Hippocampal-dependent Memory Function Research Articles

Comparative neuroscience of stimulant-induced memory dysfunction: role for neurogenesis in the adult hippocampus

The discovery that the addictive drugs impair neurogenesis in the adult hippocampus has prompted the elaboration of new biological hypotheses to explain addiction and drug-induced cognitive dysfunction. Considerable evidence now implicates the process of adult neurogenesis in at least some critical components of hippocampal-dependent memory function. In experimental models, psychomotor stimulant drugs produce alterations in the rate of birth, survival, maturation and functional integration of adult-born hippocampal neurons. Thus some of the deleterious consequences of drug abuse on memory could result from the neurotoxic actions of drugs on adult hippocampal neurogenesis. In this review, we will first summarize preclinical and clinical literature on the disruptive effects of drugs such as cocaine and ecstasy in the areas of learning, memory and attention. We will also summarize data that document the widespread effects of stimulant drugs on progenitor activity and precursor incorporation in the adult dentate gyrus. Finally, we will examine evidence that supports the involvement of hippocampal neurogenesis in specific aspects of learning and memory function and we will consider critically the hypothesis that some of the negative consequences of drug abuse on cognition might be ascribed to deficits in adult hippocampal neurogenesis. Evidence suggests that stimulant abuse impacts negatively on at least four areas of memory/cognitive function that may be influenced by adult hippocampal neurogenesis: contextual memory, spatial memory, working memory and cognitive flexibility.

Growth hormone rescues hippocampal synaptic function after sleep deprivation

Sleep is required for, and sleep loss impairs, normal hippocampal synaptic N-methyl-D-aspartate (NMDA) glutamate receptor function and expression, hippocampal NMDA receptor-dependent synaptic plasticity, and hippocampal-dependent memory function. Although sleep is essential, the signals linking sleep to hippocampal function are not known. One potential signal is growth hormone. Growth hormone is released during sleep, and its release is suppressed during sleep deprivation. If growth hormone links sleep to hippocampal function, then restoration of growth hormone during sleep deprivation should prevent adverse consequences of sleep loss. To test this hypothesis, we examined rat hippocampus for spontaneous excitatory synaptic currents in CA1 pyramidal neurons, long-term potentiation in area CA1, and NMDA receptor subunit proteins in synaptic membranes. Three days of sleep deprivation caused a significant reduction in NMDA receptor-mediated synaptic currents compared with control treatments. When rats were injected with growth hormone once per day during sleep deprivation, the loss of NMDA receptor-mediated synaptic currents was prevented. Growth hormone injections also prevented the impairment of long-term potentiation that normally follows sleep deprivation. In addition, sleep deprivation led to a selective loss of NMDA receptor 2B (NR2B) from hippocampal synaptic membranes, but normal NR2B expression was restored by growth hormone injection. Our results identify growth hormone as a critical mediator linking sleep to normal synaptic function of the hippocampus.

Emotion selectively impairs associative memory

One neural mechanism suggested for the emotionalenhancement of memory (EEM) in human behavior isamygdala modulation of hippocampal learning [1]. How-ever, there are several pathways within the hippocampus,supporting different types of memory, e.g., item memoryor associative memory. In emotional learning, the amy-gdala could modulate hippocampal function as a whole,affecting multiple types of hippocampal-dependent learn-ing. Alternatively, amygdala modulation may affect spe-cific pathways, selectively enhancing only some types ofhippocampal-dependent learning. Episodic memory foritems is hippocampal-dependent, but so is memory foritem-item associations; these may rely on different hip-pocampal pathways. Nearly all human emotional mem-ory studies test memory for items only. Apart from EEMfor single items, we tested here whether associative mem-ory, a hippocampal-dependent memory function, is par-ticularly enhanced by emotion.

