Transplantation of hippocampal cell lines restore spatial learning in rats with ventral subicular lesions.

We have demonstrated in our previous studies that ventral subicular lesion induces neurodegeneration of the hippocampus and produces cognitive impairment in rats. In the present study, the efficacy of transplanted green fluorescent protein (GFP)-labeled hippocampal cell line (H3-GFP) cells in establishing functional recovery in ventral subicular lesioned rats has been evaluated. The survival of H3-GFP transplants and their ability to express trophic factors in vivo were also investigated. Adult male Wistar rats were subjected to selective lesioning of ventral subiculum and were transplanted with H3-GFP cells into the cornu ammonis 1 (CA1) hippocampus. The transplants settled mainly in the dentate gyrus and expressed neurotrophic factors, brain-derived neurotrophic factor (BDNF), and basic fibroblast growth factor (bFGF). The ventral subicular lesioned (VSL) rats with H3-GFP transplants showed enhanced expression of BDNF in the hippocampus and performed well in eight-arm radial maze and Morris water maze tasks. The VSL rats without hippocampal transplants continued to show cognitive impairment in task learning. The present study demonstrated the H3-GFP transplants mediated recovery of cognitive functions in VSL rats. Our study supports the notion of graft meditated host regeneration and functional recovery through trophic support, although these mechanisms require further investigation. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Perturbed dentate gyrus function in serotonin 5-HT2C receptor mutant mice

Serotonin systems have been implicated in the regulation of hippocampal function. Serotonin 5-HT2C receptors are widely expressed throughout the hippocampal formation, and these receptors have been proposed to modulate synaptic plasticity in the visual cortex. To assess the contribution of 5-HT2C receptors to the serotonergic regulation of hippocampal function, mice with a targeted 5-HT2C-receptor gene mutation were examined. An examination of long-term potentiation at each of four principal regions of the hippocampal formation revealed a selective impairment restricted to medial perforant path-dentate gyrus synapses of mutant mice. This deficit was accompanied by abnormal performance in behavioral assays associated with dentate gyrus function. 5-HT2C receptor mutants exhibited abnormal performance in the Morris water maze assay of spatial learning and reduced aversion to a novel environment. These deficits were selective and were not associated with a generalized learning deficit or with an impairment in the discrimination of spatial context. These results indicate that a genetic perturbation of serotonin receptor function can modulate dentate gyrus plasticity and that plasticity in this structure may contribute to neural mechanisms underlying hippocampus-dependent behaviors.     

Hippocampal and caudate metabolic activity associated with different navigational strategies.

Hippocampal and striatal systems are widely related to spatial tasks. Depending on the strategies used, different memory systems can be activated. In this study, the authors used the cytochrome c-oxidase technique as a functional marker of the hippocampal and dorsal striatum activity related to training in several water maze tasks. Current results show a differential participation of the hippocampal and striatal systems in navigation. When spatial information is relevant, participation of the hippocampal system is more important, and when the task is similar to a response learning one, the striatal system is more active. According to computational models, CA3 seems to be more active when the associative demand is higher, whereas CA1 and dentate gyrus activity are higher when spatial information processing is required. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Exercise increases hippocampal neurogenesis to high levels but does not improve spatial learning in mice bred for increased voluntary wheel running.

The hippocampus is important for the acquisition of new memories. It is also one of the few regions in the adult mammalian brain that can generate new nerve cells. The authors tested the hypothesis that voluntary exercise increases neurogenesis and enhances spatial learning in mice selectively bred for high levels of wheel running (S mice). Female S mice and outbred control (C) mice were housed with and without running wheels for 40 days. 5-Bromodeoxyuridine was used to label dividing cells. The Morris water maze was used to measure spatial learning. C runners showed a strong positive correlation between running distance and new cell number, as well as improved learning. In S runners, neurogenesis increased to high levels that reached a plateau, but no improvement in learning occurred. This is the first evidence that neurogenesis can occur without learning enhancement. The authors propose an alternative function of neurogenesis in the control of motor behavior. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Endocrine regulation of cognition and neuroplasticity: Our pursuit to unveil the complex interaction between hormones, the brain, and behaviour.

