Impaired long-term memory retention: common denominator for acutely or genetically reduced hippocampal neurogenesis in adult mice.

In adult rodents, decreasing hippocampal neurogenesis experimentally using different approaches often impairs performance in hippocampus-dependent processes. Nonetheless, functional relevance of adult neurogenesis is far from being unraveled, and deficits so far described in animal models often lack reproducibility. One hypothesis is that such differences might be the consequence of the extent of the methodological specificity used to alter neurogenesis rather than the extent to which adult neurogenesis is altered. To address this, we focused on cranial irradiation, the most widely used technique to impair hippocampal neurogenesis and consequentially induce hippocampus-dependent behavioral deficits. To investigate the specificity of the technique, we thus exposed 4-5 months old female cyclin D2 knockout mice, a model lacking physiological levels of olfactory and hippocampal neurogenesis, to an X-ray dose of 10 Gy, reported to specifically affect transiently amplifying precursors. After a recovery period of 1.5 months, behavioral tests were performed and probed for locomotor activity, habituation, anxiety, and spatial learning and memory. Spatial learning in the Morris water maze was intact in all experimental groups. Although spatial memory retention assessed 24h following acquisition was also intact in all mice, irradiated wild type and cyclin D2 knockout mice displayed memory deficits one week after acquisition. In addition, we observed significant differences in tests addressing anxiety and locomotor activity dependent on the technique used to alter neurogenesis. Whereas irradiated mice were hyperactive regardless of their genotype, cyclin D2 knockout mice were hypoactive in most of the tests and displayed altered habituation. The present study emphasizes that different approaches aimed at decreasing adult hippocampal neurogenesis may result in distinct behavioral impairments related to locomotion and anxiety. In contrast, spatial long-term memory retention is consistently altered after both approaches suggesting a plausible implication of hippocampal neurogenesis in this cognitive process.

Long-term effects of 56Fe irradiation on spatial memory of mice: role of sex and apolipoprotein E isoform.

PURPOSE: To assess whether the effects of cranial (56)Fe irradiation on the spatial memory of mice in the water maze are sex and apolipoprotein E (apoE) isoform dependent and whether radiation-induced changes in spatial memory are associated with changes in the dendritic marker microtubule-associated protein 2 (MAP-2) and the presynaptic marker synaptophysin. METHODS AND MATERIALS: Two-month-old male and female mice expressing human apoE3 or apoE4 received either a 3-Gy dose of cranial (56)Fe irradiation (600 MeV/amu) or sham irradiation. Mice were tested in a water maze task 13 months later to assess effects of irradiation on spatial memory retention. After behavioral testing, the brain tissues of these mice were analyzed for synaptophysin and MAP-2 immunoreactivity. RESULTS: After irradiation, spatial memory retention of apoE3 female, but not male, mice was impaired. A general genotype deficit in spatial memory was observed in sham-irradiated apoE4 mice. Strikingly, irradiation prevented this genotype deficit in apoE4 male mice. A similar but nonsignificant trend was observed in apoE4 female mice. Although there was no change in MAP-2 immunoreactivity after irradiation, synaptophysin immunoreactivity was increased in irradiated female mice, independent of genotype. CONCLUSIONS: The effects of (56)Fe irradiation on the spatial memory retention of mice are critically influenced by sex, and the direction of these effects is influenced by apoE isoform. Although in female mice synaptophysin immunoreactivity provides a sensitive marker for effects of irradiation, it cannot explain the apoE genotype-dependent effects of irradiation on the spatial memory retention of the mice.

Inhibition of adult hippocampal neurogenesis disrupts contextual learning but spares spatial working memory, long-term conditional rule retention and spatial reversal.

Neurogenesis in the adult dentate gyrus (DG) of the hippocampus has been implicated in neural plasticity and cognition but the specific functions contributed by adult-born neurons remain controversial. Here, we have explored the relationship between adult hippocampal neurogenesis and memory function using tasks which specifically require the participation of the DG. In two separate experiments several groups of rats were exposed to fractionated ionizing radiation (two sessions of 7 Gy each on consecutive days) applied either to the whole brain or focally, aiming at a region overlying the hippocampus. The immunocytochemical assays showed that the radiation significantly reduced the expression of doublecortin (DCX), a marker for immature neurons, in the dorsal DG. Ultrastructural examination of the DG region revealed disruption of progenitor cell niches several weeks after the radiation. In the first experiment, whole-brain and focal irradiation reduced DCX expression by 68% and 43%, respectively. Whole-brain and focally-irradiated rats were unimpaired compared with control rats in a matching-to-place (MTP) working memory task performed in the T-maze and in the long-term retention of the no-alternation rule. In the second experiment, focal irradiation reduced DCX expression by 36% but did not impair performance on (1) a standard non-matching-to-place (NMTP) task, (2) a more demanding NMTP task with increasingly longer within-trial delays, (3) a long-term retention test of the alternation rule and (4) a spatial reversal task. However, rats irradiated focally showed clear deficits in a "purely" contextual fear-conditioning task at short and long retention intervals. These data demonstrate that reduced adult hippocampal neurogenesis produces marked deficits in the rapid acquisition of emotionally relevant contextual information but spares spatial working memory function, the long-term retention of acquired spatial rules and the ability to flexibly modify learned spatial strategies.