Hippocampal‐dependent spatial memory functions might be lateralized in rats: An approach combining gene expression profiling and reversible inactivation

The hippocampus is involved in spatial memory processes, as established in a variety of species such as birds and mammals including humans. In humans, some hippocampal-dependent memory functions may be lateralized, the right hippocampus being predominantly involved in spatial navigation. In rodents, the question of possible lateralization remains open. Therefore, we first microdissected the CA1 subregion of the left and right dorsal hippocampi for analysis of mRNA expression using microarrays in rats having learnt a reference memory task in the Morris water-maze. Relative to untrained controls, 623 genes were differentially expressed in the right hippocampus, against only 74 in the left hippocampus, in the rats that had learnt the hidden platform location. Thus, in the right hippocampus, 299 genes were induced, 324 were repressed, and about half of them participate in signaling and transport, metabolism, and nervous system functions. In addition, most differentially expressed genes associated with spatial learning have been previously related to synaptic plasticity and memory. We then subjected rats to unilateral (left or right) or bilateral reversible functional inactivations in the dorsal hippocampus; lidocaine was infused either before each acquisition session or before retrieval of a reference spatial memory in the Morris water maze. We found that after drug-free acquisition, right or bilateral lidocaine inactivation (vs. left, or bilateral phosphate buffered saline (PBS) infusions) of the dorsal hippocampus just before a delayed (24 h) probe trial impaired performance. Conversely, left or bilateral hippocampus inactivation (vs. right, or bilateral PBS infusions) before each acquisition session weakened performance during a delayed, drug-free probe trial. Our data confirm a functional association between transcriptional activity within the dorsal hippocampus and spatial memory in the rat. Further, they suggest that there could be a leftward bias of hippocampal functions in engram formation or information transfer, and a rightward bias in spatial memory storage/retrieval processes.

Committing memory errors with high confidence: Older adults do but children don't

We investigated lifespan differences of confidence calibration in episodic memory, particularly the susceptibility to high-confidence errors within samples of children, teenagers, younger adults, and older adults. Using an associative recognition memory paradigm, we drew a direct link between older adults’ associative deficit and high-confidence errors. We predicted that only older adults would show high-confidence error even though their memory performance was at a similar level to that of children. Participants of all ages showed higher confidence following correct responses compared to incorrect responses, demonstrating the ability to calibrate subjective confidence in relation to memory accuracy. However, older adults were disproportionately more likely to indicate high confidence following erroneously remembered word pairs than participants of the other three age groups. Results are discussed in relation to the misrecollection account of high-confidence errors and ageing-related decline in hippocampus-dependent episodic memory functions.

Synaptic plasticity, neurogenesis and memory

Event Abstract Back to Event Synaptic plasticity, neurogenesis and memory Serge Laroche1* 1 UMR 8620, CNRS, University Paris-Sud, Laboratoire de Neurobiologie de l'Apprentissage, de la Memoire et de la Communication, France A defining characteristic of the brain is its remarkable capacity to undergo activity-dependent functional and morphological remodelling via mechanisms of plasticity that form the basis of our capacity to encode and retain memories. To date, the idea that a form of activity-dependent synaptic plasticity known as long-term potentiation, or LTP, plays a central role in the laying down of memories has received considerable support. Beyond this mechanism of plasticity at the synapse, adult neurogenesis, the birth and growth of new neurons, is another form of neural plasticity occurring in certain brain regions such as the dentate gyrus of the hippocampus, that may also contribute to hippocampal-dependent memory function. In this presentation, I will review recent evidence which suggest that the occurrence of LTP in the dentate gyrus can promote adult neurogenesis, and that neurogenesis in turn can affect the expression of synaptic plasticity in this area as well as memory ability. I will also review recent findings in genetically modified mice suggesting that certain key molecular mechanisms required for the stabilization of synaptic plasticity and for memory consolidation play a crucial role in adult neurogenesis. Together these findings provide support to the idea that synaptic plasticity and neurogenesis in the hippocampus are two functionally linked mechanisms of brain plasticity involved in the formation of hippocampal-dependent memories. Conference: 3rd Mediterranean Conference of Neuroscience , Alexandria, Egypt, 13 Dec - 16 Dec, 2009. Presentation Type: Oral Presentation Topic: Symposium 23 – Adult-born hippocampal neurons and memory Citation: Laroche S (2009). Synaptic plasticity, neurogenesis and memory. Front. Neurosci. Conference Abstract: 3rd Mediterranean Conference of Neuroscience . doi: 10.3389/conf.neuro.01.2009.16.085 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 20 Nov 2009; Published Online: 20 Nov 2009. * Correspondence: Serge Laroche, UMR 8620, CNRS, University Paris-Sud, Laboratoire de Neurobiologie de l'Apprentissage, de la Memoire et de la Communication, Orsay, France, serge.laroche@u-psud.fr Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Serge Laroche Google Serge Laroche Google Scholar Serge Laroche PubMed Serge Laroche Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Viral Vector–mediated Delivery of Estrogen Receptor-α to the Hippocampus Improves Spatial Learning in Estrogen Receptor-α Knockout Mice