Gonadal and stress hormones modulate neuroplasticity and behaviour. This review focuses on our findings over the past decade on the effects of estrogens and androgens on hippocampal neurogenesis, hippocampus-dependent learning and memory and the effects of reproductive experience in the rodent. Evidence suggests that acute estradiol initially enhances and subsequently suppresses cell proliferation in the dentate gyrus of adult female rodents. Repeated exposure to estradiol modulates hippocampal neurogenesis and cell death in adult female, but not male, rodents while, testosterone and dihydrotestosterone upregulate hippocampal neurogenesis in adult male rodents. Estradiol dose-dependently affects different brain regions involved in working memory (prefrontal cortex, hippocampus), reference memory (hippocampus) and conditioned place preference (amygdala). Pregnancy and motherhood differentially regulate adult hippocampal neurogenesis and spatial working memory in the dam after weaning. These studies and others demonstrate that the female brain responds to steroid hormones differently than the male brain. It is of the upmost importance to investigate the effects on neuroplasticity and behaviour in both the male and the female, particularly when modelling diseases that exhibit sex differences in incidence, etiology or treatment. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Preserved neuron number in the hippocampus of aged rats with spatial learning deficits

Hippocampal neuron loss is widely viewed as a hallmark of normal aging. Moreover, neuronal degeneration is thought to contribute directly to age-related deficits in learning and memory supported by the hippocampus. By taking advantage of improved methods for quantifying neuron number, the present study reports evidence challenging these long-standing concepts. The status of hippocampal-dependent spatial learning was evaluated in young and aged Long-Evans rats using the Morris water maze, and the total number of neurons in the principal cell layers of the dentate gyrus and hippocampus was quantified according to the optical fractionator technique. For each of the hippocampal fields, neuron number was preserved in the aged subjects as a group and in aged individuals with documented learning and memory deficits indicative of hippocampal dysfunction. The findings demonstrate that hippocampal neuronal degeneration is not an inevitable consequence of normal aging and that a loss of principal neurons in the hippocampus fails to account for age-related learning and memory impairment. The observed preservation of neuron number represents an essential foundation for identifying the neurobiological effects of hippocampal aging that account for cognitive decline.     

Posttraining paradoxical sleep in rats is increased after spatial learning in the Morris water maze.

The role of posttraining paradoxical sleep (PS) in spatial or nonspatial learning in the Morris water maze was evaluated. Sprague-Dawley rats were given a 12-trial training session in either the hidden or the visible platform versions of the task. Subgroups then underwent paradoxical sleep deprivation (PSD) beginning at different times after training. Rats with PSD imposed from 14 hr after spatial training had poorer retest scores than any other group. Other rats, implanted with electrodes to permit continuous recording of sleep electroencephalography, were found to undergo a prolonged period of elevated PS after spatial training. By contrast, rats trained in the nonspatial version of the water maze task did not show retention deficits after PSD or elevated PS after training. These results support a role for PS in spatial, but not nonspatial, learning in the Morris water maze. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Increased neurogenesis in the dentate gyrus after transient global ischemia in gerbils

Neurogenesis in the dentate gyrus of adult rodents is regulated by NMDA receptors, adrenal steroids, environmental stimuli, and seizures. To determine whether ischemia affects neurogenesis, newly divided cells in the dentate gyrus were examined after transient global ischemia in adult gerbils. 5-Bromo-2'-deoxyuridine-5'-monophosphate (BrdU) immunohistochemistry demonstrated a 12-fold increase in cell birth in the dentate subgranular zone 1-2 weeks after 10 min bilateral common carotid artery occlusions. Two minutes of ischemia did not significantly increase BrdU incorporation. Confocal microscopy demonstrated that BrdU immunoreactive cells in the granule cell layer colocalized with neuron-specific markers for neuronal nuclear antigen, microtubule-associated protein-2, and calbindin D28k, indicating that the newly divided cells migrated from the subgranular zone into the granule cell layer and matured into neurons. Newborn cells with a neuronal phenotype were first seen 26 d after ischemia, survived for at least 7 months, were located only in the granule cell layer, and comprised approximately 60% of BrdU-labeled cells in the granule cell layer 6 weeks after ischemia. The increased neurogenesis was not attributable to entorhinal cortical lesions, because no cell loss was detected in this region. Ischemic preconditioning for 2 min, which protects CA1 neurons against subsequent ischemic damage, did not prevent increased neurogenesis in the granule cell layer after a subsequent severe ischemic challenge. Thus, ischemia-induced dentate neurogenesis is not attributable to CA1 neuronal loss. Enhanced neurogenesis in the dentate gyrus may be a compensatory adaptive response to ischemia-associated injury and could promote functional recovery after ischemic hippocampal injury.     

