Retrieval and reconsolidation of object recognition memory are independent processes in the perirhinal cortex.

Reconsolidation refers to the destabilization/re-stabilization process upon memory reactivation. However, the parameters needed to induce reconsolidation remain unclear. Here we evaluated the capacity of memory retrieval to induce reconsolidation of object recognition memory in rats. To assess whether retrieval is indispensable to trigger reconsolidation, we injected muscimol in the perirhinal cortex to block retrieval, and anisomycin (ani) to impede reconsolidation. We observed that ani impaired reconsolidation in the absence of retrieval. Therefore, stored memory underwent reconsolidation even though it was not recalled. These results indicate that retrieval and reconsolidation of object recognition memory are independent processes.

Safe taste memory consolidation is disrupted by a protein synthesis inhibitor in the nucleus accumbens shell.

Consolidation is the process by which a new memory is stabilized over time, and is dependent on de novo protein synthesis. A useful model for studying memory formation is gustatory memory, a type of memory in which a novel taste may become either safe by not being followed by negative consequences (attenuation of neophobia, AN), or aversive by being followed by post-digestive malaise (conditioned taste aversion, CTA). Here we evaluated the effects of the administration of a protein synthesis inhibitor in the nucleus accumbens (NAc) shell for either safe or aversive taste memory trace consolidation. To test the effects on CTA and AN of protein synthesis inhibition, anisomycin (100microg/microl) was bilaterally infused into the NAc shell of Wistar rats' brains. We found that post-trial protein synthesis blockade impaired the long-term safe taste memory. However, protein synthesis inhibition failed to disrupt the long-term memory of CTA. In addition, we infused anisomycin in the NAc shell after the pre-exposure to saccharin in a latent inhibition of aversive taste. We found that the protein synthesis inhibition impaired the consolidation of safe taste memory, allowing the aversive taste memory to form and consolidate. Our results suggest that protein synthesis is required in the NAc shell for consolidation of safe but not aversive taste memories, supporting the notion that consolidation of taste memory is processed in several brain regions in parallel, and implying that inhibitory interactions between both taste memory traces do occur.

Basolateral amygdala glutamatergic activation enhances taste aversion through NMDA receptor activation in the insular cortex.

In conditioned taste aversion (CTA), a subject learns to associate a novel taste with visceral malaise. Brainstem, limbic and neocortical structures have been implicated in CTA memory formation. Nevertheless, the role of interactions between forebrain structures during these processes is still unknown. The present experiment was aimed at investigating the possible interaction between the basolateral nucleus of the amygdala (BLA) and the insular cortex (IC) during CTA memory formation. Injection of a low dose of lithium chloride (30 mg/kg, i.p.) 30 min after novel taste consumption (saccharin 0.1%) induces a weak CTA. Unilateral BLA injection of glutamate (2 microg in 0.5 microL) just before low lithium induces a stronger CTA. Unilateral injection of an N-methyl-d-aspartate (NMDA) receptor antagonist (AP5, 5 microg in 0.5 microL) in IC has no effect. However, AP5 treatment in IC at the same time or 1 h after the ipsilateral BLA injection reverses the glutamate-induced CTA enhancement. Injection of AP5 in IC 3 h after BLA injection does not interfere with the glutamate effect. Moreover, the CTA-enhancing effect of glutamate was also blocked by contralateral IC injection of AP5 at the same time. These results provide strong evidence that NMDA receptor activation in the IC is essential to enable CTA enhancement induced by glutamate infusion in the BLA during a limited time period that extends to 1 but not to 3 hours. These findings indicate that BLA-IC interactions regulate the strength of CTA. The bilateral nature of these amygdalo-cortical interactions is discussed.

[Memory-linked morphological changes]. / Cambios morfológicos asociados a la memoria.

INTRODUCTION: It has been suggested that storing information in the brain takes place by means of changes in synaptic communication efficiency, which is known as neuronal plasticity. Plastic events include changes in the function, structure, distribution and number of synapses, and it has been suggested that these plastic events could be related to learning and memory. DEVELOPMENT: In this work we will review some studies that report structural changes in which experience and learning intervene. In particular, structural changes have been observed in a region of the brain called the hippocampus, which plays a crucial role in the learning and memory of spatial tasks. It has been claimed that the appearance of new synapses after learning a spatial task is linked to the formation of long-term memory and that the functioning of NMDA-type glutamate receptors is needed for both learning and the formation of new synapses to take place. CONCLUSIONS: Understanding the cellular mechanisms involved in the formation of memory is of utmost importance to be able to check the memory deficiencies that arise from injuries or as a consequence of old age and neurodegenerative diseases.

