Amygdala stimulation promotes recovery of behavioral performance in a spatial memory task and increases GAP-43 and MAP-2 in the hippocampus and prefrontal cortex of male rats.

The relationships between affective and cognitive processes are an important issue of present neuroscience. The amygdala, the hippocampus and the prefrontal cortex appear as main players in these mechanisms. We have shown that post-training electrical stimulation of the basolateral amygdala (BLA) speeds the acquisition of a motor skill, and produces a recovery in behavioral performance related to spatial memory in fimbria-fornix (FF) lesioned animals. BLA electrical stimulation rises bdnf RNA expression, BDNF protein levels, and arc RNA expression in the hippocampus. In the present paper we have measured the levels of one presynaptic protein (GAP-43) and one postsynaptic protein (MAP-2) both involved in synaptogenesis to assess whether structural neuroplastic mechanisms are involved in the memory enhancing effects of BLA stimulation. A single train of BLA stimulation produced in healthy animals an increase in the levels of GAP-43 and MAP-2 that lasted days in the hippocampus and the prefrontal cortex. In FF-lesioned rats, daily post-training stimulation of the BLA ameliorates the memory deficit of the animals and induces an increase in the level of both proteins. These results support the hypothesis that the effects of amygdala stimulation on memory recovery are sustained by an enhanced formation of new synapses.

Erythropoietin improves object placement recognition memory in a time dependent manner in both, uninjured animals and fimbria-fornix-lesioned male rats.

An increasing number of reports sustain a possible role of erythropoietin (EPO) as neuroprotective agent. In two previous articles we have evaluated EPO as plasticity promoting agent, and to contribute the restoration of brain function affected by acquired damage. We have shown that EPO is able to induce an increased synaptic efficacy in vivo along with a plasticity promoting effect. In the Morris water maze EPO administration to fimbria-fornix lesioned male rats induces a significant improvement of their spatial memory, affected by the lesion. Singularly, EPO was only effective when administered shortly after training (10 min) but not after several hours (5 h), suggesting a specific EPO effect on time dependent plasticity process. In the present paper we have expanded this line of evidence using a low stress paradigm of object placement recognition in lesioned and healthy male rats. The memory trace in this model is short-lasting; animals could recognize the change in object position when tested 24 h after, but not 48 or 72 h after the acquisition session. EPO administration 10 min after acquisition significantly prolongs retention to, at least, 72 h in healthy rats. No effect was seen if EPO was administered 5 h after training, suggesting a specific EPO modulatory effect on the consolidation process. Remarkably, early EPO treatment to fimbria fornix lesioned animals reverts the memory deficit caused by the lesion. An increased expression of the plasticity related gene arc, was also confirmed in the hippocampus and the prefrontal cortex, that is likely to be involved in the behavioral improvement observed.

Amygdala electrical stimulation inducing spatial memory recovery produces an increase of hippocampal bdnf and arc gene expression.

Amygdala seems to promote the consolidation of plastic modification in different brain areas and these long-term brain changes require a rapid de novo RNA and protein synthesis. We have previously shown that basolateral amygdala electrical stimulation produces a partial recovery of spatial memory in fimbria-fornix lesioned animals and it is also able to increase the BDNF protein content in the hippocampus. The emerging question is whether these increased BDNF protein content arises from previously synthesized RNA or from de novo RNA expression. Now we address the question if amygdala electrical stimulation 15min after daily water maze training produces a rapid de novo RNA synthesis in the hippocampus, a critical brain area for spatial memory recovery in fimbria-fornix lesioned animals. In addition, we also study RNA arc expression, a gene which is essential for memory and neural plasticity processes. To this purpose, we study amygdala stimulation effects on the expression of plasticity related-early-genes bdnf and arc in the hippocampus of fimbria-fornix lesioned animals trained in a water-maze for 4days. We also checked on the expression of both genes in non-lesioned, untrained animals (acute condition) at 0.5, 1, 2 and 24h after basolateral amygdala electrical stimulation. Our data from trained animals confirm that daily amygdala electrical stimulation 15min after water maze training produces a partial memory recovery and that is coupled to an increase of bdnf and arc genes expression in the hippocampus. Additionally, the acute study shows that a single session of amygdala stimulation induces a transient increase of both genes (peaking at 30min). These results confirm the memory improving effect of amygdala stimulation in fimbria-fornix-lesioned animals and sustain the assumption that the memory improving effect is mediated by newly synthetized BDNF acting on a memory relevant structure like the hippocampus. The increased amount of BDNF within the hippocampus seems to be locally synthetized by mechanisms activated by the amygdala stimulation.