Acute exposure to a 50 Hz magnetic field impairs consolidation of spatial memory in rats.

This study was planned to evaluate the effect of an exposure to magnetic fields on consolidation and retrieval of hippocampus dependent spatial memory using a water maze. In Experiments 1 and 2, rats were trained in a hidden version (spatial) of water maze task with two blocks of four trials. The retention of spatial memory was evaluated 48 h later. Exposure to a 50 Hz 8 mT, but not 2 mT magnetic fields for 20 min immediately after training impaired retention performance. The same time exposure shortly before retention testing had no effect. In Experiment 3, rats were trained in a cued version of water maze with two blocks of four trials. Exposure to magnetic field at 8 mT for 20 min immediately after training did not impair retention performance. These findings indicate that acute exposure to a 50 Hz magnetic field at 8 mT for short time can impair consolidation of spatial memory.

Facilitation of performance in a working memory task with rTMS stimulation of the precuneus: frequency- and time-dependent effects.

Although improvements in performance due to TMS have been demonstrated with some cognitive tasks, performance improvement has not previously been demonstrated with working memory tasks. In the present study, a delayed match-to-sample task was used in which repetitive TMS (rTMS) at 1, 5, or 20 Hz was applied to either left dorsolateral prefrontal or midline parietal cortex during the retention (delay) phase of the task. Only 5 Hz stimulation to the parietal site resulted in a significant decrease in reaction time (RT) without a corresponding decrease in accuracy. This finding was replicated in a second experiment, in which 5 Hz rTMS at the parietal site was applied during the retention phase or during presentation of the recognition probe. Significant speeding of RT occurred in the retention phase but not the probe phase. This finding suggests that TMS may improve working memory performance, in a manner that is specific to the timing of stimulation relative to performance of the task, and to stimulation frequency.

Post-training intracranial self-stimulation facilitates a hippocampus-dependent task.

Previous research has shown that post-training intracranial self-stimulation facilitates implicit or procedural memory. To know whether it can also facilitate explicit memory, post-training intracranial self-stimulation was given to Wistar rats immediately after every daily session of a delayed spatial alternation task that seems to depend on the integrity of the hippocampal memory system. We tested the effects of intracranial self-stimulation in three consecutive learning phases which tried to make the task progressively more difficult: 10 s delay (D10 phase), 30 s delay (D30 phase), and inverting the starting position of the animals to make their response more dependent on allocentric cues (INV phase). Every phase finished when each rat achieved a fixed learning criterion. Intracranial self-stimulation facilitated the flexible expression of the learned response (INV phase). That is, when the starting position was randomly inverted, only the rats that received intracranial self-stimulation maintained the performance level acquired in the previous training phases. Changing the starting position reduced the correct performance of the non-treated subjects, which need more training sessions to achieve the learning criterion and made less correct responses than treated rats. These findings show that post-training intracranial self-stimulation can facilitate hippocampus-dependent memories.

Reminder effects: the molecular cascade following a reminder in young chicks does not recapitulate that following training on a passive avoidance task.

Memory traces, once established, are no longer sensitive to disruption by metabolic inhibitors. However, memories reactivated by reminder are once again vulnerable, in a time-dependent manner, to amnestic treatment. To determine whether the metabolic events following a reminder recapitulate those following initial training we examined the temporal dynamics of amnesia induced by the protein synthesis inhibitor anisomycin and the glycosylation inhibitor 2-deoxygalactose. The effects of both were transient and dependent on time of reminder post-training and time of injection relative to reminder, and differed from those following initial training. 2-[(14)C]-deoxyglucose uptake increased in two brain regions, the intermediate medial hyperstriatum ventrale (IMHV) and lobus parolfactorius (LPO) following reminder as it did following training, but the increase was bilateral rather than confined to the left hemisphere and was more marked in LPO than IMHV. C-fos expression after reminder was increased only in the LPO, the chick brain region associated with a late phase of memory processing and recall. Thus although, like initial consolidation, memory processing after reminder is sensitive to inhibitors of protein synthesis and glycosylation, the temporal and pharmacological dynamics indicate differences between these two processes.