Estrogen, which influences both classical genomic and rapid membrane-associated signaling cascades, has been implicated in the regulation of hippocampal function, including spatial learning. Gene mutation studies suggest that estrogen effects are mediated by estrogen receptor-α (ER-α); however, because gonadal steroids influence the organization of the hippocampus during development, it has been difficult to distinguish developmental effects from those specific to adults. In this study we show that lentiviral delivery of the gene encoding ER-α to the hippocampus of adult ER-α-knockout (ER-αKO) mice restores hippocampal responsiveness to estrogen and rescues spatial learning. We propose that constitutive estrogen receptor activity is important for maintaining hippocampus-dependent memory function in adults.

Human apolipoprotein C-I expression in mice impairs learning and memory functions

The H2 allele of APOC1, giving rise to increased gene expression of apolipoprotein C-I (apoC-I), is in genetic disequilibrium with the APOE4 allele and may provide a major risk factor for Alzheimer's disease (AD). We found that apoC-I protein is present in astrocytes and endothelial cells within hippocampal regions in both human control and AD brains. Interestingly, apoC-I colocalized with beta-amyloid (Abeta) in plaques in AD brains, and in vitro experiments revealed that aggregation of Abeta was delayed in the presence of apoC-I. Moreover, apoC-I was found to exacerbate the soluble Abeta oligomer-induced neuronal death. To establish a potential role for apoC-I in cognitive functions, we used human (h) APOC1(+/0) transgenic mice that express APOC1 mRNA throughout their brains and apoC-I protein in astrocytes and endothelial cells. The hAPOC1(+/0) mice displayed impaired hippocampal-dependent learning and memory functions compared with their wild-type littermates, as judged from their performance in the object recognition task (P = 0.012) and in the Morris water maze task (P = 0.010). ApoC-I may affect learning as a result of its inhibitory properties toward apoE-dependent lipid metabolism. However, no differences in brain mRNA or protein levels of endogenous apoE were detected between transgenic and wild-type mice. In conclusion, human apoC-I expression impairs cognitive functions in mice independent of apoE expression, which supports the potential of a modulatory role for apoC-I during the development of AD.

Differential Sensitivity of Men and Women to Anorexigenic and Memory-Improving Effects of Intranasal Insulin

Brain insulin is critically involved in the regulation of body weight and memory processing. Long-term administration of intranasal insulin reduces body weight in men, but not in women, while improving hippocampus-dependent memory processing in both genders. Our objectives were to assess the effects of a single dose of intranasal insulin on food intake and memory function in men and women, and to determine any gender differences. A total of 32 healthy, normal-weight subjects (14 men, 18 women) were intranasally administered 160 IU regular human insulin or vehicle before performing a hippocampus-dependent two-dimensional-object location task, a working memory task (digit span), and a hippocampus-independent mirror tracing task. Subsequently, food intake from an ad libitum breakfast buffet was measured. Insulin treatment decreased food intake in men but not in women (difference to placebo condition, men: -192.57 +/- 78.48 kcal, P < 0.03; women: 18.54 +/- 42.89 kcal, P > 0.67). In contrast, hippocampus-dependent memory and working memory were improved in women (P < 0.03, P < 0.05, respectively), whereas men did not benefit from acute insulin treatment (P > 0.17, P > 0.20). Performance on the hippocampus-independent mirror tracing task was not affected by insulin in women or men. In accordance with animal data, results indicate that men are more sensitive than women to the acute anorexigenic effect of central nervous insulin signaling, whereas insulin's beneficial effect on hippocampus-dependent memory functions is more pronounced in women. Our findings provide support for the notion of a fundamental gender difference in central nervous insulin signaling that pertains to the regulation of energy homeostasis and memory functions.