Basolateral amygdala stimulation does not recruit LTP at depotentiated synapses.

Hippocampal long-term potentiation (LTP) is a long-lasting increase in synaptic efficacy considered to be the cellular basis of memory. LTP consists of an early, protein synthesis-independent phase (E-LTP) and a late phase that depends on protein synthesis (L-LTP). Application of a weak tetanus can induce E-LTP in the dentate gyrus (DG) which can be reinforced into L-LTP by direct stimulation of the basolateral amygdala (BLA) within 30 min before or after LTP induction (structural LTP-reinforcement). LTP can be depotentiated by low-frequency stimulation (LFS) to the same synaptic input if applied shortly after tetanization (<10 min). Here, we addressed the question of whether stimulation of the BLA is able to recover LTP at depotentiated synaptic inputs. We hypothesized that E-LTP can activate synaptic tags, which were then reset by depotentiation. Stimulation of the BLA thereafter could beneficially act on tag-reactivation as well as on the activation of the synthesis of plasticity-related proteins (PRPs), normally captured by the tags and thus transforming E-LTP into L-LTP. Our results show, that BLA-stimulation was not able to reactivate the resetting of tags by depotentiation in the DG of freely moving rats.

Differential effects of electrical stimulation patterns, motivational-behavioral stimuli and their order of application on functional plasticity processes within one input in the dentate gyrus of freely moving rats in vivo.

Hippocampal long-term potentiation (LTP) is a long-lasting increase in synaptic efficacy considered to be the cellular basis of memory. LTP consists of an early, protein synthesis-independent phase (E-LTP) and a late phase that depends on protein synthesis (L-LTP). In water-deprived rats E-LTP in the dentate gyrus (DG) can be reinforced into L-LTP, if the rats were allowed to drink within 15 min after E-LTP induction (behavioral LTP-reinforcement, BR). LTP can be depotentiated by low-frequency stimulation (LFS) to the same synaptic input if applied shortly after tetanization (<10 min). Here, we addressed the question of whether a BR protocol is able to recover LTP at depotentiated synaptic inputs. We show that LTP, depotentiation, LFS and BR specifically interact within one afferent input, which could be explained by the "synaptic tagging" hypothesis outlined by [Frey and Morris (1997) Nature 385:533-536]. E-LTP induced by a weak tetanus (WTET) sets tags in the activated inputs which are able to capture and to process plasticity-related proteins (PRPs) required for L-LTP, the synthesis of which was induced by BR. Synaptic tags could be reset by LFS. BR alone was unable to rescue depotentiated LTP, but the combination of BR and subsequent WTET transformed E-LTP into L-LTP. We show that LTP, LTD and behavioral stimuli alternatively and reversibly affect a single afferent input for long periods of time by LTP as well as LTD mechanisms, competing with each other under the influence of different concurrent stimuli. Affective modulation can shift the balance to one or the other. We show that the result will depend not only on the last stimulus, but on the history of previous stimuli applied to the specific input. Afferent stimuli activate alternative, but partially overlapping cascades with long-lasting consequences for the input including spaced-associative processes of "synaptic tagging" as well as "cross-tagging" which could be demonstrated in single synaptic afferents to one neuronal population in freely behaving animals.

[Synaptic tagging and memory trace]. / La 'marca sinaptica' y la huella de la memoria.