Cambios morfológicos asociados a la memoria / Memory-linked morphological changes

Introducción. Se ha sugerido que el almacenamiento de la información en el cerebro ocurre a través de cambios en la eficiencia de la comunicación sináptica, llamada plasticidad neuronal. Los eventos plásticos incluyen cambios en la función, la estructura, la distribución y el número de sinapsis, y se ha sugerido que estos eventos plásticos pueden relacionarse con el aprendizaje y la memoria. Desarrollo. En este trabajo se revisarán algunos estudios que comunican cambios estructurales mediados por la experiencia y el aprendizaje. En particular, se han observado cambios estructurales en una región del cerebro llamada hipocampo, que es crucial para el aprendizaje y la memoria de tareas espaciales. Se ha sugerido que la aparición de nuevas sinapsis después del aprendizaje de una tarea espacial se relaciona con la formación de la memoria a largo plazo, y que para que ocurran tanto el aprendizaje como la formación de nuevas sinapsis se necesita el funcionamiento de los receptores para glutamato del tipo NMDA. Conclusión. Entender los mecanismos celulares implicados en la formación de la memoria es de suma importancia para poder revertir los déficit de memoria ocasionados por lesiones, o como consecuencia de la vejez y de enfermedades neurodegenerativas (AU)

Introduction. It has been suggested that storing information in the brain takes place by means of changes in synaptic communication efficiency, which is known as neuronal plasticity. Plastic events include changes in the function, structure, distribution and number of synapses, and it has been suggested that these plastic events could be related to learning and memory. Development. In this work we will review some studies that report structural changes in which experience and learning intervene. In particular, structural changes have been observed in a region of the brain called the hippocampus, which plays a crucial role in the learning and memory of spatial tasks. It has been claimed that the appearance of new synapses after learning a spatial task is linked to the formation of long-term memory and that the functioning of NMDA-type glutamate receptors is needed for both learning and the formation of new synapses to take place. Conclusions. Understanding the cellular mechanisms involved in the formation of memory is of utmost importance to be able to check the memory deficiencies that arise from injuries or as a consequence of old age and neurodegenerative diseases (AU)

Blockade of noradrenergic receptors in the basolateral amygdala impairs taste memory.

In conditioned taste aversion (CTA), a subject learns to associate a novel taste (conditioned stimulus, CS) with visceral malaise (unconditioned stimulus, US). Considerable evidence indicates that the noradrenergic system in the amygdala plays an important role in memory consolidation for emotionally arousing experiences. The specific aim of the present set of experiments was to determine the involvement of noradrenergic activity in the basolateral amygdala (BLA) during the US presentation and consolidation of CTA as well as during the consolidation of a nonaversive/incidental gustatory memory. Selective bilateral microinfusions of the beta-adrenergic antagonist propranolol administered into the BLA immediately before intraperitoneal (i.p.) lithium chloride (LiCl) injections disrupted CTA memory. Additionally, propranolol infused into the BLA immediately after a pre-exposure to the saccharin (CS) significantly attenuated latent inhibition. The present findings indicating that alterations in noradrenergic function in the BLA affect taste memory formation, provide additional evidence that the BLA plays a critical role in modulating the consolidation of memory and that the influence is mediated by interactions with other brain regions that support memory for different kinds of experiences.

Differential involvement of cortical muscarinic and NMDA receptors in short- and long-term taste aversion memory.