Cerebral ischemic preconditioning induces lasting effects on CA1 neuronal survival, prevents memory impairments but not ischemia-induced hyperactivity

In ischemic preconditioning, prior exposure to a short 3-min global ischemia provides substantial protection against the deleterious effects of a subsequent prolonged ischemic insult in rats. The objective of the present study was to determine if the neuronal protection induced by ischemic preconditioning influence functional recovery following a 6-min ischemic insult in rats. Animals received either sham-operation, a 3-min ischemia, a preconditioning 3-min global ischemia followed 3 days later by a 6-min global ischemia or a single 6-min global ischemia. Open field habituation, memory performance in the 8-arm radial maze and object recognition were assessed at different intervals following ischemia. Our findings revealed that preconditioning reversed ischemia-induced spatial memory deficits in the 8-arm radial maze, as suggested by significant reduction of working memory errors in preconditioned as compared to ischemic animals. Preconditioning also attenuated ischemia-induced object recognition deficits at short-term intervals. Nonetheless, preconditioning failed to alter ischemia-induced hyperactivity as demonstrated by enhanced behavioral activity in the open field in both preconditioned and ischemic animals compared to 3-min ischemic and sham-operated rats. CA1 cell counts revealed significant neuronal sparing in preconditioned animals that was observed 6-month following reperfusion. Together, these findings suggest that neuronal survival in preconditioned rats is associated with significant improvements of hippocampal-dependent memory functions and, further support that ischemia-induced hyperactivity may not solely depend on selective neuronal damage to hippocampal neurons.

Differential effects of acute intranasal insulin administration on memory and food intake in men and women

Background: Central nervous insulin is involved in the regulation of body weight and memory processing. Intracerebroventricular insulin administration decreases food intake in male but not in female rats while improving hippocampus-dependent memory in both males and females. We scrutinized acute effects of intranasal insulin on food intake and memory functions in men and women. Methods: Thirty-two healthy, normal-weight subjects (18 women) were intranasally administered 160 IU regular human insulin or vehicle according to a double-blind within-subject design before performing a hippocampus-dependent 2-D-object location task, a working memory task (digit span) and a hippocampus-independent mirror tracing task. Subsequently, food intake at an ad libitum breakfast buffet was registered. Results: Intranasal insulin decreased food intake in men but not in women (difference to placebo condition, men: -192.57±78.48kcal, p<0.03; women: 18.54±42.89kcal, p>0.67; Treat x Gender: p<0.02). In contrast, hippocampus-dependent memory and working memory were improved in female subjects (p<0.03, p<0.05, respectively) while men did not benefit from acute insulin treatment (p>0.17, p>0.20; Treat x Gender: p<0.01, p<0.03, respectively). Performance on the hippocampus-independent mirror tracing task was not affected by insulin either in women (p>0.50) or in men (p>0.86). Conclusions: In accordance with animal data, results indicate that men are more sensitive than women to the acute anorexigenic effect of central nervous insulin signaling whereas insulin's beneficial effect on hippocampus-dependent memory functions are more pronounced in women. Our findings provide strong support for the notion of a fundamental gender difference in central nervous insulin signaling that pertains to the regulation of energy homeostasis and memory functions.

Neprilysin-sensitive Synapse-associated Amyloid-β Peptide Oligomers Impair Neuronal Plasticity and Cognitive Function

Neprilysin-sensitive Synapse-associated Amyloid-β Peptide Oligomers Impair Neuronal Plasticity and Cognitive Function

Sex differences in the hilar mossy cells of the guinea-pig before puberty

Numerous sex differences have been detected in the morphology of the dentate and hippocampal neurons and hippocampus-dependent memory functions. The aim of the present study was to ascertain whether the mossy cells, an interneuron population forming a recurrent excitatory circuit with the dentate granule cells, are sexually dimorphic. The brains of juvenile (15–16 days old) and peripubescent (45–46 days old) male and female guinea-pigs were Golgi-Cox stained. Mossy cells were sampled from the hilus in the septal third of the dentate gyrus and their dendritic tree and somata were analyzed. The analysis was separately conducted on mossy cells with soma located in the portions of the hilus that face the upper blade (upper hilus) and lower blade (lower hilus), respectively. The mossy cells in the upper hilus were found to be sexually dimorphic in both juvenile and peripubescent animals. At both ages females had a larger dendritic tree than males. This difference was due to a greater mean branch length and, in peripubescent animals, also to a greater number of branches. In juvenile males, the spines on the proximal dendrites (thorny excrescences) had a greater density than in females. No differences in spine density were present in peripubescent animals. Unlike the mossy cells in the upper hilus, the mossy cells in the lower hilus showed very few sex differences in juvenile animals and no differences in peripubescent animals. The few differences favored females, that had more proximal branches and a greater spine density on the distal dendrites than males. The results show that the mossy cells of the guinea-pig are sexually dimorphic prior to puberty. Extending a previous investigation, the present data provide evidence that sex differences are mainly confined to the dentate region corresponding to the upper blade and upper hilus. The observed segregation of the sexual dimorphism in the upper blade/upper hilus suggests that this region might underlie the sexual dimorphism in hippocampus-dependent memory functions.