AIM: To present a panorama of the main features and possible identity of the synaptic tag, such as to discuss some of its functional implications. DEVELOPMENT: Long-term potentiation (LTP) constitutes a very attractive synaptic/cellular memory model. LTP, like memory, can manifest itself early (essentially depending on the modification of pre-existing proteins at synapse) and late (depending on new protein synthesis). As LTP is a highly specific phenomenon, a dilemma arises: how can the proteins, required to plastic change stabilization, that are synthesized at the soma of a neuron containing thousands of synaptic contacts--all depending of the same nucleus--go to the appropriate synapses? In this review, we present some of the models that intend to explain this question, making emphasis on synaptic tagging hypothesis. Some of the main findings that have contributed to tagging hypothesis are exposed. The local protein synthesis and the activation of protein kinases are analyzed as candidates to be the synaptic tag. Additionally, some of the functional implications of synaptic tagging are discussed. CONCLUSIONS: The synaptic tagging hypothesis offers a very flexible and reasonable solution to the specificity of long-lasting synaptic changes. Although some of the tagging features are known, the synaptic tag identity has not yet been elucidated. It seems that there is not a unique synaptic tag, but there are rather multiple molecular synaptic tags involved. Each of them might function as a synaptic tag under particular circumstances. Each might be differentially recruited by specific stimuli and mediate plasticity over different time domains.

La ‘marca sináptica’ y la huella de la memoriar / Synaptic tagging and memory trace

Presentar una visión de las principales características y posible identidad de la marca sináptica, así comodiscutir algunas de sus implicaciones funcionales. Desarrollo. La potenciación sináptica a largo plazo, dadas sus características, se ha impuesto como un modelo sinapticocelular de memoria muy atractivo. De modo similar a la memoria, puede manifestarse como temprana (dependiente fundamentalmente de la modificación de proteínas preexistentes en la sinapsis) otardía (dependiente de la síntesis de nuevas proteínas). Debido a que la potenciación sináptica a largo plazo es un fenómeno altamente específico, surge un dilema: ¿cómo llegan a las sinapsis apropiadas las proteínas requeridas para la estabilizacióndel cambio plástico en una neurona que normalmente posee miles de contactos sinápticos, todos dependientes del mismo núcleo? En este trabajo se presentan algunos de los modelos que aportan posibles soluciones a este interrogante, haciendo énfasisen la hipótesis del marcaje sináptico. Se exponen los principales hallazgos que han ido conformando esta hipótesis y se analiza la síntesis local y la activación de proteincinasas como posibles candidatos de ser la marca sináptica. Adicionalmente, sediscuten algunas implicaciones funcionales del marcaje sináptico. Conclusiones. La hipótesis de la marca sináptica ofrece una explicación muy flexible y razonable acerca de la especificidad del cambio sináptico duradero. Aunque se conocen algunas desus características, la identidad de la marca no se ha dilucidado aún. Al parecer, existen múltiples marcas que, al ser reclutadas por estímulos específicos, median los efectos plásticos en diferentes dominios temporales

To present a panorama of the main features and possible identity of the synaptic tag, such as to discuss someof its functional implications. Development. Long-term potentiation (LTP) constitutes a very attractive synaptic/cellular memory model. LTP, like memory, can manifest itself early (essentially depending on the modification of pre-existing proteins atsynapse) and late (depending on new protein synthesis). As LTP is a highly specific phenomenon, a dilemma arises: how can the proteins, required to plastic change stabilization, that are synthesized at the soma of a neuron containing thousands ofsynaptic contacts –all depending of the same nucleus– go to the appropriate synapses? In this review, we present some of the models that intend to explain this question, making emphasis on synaptic tagging hypothesis. Some of the main findings that have contributed to tagging hypothesis are exposed. The local protein synthesis and the activation of protein kinases areanalyzed as candidates to be the synaptic tag. Additionally, some of the functional implications of synaptic tagging are discussed. Conclusions. The synaptic tagging hypothesis offers a very flexible and reasonable solution to the specificity oflong-lasting synaptic changes. Although some of the tagging features are known, the synaptic tag identity has not yet been elucidated. It seems that there is not a unique synaptic tag, but there are rather multiple molecular synaptic tags involved.Each of them might function as a synaptic tag under particular circumstances. Each might be differentially recruited by specific stimuli and mediate plasticity over different time domains