Sustained long term potentiation and anxiety in mice lacking the Mas protooncogene

The Mas protooncogene is a maternally imprinted gene encoding an orphan G protein-coupled receptor expressed mainly in forebrain and testis. Here, we provide evidence for a function of Mas in the central nervous system. Targeted disruption of the Mas protooncogene leads to an increased durability of long term potentiation in the dentate gyrus, without affecting hippocampal morphology, basal synaptic transmission, and presynaptic function. In addition, Mas-/- mice show alterations in the onset of depotentiation. The permissive influence of Mas ablation on hippocampal synaptic plasticity is paralleled by behavioral changes. While spatial learning in the Morris water maze is not significantly influenced, Mas-deficient animals display an increased anxiety as assessed in the elevated-plus maze. Thus, Mas is an important modulating factor in the electrophysiology of the hippocampus and is involved in behavioral pathways in the adult brain.     

Long-term potentiation and spatial learning are associated with increased phosphorylation of TrkB and extracellular signal-regulated kinase (ERK) in the dentate gyrus: Evidence for a role for brain-derived neurotrophic factor.

In this study, the authors investigate changes in the presynaptic terminal of the dentate gyrus that accompany 2 types of hippocampal-dependent plasticity: spatial leanting and long-term potentiation (LTP). Parallel changes occurred in the dentate gyrus of rats that had undergone training in the Morris water maze and had sustained LTP. In both cases, KCl-induced brain-derived neurotrophic factor release was increased, and this was accompanied by increased phosphorylation of TrkB and the mitogen-activated protein kinase, ERK. Glutamate release was also enhanced, and the data suggest thak this may be a consequence of increased activation of TrkB and ERK. Because the data indicate that similar cellular modifications are shared by these 2 forms of plasticity, they provide circumstantial evidence that LTP satisfies some of the requirements of a memory-inducing cellular substrate. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Correction to Rhodes et al. (2003): Exercise Increases Hippocampal Neurogenesis to High Levels but Does Not Improve Spatial Learning in Mice Bred for Increased Voluntary Wheel Running.

Reports an error in the original article by Justin S. Rhodes, Henriette van Praag, Susan Jeffrey, Isabelle Girard, Gordon S. Mitchell, Theodore Garland Jr., and Fred H. Gage (Behavioral Neuroscience, 2003, Vol. 117, No. 5, pp. 1006-1016. In Figure 3, the symbols representing the "Control runners" and "Selected no wheels" groups were reversed in Panel B. They should match the legend in Panel A: Open circles should appear as solid squares, and solid squares as open circles. (The following abstract of this article originally appeared in record 2003-08567-013.) The hippocampus is important for the acquisition of new memories. It is also one of the few regions in the adult mammalian brain that can generate new nerve cells. The authors tested the hypothesis that voluntary exercise increases neurogenesis and enhances spatial learning in mice selectively bred for high levels of wheel running (S mice). Female S mice and outbred control (C) mice were housed with and without running wheels for 40 days. 5-Bromodeoxyuridine was used to label dividing cells. The Morris water maze was used to measure spatial learning. C runners showed a strong positive correlation between running distance and new cell number, as well as improved learning. In S runners, neurogenesis increased to high levels... (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Extinction, renewal, and spontaneous recovery of a spatial preference in the water maze.