Factors That Determine the Non-Linear Amygdala Influence on Hippocampus-Dependent Memory

Stressful experiences are known to either improve or impair hippocampal-dependent memory tasks and synaptic plasticity. These positive and negative effects of stress on the hippocampus have been largely documented, however little is known about the mechanism involved in the twofold influence of stress on hippocampal functioning and about what factors define an enhancing or inhibitory outcome. We have recently demonstrated that activation of the basolateral amygdala can produce a biphasic effect, enhancement or inhibition, of hippocampal synaptic plasticity, depending on the timing of activation (priming or spaced activation). A key question is under which conditions do the effects of amygdala activation on hippocampus dependent memory functions change from improvement to impairment of learning and memory. In this chapter we suggest that hippocampal outcome of amygdala activation may be critically dependent on four main factors: (1) The intensity of amygdala activation, (2) the temporal relation between the activation of the amygdala and the hippocampus dependent memory function, (3) the duration of amygdala activation, and (4) the contextual input during the processing of the information.

Synaptic localization of a functional NADPH oxidase in the mouse hippocampus

Superoxide has been shown to be critical for hippocampal long-term potentiation (LTP) and hippocampus-dependent memory function. A possible source for the generation of superoxide during these processes is NADPH oxidase. The active oxidase consists of two membrane proteins, gp91 phox and p22 phox , and four cytosolic proteins, p40 phox , p47 phox , p67 phox , and Rac. Upon stimulation, the cytosolic proteins translocate to the membrane to form a complex with the membrane components, which results in production of superoxide. Here, we determined the presence, localization, and functionality of a NADPH oxidase in mouse hippocampus by examining the NADPH oxidase proteins as well as the production of superoxide. All of the NADPH oxidase proteins were present in hippocampal homogenates and enriched in synaptoneurosome preparations. Immunocytochemical analysis of cultured hippocampal neurons indicated that all NADPH oxidase proteins were localized in neuronal cell bodies as well as dendrites. Furthermore, double labeling analysis using antibodies to p67 phox and the presynaptic marker synaptophysin suggest a close association of the NADPH oxidase subunits with synaptic sites. Finally, stimulation of hippocampal slices with phorbol esters triggered translocation of the cytoplasmic NADPH oxidase proteins to the membrane and an increase in superoxide production that was blocked by inhibitors of NADPH oxidase. Taken together, our data suggest that NADPH oxidase is present in mouse hippocampus and might be the source of superoxide production required for LTP and memory function.

Intranasal insulin improves memory in humans

Previous studies have suggested an acutely improving effect of insulin on memory function. To study changes in memory associated with a prolonged increase in brain insulin activity in humans, here we used the intranasal route of insulin administration known to provide direct access of the substance to the cerebrospinal fluid compartment. Based on previous results indicating a prevalence of insulin receptors in limbic and hippocampal regions as well as improvements in memory with systemic insulin administration, we expected that intranasal administration of insulin improves primarily hippocampus dependent declaration memory function. Also, improvements in mood were expected. We investigated the effects of 8 weeks of intranasal administration of insulin (human regular insulin 4 x 40 IU/d) on declarative memory (immediate and delayed recall of word lists), attention (Stroop test), and mood in 38 healthy subjects (24 males) in a double blind, between-subject comparison. Blood glucose and plasma insulin levels did not differ between the placebo and insulin conditions. Delayed recall of words significantly improved after 8 weeks of intranasal insulin administration (words recalled, Placebo 2.92±1.00, Insulin 6.20±1.03, p<0.05). Moreover, subjects after insulin reported signs of enhanced mood, such as reduced anger ( p<0.02) and enhanced self-confidence ( p<0.03). Results indicate a direct action of prolonged intranasal administration of insulin on brain functions, improving memory and mood in the absence of systemic side effects. These findings could be of relevance for the treatment of patients with memory disorders like in Alzheimer’s disease.