[Effects of different light-dark cycle on learning and memory in mice].

OBJECTIVE: To study the effect of different light-dark cycles on learning and memory in mice. METHOD: Seventy-two ICR mice were raised under different light-dark cycles including LD 5h/5h, LD 12h/12h and LD 22h/22h for 6 weeks. The locomotor activity was recorded continuously. Morris water-maze task was used as the judging criteria for spatial learning and memory. RESULT: The locomotor activity rhythm was consistent with the light-dark cycle. The period of light-dark cycle shorter than 24 h such as 10 h could effect on the ability of learning and memory in mice. CONCLUSION: The short period of light-dark cycle can improve the ability of learning and memory in mice.

Suppression of adult neurogenesis impairs olfactory learning and memory in an adult insect.

Although adult neurogenesis has now been demonstrated in many different species, the functional role of newborn neurons still remains unclear. In the house cricket, a cluster of neuroblasts, located in the main associative center of the insect brain, keeps producing new interneurons throughout the animal's life. Here we address the functional significance of adult neurogenesis by specific suppression of neuroblast proliferation using gamma irradiation of the insect's head and by examining the impact on the insect's learning ability. Forty gray irradiation performed on the first day of adult life massively suppressed neuroblasts and their progeny without inducing any noticeable side effect. We developed a new operant conditioning paradigm especially designed for crickets: the "escape paradigm." Using olfactory cues, visual cues, or both, crickets had to choose between two holes, one allowing them to escape and the other leading to a trap. Crickets lacking adult neurogenesis exhibited delayed learning when olfactory cues alone were used. Furthermore, retention 24 hr after conditioning was strongly impaired in irradiated crickets. By contrast, when visual cues instead of olfactory ones were provided, performance of irradiated insects was only slightly affected; when both olfactory and visual cues were present, their performance was not different from that of controls. From these results, it can be postulated that newborn neurons participate in the processing of olfactory information required for complex operant conditioning.

Progress of memory function after radiation therapy in patients with nasopharyngeal carcinoma.

The authors evaluated the late neurocognitive profile and progress of memory functions in 60 patients with primary nasopharyngeal carcinoma who had been treated with radiation therapy for more than 2 years. Forty had imaging evidence of temporal lobe injury (TLI-positive), and 20 did not (TLI-negative). The patients and 19 healthy control subjects, matched with the patients for age and educational level, underwent extensive memory assessments. Seventeen patients (10 TLI-positive, 7 TLI-negative) were reassessed after an average of 28 months for progress of memory functions. The patient groups performed significantly worse on most memory tests compared with the normal subjects. Patients with memory complaints had lower scores for verbal memory than those without such complaints. The TLI-positive and TLI-negative groups did not differ significantly from each other in cognitive performance. At follow-up, visual memory performance had deteriorated, while verbal memory remained more stable.

Behavioral sensitivity of rats to extremely-low-frequency magnetic fields.

Work in our laboratory has revealed autonomic and/or behavioral sensitivity of mice, rats, and a domestic fowl to extremely-low-frequency (ELF) or nominally static magnetic (B) fields at flux densities between 250 and 1700 microT (rms). To extend our work, an automated exposure and data-acquisition system was used with the technique of conditional suppression to assess behavioral sensitivity to time-varying B fields. Each of five rats was exposed aperiodically to a B field during 3 min warning periods that terminated in a brief electric shock. The difference between rates of lever pressing during B-field warning periods and rates during immediately antecedent, 3 min control periods was analyzed at frequencies of 7, 16, 30, 60, and 65.1 Hz. To produce equivalent induced voltages in the rat at each frequency, graded flux densities were established that ranged from 1900 microT at 7 Hz to 200 microT at 65.1 Hz. Analysis of differences in lever-pressing rates revealed that in a given session of testing the rats would increasingly suppress responding when exposed to a B field, but this trend was independent of frequency. This experiment provides evidence of behavioral sensitivity by a mammal to an ELF magnetic field.

Memory-based learning in preweanling and adult rats after infantile x-irradiation-induced hippocampal granule cell hypoplasia.

Infantile exposure to x-irradiation induced severe hippocampal granule cell hypoplasia in preweanling and young adult rats. Hippocampally damaged pups, tested at 16 days of age, showed deficits in a memory-based discrimination based on single alternations of reward and nonreward when training was conducted at a 60-s intertrial interval (ITI) but not when conducted at a 30-s ITI. This deficit was still present at the 60-s ITI in animals x-irradiated in infancy and tested at 60-65 days of age. These data provide further support for the role of the hippocampus in intermediate-term memory and demonstrate, in a developmental context, the importance of an intact hippocampus in learning that depends on nonspatial memory.