Four experiments with C57BL/6 mice investigated extinction of a spatial preference in the Morris water maze. In Experiment 1, a spatial preference was extinguished by exposing mice to the water maze in the absence of a platform but in the presence of the distal spatial cues. In Experiment 2, extinction occurred when the platform was removed from the pool, when it was presented in random locations, or when it was presented consistently in the opposite location. Contextual renewal (Experiment 3) and spontaneous recovery (Experiment 4) of spatial preferences argue against an interpretation of extinction in terms of unlearning and instead suggest that extinction in the water maze, like extinction in Pavlovian conditioning, suppresses the original association. Implications of these findings for theories of spatial learning and hippocampal function are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Performance on spatial working memory tasks after dorsal or ventral hippocampal lesions and adjacent damage to the subiculum.

Rats with excitotoxic lesions of the dorsal or ventral hippocampus and control rats were trained on 2 spatial working memory tasks: the standard version of the radial maze with 8 baited arms and the nonmatching-to-place procedure in the T maze. Dorsal lesions produced deficits in both tasks, whereas ventral lesions did not affect learning in either of them. A volumetric analysis of subicular damage showed that dorsal hippocampal lesions caused a deficit in the nonmatching-to-place only when accompanied by damage to the dorsal subiculum; on the other hand, lesions to the dorsal hippocampus impaired performance in the radial-arm maze regardless of the extent of subicular damage. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Beacon training in a water maze can facilitate and compete with subsequent room cue learning in rats.

In Stage 1 of 4 experiments in which rats completed a water-maze blocking procedure, experimental groups were trained to use a predictive beacon (hanging above, connected to, or displaced from the platform) to find a submerged escape platform in the presence of predictive or irrelevant background cues and in the presence or absence of irrelevant landmarks. In Stage 2, a fixed beacon, landmarks, and background cues all predicted the platform location. A Room Test (landmarks and background cues only) showed that Stage 1 training with a fixed hanging beacon or the moving displaced beacon facilitated Stage 2 learning of predictive room cues for experimental relative to control subjects. In contrast, Stage 1 training with a moving pole beacon interfered with Stage 2 learning about predictive room cues relative to controls, whereas training with a fixed pole or moving hanging beacon had no effect. We conclude that multiple spatial learning processes influence locating an escape platform in the water maze. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Learning impairments of hippocampal-lesioned mice in a paddling pool.

Control mice rapidly learned to escape from shallow water in a paddling pool, which combined elements of the Morris water maze and the Barnes holeboard maze. The pool's transparent perimeter wall contained 12 exits, only 1 of which led to an escape tunnel. Learning was impaired in mice with cytotoxic lesions of the hippocampus. Probe trials suggested that the controls were using extramaze cues. When the exit was blocked, controls, but not hippocampals, spent more time searching in this previously correct sector. When the spatial location of the exit was changed, hippocampals escaped more quickly, as they showed no preference for the old location. These results may be useful in the assessment of hippocampal dysfunction, particularly in genetically manipulated mice. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Unpacking the cognitive map: The parallel map theory of hippocampal function.

In the parallel map theory, the hippocampus encodes space with 2 mapping systems. The bearing map is constructed primarily in the dentate gyrus from directional cues such as stimulus gradients. The sketch map is constructed within the hippocampus proper from positional cues. The integrated map emerges when data from the bearing and sketch maps are combined. Because the component maps work in parallel, the impairment of one can reveal residual learning by the other. Such parallel function may explain paradoxes of spatial learning, such as learning after partial hippocampal lesions, taxonomic and sex differences in spatial learning, and the function of hippocampal neurogenesis. By integrating evidence from physiology to phylogeny, the parallel map theory offers a unified explanation for hippocampal function. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Effects of transplantation of fetal hippocampal or hindbrain tissue into the brains of adult rats with hippocampal lesions on water maze acquisition.