Low-density lipoprotein receptor-knockout mice display impaired spatial memory associated with a decreased synaptic density in the hippocampus

The low-density lipoprotein receptor (LDLR) is the first described receptor for apolipoprotein E (apoE). We hypothesize that the absence of the LDLR, similar to the absence of apoE, results in impaired learning and memory processes. Six-month-old homozygous Ldlr−/− and wild-type littermates (Ldlr+/+), maintained on a standard lab chow diet, were used. Unlike humans, Ldlr−/− mice, under these conditions, do not develop atherosclerosis. The results of the Morris water escape task revealed an impaired spatial memory in the Ldlr−/− mice in comparison with Ldlr+/+ mice. Also in a T-maze task, the working memory performance of the Ldlr−/− mice was impaired. Furthermore, Ldlr−/− mice, in comparison with Ldlr+/+ mice, display a decreased number of synaptophysin-immunoreactive presynaptic boutons in the hippocampus CA1. In conclusion, the results show in mice deficiency for the LDLR results in impaired hippocampal-dependent memory functions. A decrease in the number of presynaptic boutons may underlay these behavioral alterations. Therefore, the LDLR may be an important receptor for apoE in the central nervous system.

Chronic intermittent ethanol (CIE) administration in rats decreases levels of neurosteroids in hippocampus, accompanied by altered behavioral responses to neurosteroids and memory function

The administration of ethanol on a chronic intermittent regimen (CIE) involving multiple withdrawal episodes is a model for ethanol dependence. After CIE, rats exhibited reduced seizure threshold, increased anxiety, tolerance to GABAergic sedative-hypnotic drugs, and changes in GABA A receptor function and subunit composition in hippocampus. Previous studies have shown that acute and chronic ethanol may induce changes in the levels of the neurosteroid 3α-hydroxysteroid-5α-pregnan-20-one (3α, 5α-THP) in the brain. Therefore, the current study analyses the correlation between chronic intermittent ethanol effects on the level of 3α, 5α-THP in hippocampus of CIE rats and the behavioral changes in sensitivity to neurosteroids. After CIE, the levels for 3α, 5α-THP were significantly reduced in hippocampus of rats. The mRNA levels for the enzymes 5α-reductase and 3α-HSD in hippocampus were also reduced. In vivo, (in contrast to a tolerance to the hypnotic effect of steroids), CIE rats showed increased sensitivity to the anticonvulsant and to the anxiolytic effect of the steroid alphaxalone. Perhaps, this is a response to lowered levels of endogenous neuroactive steroids. CIE rats also showed impairment of hippocampus-dependent memory function. These results suggest that changes in neurosteroids level and in vivo sensitivity to these compounds are involved in the development of ethanol dependence in the CIE model.

2-Buten-4-olide, an endogenous feeding suppressant, improves spatial performance through brain acidic fibroblast growth factor in mice

Endogenous sugar acid 2-buten-4-olide, a satiety substance, has been shown to increase the blood glucose, norepinephrine, and glucocorticoid concentrations that are known to modulate learning and memory processes. The glucose-induced release of acidic fibroblast growth factor facilitated the hippocampus-dependent memory function. In the present study, we investigated the effect of 2-buten-4-olide on the spatial performance of male DDY mice undergoing the water maze task. The intraperitoneal injection of 2-buten-4-olide (5 mg/kg) facilitated the spatial performance, which was indicated by a reduction in the escape latency in which the mouse finds and climbs the goal platform in comparison to the vehicle-injected control mice. In the probe test after removing the platform, the 2-buten-4-olide-treated mice stayed a longer time in the quadrant where the platform was originally located and crossed more frequently at the platform location than did the control mice. The pretreatment of acidic fibroblast growth factor antibody injected into the lateral ventricle eliminated the effect of 2-buten-4-olide both during the training sessions and during the probe test. Therefore, 2-buten-4-olide was found to improve the spatial performance, and this effect is mediated, at least in part, by acidic fibroblast growth factor.

Neonatal exposure to novel environment enhances hippocampal-dependent memory function during infancy and adulthood.

Early life experience affects behavior and brain mechanisms. Handling rats during the first three weeks in life can slow age-related cognitive decline (as measured by a hippocampal-dependent spatial learning task) and reduce age-related hippocampal neuron loss. It is not clear, however, whether this early environmental influence on learning is selective for old age or is more general, affecting cognitive development during infancy and young adulthood as well. We briefly exposed neonatal rats to a novel non-home environment for 3 min daily during the first three weeks of life (as a component of the handling method). We found that this brief early environmental manipulation resulted in enhanced hippocampal-dependent learning immediately after weaning and that this learning enhancement persisted into adulthood. These results suggest that subtle early life events can affect cognitive development in all developmental stages and that changes in neural mechanisms other than neuron number are likely to mediate the learning enhancement at multiple developmental stages.