In conditioned taste aversion, an animal avoids a taste previously associated with toxic effects, and this aversive memory formation requires an intact insular cortex. In this paper, we investigated the possible differential involvement of cholinergic and glutamatergic receptors in the insular cortex in short-term memory (STM) and long-term memory (LTM) of taste aversion in rats. Taste aversion was induced by intraperitoneal administration of lithium chloride (a malaise-inducing drug) 15 min after experience with an unfamiliar taste. In order to test STM and LTM of taste aversion, taste stimulus was again presented 4 h and 72 h after lithium injection, respectively. During the acquisition, microinjection of the muscarinic antagonist, scopolamine, in the insular cortex before, but not after, the presentation of the new taste, abolished STM as well as LTM. Blockade of the NMDA receptor, in the insular cortex, by AP5 before, but not after, the presentation of the taste stimulus, impaired LTM but left STM intact. Moreover, when injected 1 h after malaise induction (i.e., during taste-illness association), AP5 disrupted both STM and LTM. These results suggest that activation of muscarinic receptors in the insular cortex is involved in the acquisition of taste memory, whereas NMDA receptors participate in taste memory consolidation. These data demonstrate that different neurochemical mechanisms subserve different memory phases. NMDA receptors are also probably involved in processing the visceral input, thus allowing subsequent taste-illness association. This indicates that in the same cortical area the same neurotransmitter system can be involved in distinct processes: taste memory consolidation vs. taste-illness association.

Differential effects of bicuculline and muscimol microinjections into the nucleus basalis magnocellularis in taste and place aversive memory formation.

The role of the nucleus basalis magnocellularis (NBM) in learning and memory has been demonstrated in different learning paradigms such as conditioned taste aversion (CTA) and inhibitory avoidance (IA). This participation has been related to the cholinergic system, but recent studies have reported the potential role of other neurotransmitters such as GABA. The effects of acute intracerebral administration of the GABAergic antagonist bicuculline (0.05 microg) and the GABAergic agonist muscimol (0.05 microg) into the NBM of male Wistar rats were assessed in CTA and IA learning. In both learning tasks, the drug administration was performed before the acquisition. Taste aversion learning was not affected by the infusion of any of the drugs administered. IA acquisition was not affected by the administration of bicuculline or muscimol, requiring similar number of trials to reach the learning criterion. However, when the rats were tested 24 h later, those injected with bicuculline or muscimol showed an impairment of the IA learning. The present results support a role of the GABAergic system in the consolidation process of IA learning.

Spatial long-term memory is related to mossy fiber synaptogenesis.

Structural synaptic changes have been suggested to underlie long-term memory formation. In this work, we investigate if hippocampal mossy fiber synaptogenesis induced by water maze overtraining can be related with long-term spatial memory performance. Rats were trained in a Morris water maze for one to five identical daily sessions and tested for memory retrieval 1 week and 1 month after training. After the last test session, the rat brains were obtained and processed for Timm's staining to analyze mossy fiber projection. The behavioral results showed that with more training, animals showed a better performance in the memory tests, and this performance positively correlates with Timm's staining in the stratum oriens. Furthermore, with the use of the NMDA antagonist MK801 before, but not after acquisition, water maze spatial memory was impaired. Increased Timm's staining in the stratum oriens was observed in the animals treated with MK801 after acquisition but not in those treated before. Finally, we observed that mossy fiber synaptogenesis occurs mainly in the septal region of the dorsal hippocampus, supporting the idea that this anterior region is important for spatial memory. Altogether, these results suggest that mossy fiber synaptogenesis can be related with spatial long-term memory formation.

[Behavior-immunity relationship: the role of cytokines]. / Relación conducta-inmunidad: el papel de las citocinas.

There are several phenomena in which the immune and the central nervous systems regulate each other. However, their mechanisms are poorly understood. Since cytokines have a central role in the regulation of the immune response, this review describes their participation in two forms of neuro-immune communication, immunomodulation by psychological stress and behavioral conditioning of immune response. The role of cytokines in the endocrine and behavioral effects of acute phase, where cytokines have an effect in functions of the central nervous system, is also reviewed. The effects of psychological stress are described as both immunosuppressing and immunoenhancing. Among them, a relevant immunosuppressing one is the reduction of IL-1, IL-2, and IFN-gamma levels. In contrast, some of the pro-inflammatory effects of stress are mediated by an increase in the levels of IL-6, IL-1, and TNF mediated by the neurotransmitter Substance P. A possible role for IL-1 and IFN-beta as possible messengers in immune regulation by behavioral conditioning is proposed. Pro-inflammatory cytokines in turn can activate the hypothalamus-pituitary-adrenal axis and induce sickness behavior during the acute phase response, during which the parasympathetic nervous system serves as pathway for their detection by the central nervous system. An account is given about recent findings on the regulation of cytokine expression by neurotransmitters from the sympathetic nervous system (epinephrine and norepinephrine), a key piece in all these mechanisms of brain-immune communication. Possible mechanisms and pathways of communication between the brain and the immune system, as well as the possible participation of other cytokines are discussed.

