitive impairments, we examined the effect of AGR and URE on ischemia-induced cell death in the striatum, cortex and hippocampus, and on the impaired learning and memory in the Morris water maze and radial eight-arm maze in rats. After middle cerebral artery occlusion (MCAO) for 2 h, rats were administered saline, AGR or URE (100 mg/kg, p.o.) daily for three weeks, followed by their training to the tasks. In the water maze test, the animals were trained to find a platform in a fixed position during 6 days and then received a 60-s probe trial in which the platform was removed from the pool on the 7th day. In the radial eight-arm maze, animals were tested six times per week for 1 week. Rats with ischemic insults showed impaired learning and memory on the tasks. Pretreatment with AGR and URE produced a significant improvement in escape latency to find the platform in the Morris water maze and in the number of choice errors in the radial arm maze test. Consistent with behavioral data, pretreatments with AGR and URE significantly reduced ischemia-induced cell death in the hippocampal CA1 area. These results demonstrated that AGR and URE have a protective effect against ischemia-induced neuronal loss and learning and memory damage. Our studies suggest that AGR and URE may be useful in the treatment of vascular dementia.     

Pharmacological correction of ketamine-impaired spatial memory of rats

Ketamine in dose 10 mg/kg increased the number of erroneous choices of rats with spatial strategy and didn't effect searching accuracy of rats with non-spatial strategy in 8-arm radial maze. Ketamine in doses 1 and 5 mg/kg disrupted rat short-term memory in delayed response reaction. Physostigmine and aspartic acid, but not haloperidol, diminished ketamine amnesia, therefore ketamine impaired the interaction of cholinergic and glutamate/aspartatergic neurons of hippocampal areas.     

Involvement of reduced acetylcholine release in Delta9-tetrahydrocannabinol-induced impairment of spatial memory in the 8-arm radial maze

To clarify the mechanism by which Delta9-tetrahydrocannabinol, a major psychoactive component of marijuana, impairs spatial memory in the 8-arm radial maze in rats via the cholinergic system, we used two acetylcholinesterase inhibitors, physostigmine and tetrahydroaminoacridine. Moreover, we examined the effect of Delta9-tetrahydrocannabinol on acetylcholine release in the frontal cortex and dorsal and ventral hippocampus using in vivo microdialysis. Physostigmine (0.01-0.05 mg/kg, i.p.) and tetrahydroaminoacridine (1-5 mg/kg, p.o.) improved the impairment of spatial memory induced by Delta9-tetrahydrocannabinol (6 mg/kg, i.p.) in the 8-arm radial maze. Delta9-tetrahydrocannabinol (6 mg/kg, i.p.) produced a significant decrease in acetylcholine release in the dorsal hippocampus as assessed by microdialysis. Moreover, tetrahydroaminoacridine at a dose of 1 mg/kg, which improved the impairment of spatial memory, reversed the decrease in acetylcholine release induced by Delta9-tetrahydrocannabinol in the dorsal hippocampus during 60-120 min after the Delta9-tetrahydrocannabinol injection. These findings suggest that inhibition of the cholinergic pathway by reduced acetylcholine release is one of the means by which Delta9-tetrahydrocannabinol impairs spatial memory in the 8-arm radial maze.     

Hippocampal Synaptic Expansion Induced by Spatial Experience in Rats Correlates with Improved Information Processing in the Hippocampus

Spatial water maze (WM) overtraining induces hippocampal mossy fiber (MF) expansion, and it has been suggested that spatial pattern separation depends on the MF pathway. We hypothesized that WM experience inducing MF expansion in rats would improve spatial pattern separation in the hippocampal network. We first tested this by using the the delayed non-matching to place task (DNMP), in animals that had been previously trained on the water maze (WM) and found that these animals, as well as animals treated as swim controls (SC), performed better than home cage control animals the DNMP task. The “catFISH” imaging method provided neurophysiological evidence that hippocampal pattern separation improved in animals treated as SC, and this improvement was even clearer in animals that experienced the WM training. Moreover, these behavioral treatments also enhance network reliability and improve partial pattern separation in CA1 and pattern completion in CA3. By measuring the area occupied by synaptophysin staining in both the stratum oriens and the stratun lucidum of the distal CA3, we found evidence of structural synaptic plasticity that likely includes MF expansion. Finally, the measures of hippocampal network coding obtained with catFISH correlate significantly with the increased density of synaptophysin staining, strongly suggesting that structural synaptic plasticity in the hippocampus induced by the WM and SC experience is related to the improvement of spatial information processing in the hippocampus.     