Rats were given bilateral aspiration lesions of the hippocampus. Some of these rats then received bilateral transplants of fetal hippocampal or dorsal ventricular ridge tissue that was dissected from embryonic rat brains at 16 or 17 days of gestation. The remaining rats with hippocampal lesions did not receive fetal brain transplants. Rats with neocortical aspiration lesions, but without transplants, and rats without brain damage were also included in the study. All of the rats were trained to find a submerged platform in a Morris water maze. Rats with the fetal brain transplants were more impaired in some measures of maze learning than were rats with hippocampal lesions only. The results indicate that transplants of fetal brain tissue are not always associated with recovery of behavioral function after brain damage and may even increase a lesion-induced behavioral impairment in tasks that require complex cognitive functioning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

MDMA pretreatment leads to mild chronic unpredictable stress-induced impairments in spatial learning.

3,4-Methylenedioxymethamphetamine (MDMA) is a drug of abuse worldwide and a selective serotonin (5-HT) neurotoxin. An important factor in the risk of drug abuse and relapse is stress. Although multiple parallels exist between MDMA abuse and stress, including effects on 5-HTergic neurotransmission, few studies have investigated the consequences of combined exposure to MDMA and chronic stress. Therefore, rats were pretreated with MDMA and exposed 7 days later to 10 days of mild chronic unpredictable stress (CUS). MDMA pretreatment was hypothesized to enhance the effects of CUS leading to enhanced 5-HT transporter (SERT) depletion in the hippocampus and increased anxiety and cognitive impairment. Whereas MDMA alone increased anxiety-like behavior on the elevated plus maze, CUS alone or in combination with MDMA pretreatment did not increase anxiety-like behavior. In contrast, MDMA pretreatment led to CUS-induced learning impairment in the Morris water maze but not an enhanced depletion of hippocampal SERT protein. These results show that prior exposure to MDMA leads to stress-induced impairments in learning behavior that is not otherwise observed with stress alone and appear unrelated to an enhanced depletion of SERT. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Neurogenesis in the dentate gyrus of the adult tree shrew is regulated by psychosocial stress and NMDA receptor activation

These studies were designed to determine whether adult neurogenesis occurs in the dentate gyrus of the tree shrew, an animal phylogenetically between insectivores and primates, and to explore the possibility that this process is regulated by stressful experiences and NMDA receptor activation. We performed immunohistochemistry for cell-specific markers and the thymidine analog bromodeoxyuridine (BrdU), a marker of DNA synthesis that labels proliferating cells and their progeny, on the brains of adult tree shrews subjected to psychosocial stress or NMDA receptor antagonist treatment. Cells that incorporated BrdU in the dentate gyrus of adult tree shrews were primarily located in the subgranular zone, had morphological characteristics of granule neuron precursors, and appeared to divide within 24 hr after BrdU injection. Three weeks after BrdU injection, BrdU-labeled cells had neuronal morphology, expressed the neuronal marker neuron specific enolase, and were incorporated into the granule cell layer. Vimentin-immunoreactive radial glia were observed in the dentate gyrus with cell bodies in the subgranular zone and processes extending into the granule cell layer. Exposure to acute psychosocial stress resulted in a rapid decrease in the number of BrdU-labeled cells in the dentate gyrus. In contrast, blockade of NMDA receptors, with the NMDA receptor antagonist MK-801, resulted in an increase in the number of BrdU-labeled cells in the dentate gyrus. These results indicate that adult neurogenesis occurs in the tree shrew dentate gyrus and is regulated by a stressful experience and NMDA receptor activation. Furthermore, we suggest that these characteristics may be common to most mammalian species.     

Genetic influence on neurogenesis in the dentate gyrus of adult mice

To address genetic influences on hippocampal neurogenesis in adult mice, we compared C57BL/6, BALB/c, CD1(ICR), and 129Sv/J mice to examine proliferation, survival, and differentiation of newborn cells in the dentate gyrus. Proliferation was highest in C57BL/6; the survival rate of newborn cells was highest in CD1. In all strains approximately 60% of surviving newborn cells had a neuronal phenotype, but 129/SvJ produced more astrocytes. Over 6 days C57BL/6 produced 0.36% of their total granule cell number of 239,000 as new neurons, BALB/c 0.30% of 242,000, CD1 (ICR) 0.32% of 351,000, and 129/SvJ 0.16% of 280,000. These results show that different aspects of adult hippocampal neurogenesis are differentially influenced by the genetic background.