Cortical cholinergic activity is related to the novelty of the stimulus.

A number of studies have related cholinergic activity to the mediation of learning and memory. However, the acetylcholine (ACh) participation has been recently implicated in the early stages of memory formation but not during retrieval. The aim of the present study is to evaluate ACh release in the insular cortex (IC) during presentation of different taste stimuli and during their re-exposition by means of the free-moving microdialysis technique. We evaluated the changes in ACh release when a novel taste, saccharin or quinine was presented to the rat and after several presentations of saccharin. Unilateral microdialysis was performed in the IC 1 h before and 1 h after the presentation of: (1) a familiar stimulus (water), (2) a novel taste (quinine), (3) another novel taste (saccharin), (4) a second presentation, (5) a third presentation, and (6) a fourth presentation of saccharin. The volume consumed by the animals was registered as a behavioral parameter. The ACh levels from the microdialysis fractions were analyzed by an HPLC-ED system. Biochemical results showed a significant increment in the cortical ACh release induced by a novel stimulus compared with the release observed during the presentation of a familiar stimulus. The ACh release observed after several presentations of the stimuli decreased to the same levels as those produced by the familiar taste, indicating an inverse relationship between familiarity and cortical ACh release. These results suggest that the cholinergic system plays an important role in the identification and characterization of different kinds of stimuli.

Differential participation of the NBM in the acquisition and retrieval of conditioned taste aversion and Morris water maze.

Deficits in both learning and memory after lesions of the cholinergic basal forebrain, in particular the nucleus basalis magnocellularis (NBM), have been widely reported. However, the participation of the cholinergic system in either acquisition or retrieval of memory process is still unclear. In this study, we tested the possibility that excitotoxic lesions of the NBM affect either acquisition or retrieval of two tasks. In the first experiment, animals were trained for two conditioned taste aversion tasks using different flavors, saccharine and saline. The acquisition of the first task was before NBM lesions (to test retrieval) and the acquisition of the second task was after the lesions (to test acquisition). Accordingly, in the first part of the second experiment, animals were trained in the Morris water maze (MWM), lesioned and finally tested. In the final part of this experiment, another set of animals was lesioned, then trained in the MWM and finally tested. All animals were able to retrieve conditioned taste aversion (CTA) and MWM when learned before NBM lesions; however, lesions disrupted the acquisition of CTA and MWM. The results suggest that the NBM and cholinergic system may play an important role in acquisition but not during retrieval of aversive memories.

Long-term potentiation in the insular cortex enhances conditioned taste aversion retention.

Long-lasting changes in synaptic strength, such as long-term potentiation (LTP), are thought to underlie memory formation. Recent studies on the insular cortex (IC), a region of the temporal cortex implicated in the acquisition and retention of conditioned taste aversion (CTA), have demonstrated that tetanic stimulation of the basolateral nucleus of the amygdala (Bla) induce LTP in the IC of adult rats in vivo, as well as, that blockade of N-methyl-D-aspartate (NMDA) receptors disrupts CTA and IC-LTP induction in vivo. Here, we present experimental data showing that induction of LTP in the Bla-IC projection previous to CTA training enhances the retention of this task. These findings are of particular interest since they provide support for the view that the neural mechanisms underlying neocortical LTP may contribute to memory related functions performed by the IC.

Redundant basal forebrain modulation in taste aversion memory formation.

Mnemonic deficits resulting from excitotoxic lesion of the basal forebrain have been classically attributed to the resulting depletion of cortical acetylcholine activity. It has been demonstrated that in spite of the strong cholinergic depletion after injections into the basal forebrain of the immunotoxin 192IgG-saporin, no detectable deficit can be found in the acquisition of several learning tasks, including conditioned taste aversion. Conversely, NMDA-induced lesions of the basal forebrain strongly impair taste aversion learning. In this study we show that 192IgG-saporin produces an efficient and selective cholinergic deafferentation of the rat neocortex but not the amygdala. Furthermore, a stronger relationship between severity of memory impairment after NMDA lesions and basoamygdaloid cholinergic deafferentation was found. Therefore, in a second experiment, we show that combining NMDA-induced lesions into the basolateral amygdala with 192IgG-saporin injections into the basal forebrain results in a strong disruption of taste aversion learning, whereas none of these treatments were by themselves capable of producing any detectable impairment in this learning task. The double lesion effect was only paralleled by simple NMDA lesions into the basal forebrain, suggesting that the learning deficits associated to excitotoxic lesions of the basal forebrain are the result of the simultaneous destruction of the corticopetal and basoamygdaloid interaction. A model is proposed, according to which the modulation of learning processes exerted by the basal forebrain can be redundantly performed by both the basocortical and basoamygdaloid pathway.