Ablating Adult Neurogenesis in the Rat Has No Effect on Spatial Processing: Evidence from a Novel Pharmacogenetic Model

The function of adult neurogenesis in the rodent brain remains unclear. Ablation of adult born neurons has yielded conflicting results about emotional and cognitive impairments. One hypothesis is that adult neurogenesis in the hippocampus enables spatial pattern separation, allowing animals to distinguish between similar stimuli. We investigated whether spatial pattern separation and other putative hippocampal functions of adult neurogenesis were altered in a novel genetic model of neurogenesis ablation in the rat. In rats engineered to express thymidine kinase (TK) from a promoter of the rat glial fibrillary acidic protein (GFAP), ganciclovir treatment reduced new neurons by 98%. GFAP-TK rats showed no significant difference from controls in spatial pattern separation on the radial maze, spatial learning in the water maze, contextual or cued fear conditioning. Meta-analysis of all published studies found no significant effects for ablation of adult neurogenesis on spatial memory, cue conditioning or ethological measures of anxiety. An effect on contextual freezing was significant at a threshold of 5% (P = 0.04), but not at a threshold corrected for multiple testing. The meta-analysis revealed remarkably high levels of heterogeneity among studies of hippocampal function. The source of this heterogeneity remains unclear and poses a challenge for studies of the function of adult neurogenesis.     

Tetrachlorodibenzo-p-dioxin exposure alters radial arm maze performance and hippocampal morphology in female AhR mice

Perinatal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been reported to alter spatial learning in rats tested on a radial arm maze (RAM). TCDD is believed to exert most of its effects through binding to the aryl hydrocarbon receptor (AhR). To determine whether the AhR mediates TCDD-induced alterations in spatial learning, we tested male and female AhR-knockout (AhR-/-), heterozygous (AhR+/-) and wild-type (AhR+/+) mice on the RAM. AhR+/- male and female mice were time mated, and treated dams were dosed with 5 microg TCDD/kg body weight on day 13 of gestation. When offspring reached adulthood, male and female AhR+/+, AhR+/- and AhR-/- mice from TCDD-exposed and unexposed litters were tested on the eight-arm RAM. After testing, we examined hippocampal morphology as visualized by the Timm's silver sulfide stain. TCDD-exposed female AhR+/- mice made more errors than their respective controls on the RAM and exhibited a decrease in the size of the intra- and infrapyramidal mossy fiber (IIP-MF) field of the hippocampus. None of the other TCDD-exposed groups differed from their respective control groups with regard to maze performance or hippocampal morphology. The reduction of IIP-MF field indicates a possible morphological basis for the learning deficit that was observed in the female AhR+/- mice. It is hypothesized that the effect of TCDD exposure is AhR dependent and that TCDD may alter GABAergic activity in the hippocampus of female mice during development.     

Increasing Hippocampal Estrogen Receptor Alpha Levels via Viral Vectors Increases MAP Kinase Activation and Enhances Memory in Aging Rats in the Absence of Ovarian Estrogens

We previously demonstrated that aged ovariectomized rats that had received prior estradiol treatment in middle-age exhibited increased levels of estrogen receptor alpha (ERα) in the hippocampus as well as enhanced hippocampal dependent memory as compared to aged rats that had not received mid-life estradiol treatment. These effects persisted long after the estradiol treatment had been terminated. The goal of the current experiment was to determine if increased expression of ERα in the hippocampus, in the absence of exogenously administered estrogens, can impact the hippocampus and cognitive function in aging ovariectomized rats. Middle-aged rats were trained for 24 days on an eight-arm radial maze spatial memory task. All rats were then ovariectomized. Forty days later, rats received either lentiviral delivery to the hippocampus of the gene encoding ERα (lenti-ERα) or a control virus. Rats were tested on delay trials in the radial-maze in which delays of varying lengths were imposed between the fourth and fifth arm choices. Following behavior testing, hippocampi were immunostained using western blotting for ERα, the ERα-regulated protein choline acetyltransferase, and phosphorylation of the ERα-regulated kinases, ERK/MAPK and Akt. Results revealed that aging ovariectomized rats that received delivery of lenti-ERα to the hippocampus exhibited enhanced spatial memory as indicated by increased arm-choice accuracy across delays as compared to ovariectomized rats that received control virus. Western blot data revealed that lenti-ERα delivery significantly increased levels of ERα and phosphorylated ERK/MAPK and had no impact on levels of ChAT or phosphorylation of Akt. Results indicate that increasing hippocampal levels of ERα in aging females in the absence of ovarian or exogenously administered estrogens leads to increases in phosphorylation of ERK/MAPK as well as in enhanced memory.     

Time‐of‐Day Discriminative Learning: Contrasting the Use of Spatial Compared to Feature Information in Homing Pigeons (Columba livia)

This study examined time‐of‐day associative learning to either spatial or feature information in homing pigeons in an open‐field, laboratory setting. Homing pigeons are well known for their navigational abilities and generally have been shown to rely more heavily on spatial than nonspatial cues in recognizing a goal. However, during goal localization, homing pigeons also successfully use nonspatial, feature information. Homing pigeons were divided into two groups and were trained to locate two time‐of‐day dependent, food reward sites using either discriminative spatial or feature information. Because of the importance of the hippocampus in controlling avian memory, we hypothesized that homing pigeons trained with spatial cues would be superior in learning the time‐of‐day discrimination compared to the pigeons trained with feature cues. Indeed, homing pigeons that were trained with spatial information outperformed the pigeons trained with feature information in learning the time‐of‐day discrimination task.