Differential effects of 192IgG-saporin and NMDA-induced lesions into the basal forebrain on cholinergic activity and taste aversion memory formation.

Mnemonic deficits resulting from excitotoxic lesion of the basal forebrain have been classically attributed to the resulting depletion of cortical acetylcholine activity. In this study, we have performed a detailed analysis of the cholinergic status of the insular cortex (IC) following local injections of either 192IgG-saporin (192IgG-sap) or N-methyl-D-aspartate (NMDA) directly into the nucleus basalis magnocellularis (NBM). By means of in vivo microdialysis, we show that the immunotoxin lesion results in an almost complete lack of extracellular acetylcholine release, whereas NMDA-induced lesions result in a marginal reduction in cortical cholinergic activity. Choline-acetyltransferase activity in the IC further confirmed this differential pattern of cortical deafferentation. Surprisingly, however, only NMDA-induced lesions showed a strong disruptive effect upon taste aversion learning whereas no detectable deficits could be found following 192IgG-sap lesions. By combining intrabasal injections of 192IgG-sap with acute pre-training infusions of the cholinergic antagonist scopolamine into the IC, a strong disruption of taste aversion was attained. These results imply that residual cholinergic activity, following 192IgG-saporin lesions, might be still critical for normal cortical mediation of memory processing. They also support the role of basal forebrain in mediating learning and memory processes, and demonstrate that mnemonic deficits resulting from excitotoxic lesions of the basal forebrain are not the sole result of cortical acetylcholine activity hypofunction.

Conditioned enhancement of antibody production is disrupted by insular cortex and amygdala but not hippocampal lesions.

Pavlovian conditioning procedures can be used to activate the immune system. A reliable conditioned increase of antibody production can be obtained in rats that have previously received a gustative or odor stimulus as the conditioned stimulus paired with an antigen, by exposing the animals to the conditioned stimulus alone. We showed evidence that an excitotoxic lesion bilaterally applied into the insular cortex or the amygdala, but not into the dorsal hippocampus, impaired the acquisition of both odor and gustatory conditioned immune enhancement. We found no effects of lesions on normal antibody production. These results suggest that the amygdala and the insular cortex are involved in the neural-immune interactions that mediate conditioned immunity.

Reversible inactivation of the nucleus basalis magnocellularis induces disruption of cortical acetylcholine release and acquisition, but not retrieval, of aversive memories.

The basal forebrain complex, which includes the nucleus basalis magnocellularis (NBM), provides widespread cholinergic and gamma-aminobutyric acid-containing projections throughout the brain, including the insular and pyriform cortices. A number of studies have implicated the cholinergic neurons in the mediation of learning and memory processes. However, the role of basal forebrain activity in information retrieval mechanisms is less known. The aim of the present study is to evaluate the effects of reversible inactivation of the NBM by tetrodotoxin (TTX, a voltage-sensitive sodium channel blocker) during the acquisition and retrieval of conditioned taste aversion (CTA) and to measure acetylcholine (ACh) release during TTX inactivation in the insular cortex, by means of the microdialysis technique in free-moving rats. Bilateral infusion of TTX in the NBM was performed 30 min before the presentation of gustative stimuli, in either the CTA acquisition trial or retrieval trial. At the same time, levels of extracellular ACh release were measured in the insular cortex. The behavioral results showed significant impairment in CTA acquisition when the TTX was infused in the NBM, whereas retrieval was not affected when the treatment was given during the test trial. Biochemical results showed that TTX infusion into the NBM produced a marked decrease in cortical ACh release as compared with the controls during consumption of saccharin in the acquisition trial. Depleted ACh levels were found during the test trial in all groups except in the group that received TTX during acquisition. These results suggest a cholinergic-dependent process during acquisition, but not during memory retrieval, and that NBM-mediated cholinergic cortical release may play an important role in early stages of learning, but not during recall of aversive memories.

Blockade of N-methyl-D-aspartate receptors in the insular cortex disrupts taste aversion and spatial memory formation.

The present experiments examined the effects of direct intracortical microinjections of the N-methyl-D-aspartate receptor antagonist 2-amino-5-phosphonovaleric acid directly into the insular cortex of rats, before or immediately after training of conditioned taste aversion and the water maze spatial learning task. In the first series of experiments animals received bilateral injections of 2-amino-5-phosphonovaleric acid prior to taste aversion conditioning or spatial training. A strong disruptive effect was found in the acquisition of training tasks. To determine the possible involvement of N-methyl-D-aspartate receptors in the early post-training processes taking place in the cortex during both learning paradigms, in a second series of experiments, animals received bilateral 2-amino-5-phosphonovaleric acid microinjections 30, 60 or 120 min after the acquisition trial, and 15 min before the retention test. For spatial learning successive treatments were independently done either starting at the onset of the asymptotic phase of the learning curve, 0, 30 or 120 min after finishing the training session, as well as 15 min before the retention test trial. The conditioned taste aversion task remained sensitive to N-methyl-D-aspartate blockade during a period of at least 2 h after the first presentation of the gustatory stimulus, while in the case of the spatial learning task, a gradually decreasing effect was observed from the onset of the asymptotic phase onwards. Taken together, these results provide direct evidence for N-methyl-D-aspartate receptor involvement in cortical regulation of memory formation. Furthermore, our results suggest that in the same cortical region, a different time-course for the activation of N-methyl-D-aspartate-dependent mechanisms occurs during the early formation of cortically mediated memories, depending on the particular behavioural task.

Cholinergic modulation of neostriatal output: a functional antagonism between different types of muscarinic receptors.

It is demonstrated that acetylcholine released from cholinergic interneurons modulates the excitability of neostriatal projection neurons. Physostigmine and neostigmine increase input resistance (RN) and enhance evoked discharge of spiny projection neurons in a manner similar to muscarine. Muscarinic RN increase occurs in the whole subthreshold voltage range (-100 to -45 mV), remains in the presence of TTX and Cd2+, and can be blocked by the relatively selective M1,4 muscarinic receptor antagonist pirenzepine but not by M2 or M3 selective antagonists. Cs+ occludes muscarinic effects at potentials more negative than -80 mV. A Na+ reduction in the bath occludes muscarinic effects at potentials more positive than -70 mV. Thus, muscarinic effects involve different ionic conductances: inward rectifying and cationic. The relatively selective M2 receptor antagonist AF-DX 116 does not block muscarinic effects on the projection neuron but, surprisingly, has the ability to mimic agonistic actions increasing RN and firing. Both effects are blocked by pirenzepine. HPLC measurements of acetylcholine demonstrate that AF-DX 116 but not pirenzepine greatly increases endogenous acetylcholine release in brain slices. Therefore, the effects of the M2 antagonist on the projection neurons were attributable to autoreceptor block on cholinergic interneurons. These experiments show distinct opposite functions of muscarinic M1- and M2-type receptors in neostriatal output, i.e., the firing of projection neurons. The results suggest that the use of more selective antimuscarinics may be more profitable for the treatment of motor deficits.

Synaptogenesis of mossy fibers induced by spatial water maze overtraining.

Synaptic plasticity has been proposed as a mechanism underlying learning and memory. Synaptic reorganization of hippocampal mossy fibers has been observed after experimentally induced epilepsy, and after brief high-frequency activation inducing long-term potentiation. Furthermore, it has been suggested that synaptic changes in the hippocampus may occur after spatial learning. In this study, by using a zinc-detecting histologic technique (Timm), we demonstrate a significant increase of mossy fiber terminals in the CA3 stratum oriens region induced by training rats during 3 days in a spatial Morris water maze. In contrast, animals trained for only 1 day and animals that were just allowed to swim or were overtrained in a stress-motivated inhibitory avoidance task did not show increments of mossy fiber terminals in the stratum oriens. Electron microscopy confirmed that synaptic density of mossy fiber terminals in the stratum oriens increases significantly in water maze overtrained animals compared with the swimming control animals. Taken together, these results suggest that overtraining in a spatial learning task induces mossy fiber synaptogenesis that could be involved in the mechanisms underlying long-term memory storage. Hippocampus 1999;9:631-636.