La marca sináptica y la huella de la memoria / Synaptic tagging and memory trace

Objetivo. Presentar una visión de las principales características y posible identidad de la marca sináptica, así comodiscutir algunas de sus implicaciones funcionales. Desarrollo. La potenciación sináptica a largo plazo, dadas sus características, se ha impuesto como un modelo sinapticocelular de memoria muy atractivo. De modo similar a la memoria, puede manifestarse como temprana (dependiente fundamentalmente de la modificación de proteínas preexistentes en la sinapsis) otardía (dependiente de la síntesis de nuevas proteínas). Debido a que la potenciación sináptica a largo plazo es un fenómeno altamente específico, surge un dilema: ¿cómo llegan a las sinapsis apropiadas las proteínas requeridas para la estabilizacióndel cambio plástico en una neurona que normalmente posee miles de contactos sinápticos, todos dependientes del mismo núcleo? En este trabajo se presentan algunos de los modelos que aportan posibles soluciones a este interrogante, haciendo énfasisen la hipótesis del marcaje sináptico. Se exponen los principales hallazgos que han ido conformando esta hipótesis y se analiza la síntesis local y la activación de proteincinasas como posibles candidatos de ser la marca sináptica. Adicionalmente, se discuten algunas implicaciones funcionales del marcaje sináptico. Conclusiones. La hipótesis de la marca sináptica ofrece unaexplicación muy flexible y razonable acerca de la especificidad del cambio sináptico duradero. Aunque se conocen algunas de sus características, la identidad de la marca no se ha dilucidado aún. Al parecer, existen múltiples marcas que, al ser reclutadaspor estímulos específicos, median los efectos plásticos en diferentes dominios temporales(AU)

AIM: To present a panorama of the main features and possible identity of the synaptic tag, such as to discuss some of its functional implications. DEVELOPMENT: Long-term potentiation (LTP) constitutes a very attractive synaptic/cellular memory model. LTP, like memory, can manifest itself early (essentially depending on the modification of pre-existing proteins at synapse) and late (depending on new protein synthesis). As LTP is a highly specific phenomenon, a dilemma arises: how can the proteins, required to plastic change stabilization, that are synthesized at the soma of a neuron containing thousands of synaptic contacts--all depending of the same nucleus--go to the appropriate synapses? In this review, we present some of the models that intend to explain this question, making emphasis on synaptic tagging hypothesis. Some of the main findings that have contributed to tagging hypothesis are exposed. The local protein synthesis and the activation of protein kinases are analyzed as candidates to be the synaptic tag. Additionally, some of the functional implications of synaptic tagging are discussed. CONCLUSIONS: The synaptic tagging hypothesis offers a very flexible and reasonable solution to the specificity of long-lasting synaptic changes. Although some of the tagging features are known, the synaptic tag identity has not yet been elucidated. It seems that there is not a unique synaptic tag, but there are rather multiple molecular synaptic tags involved. Each of them might function as a synaptic tag under particular circumstances. Each might be differentially recruited by specific stimuli and mediate plasticity over different time domains(AU)

Subcortical deafferentation impairs behavioral reinforcement of long-term potentiation in the dentate gyrus of freely moving rats.

Long-term potentiation is a form of neural functional plasticity which has been related with memory formation and recovery of function after brain injury. Previous studies have shown that a transient early-long-term potentiation can be prolonged by direct stimulation of distinct brain areas, or behavioral stimuli with a high motivational content. The basolateral amygdala and other subcortical structures, like the medial septum and the locus coeruleus, are involved in mediating the reinforcing effect. We have previously shown that the lesion of the fimbria-fornix--the main entrance of subcortical afferents to the hippocampus--abolishes the reinforcing basolateral amygdala-effects on long-term potentiation in the dentate gyrus in vivo. It remains to be investigated, however, if such subcortical afferents may also be important for behavioral reinforcement of long-term potentiation. Young-adult (8 weeks) Sprague-Dawley male rats were fimbria-fornix-transected under anesthesia, and electrodes were implanted at the dentate gyrus and the perforant path. One week after surgery the freely moving animals were studied. Fimbria-fornix-lesion reduced the ability of the animals to develop long-term potentiation when a short pulse duration was used for tetanization (0.1 ms per half-wave of a biphasic stimulus), whereas increasing the pulse duration to 0.2 ms per half-wave during tetanization resulted in a transient early-long-term potentiation lasting about 4 h in the lesioned animals, comparable to that obtained in non-lesioned or sham-operated control rats. In water-deprived (24 h) control animals, i.e. in non-lesioned and sham-operated rats, early-long-term potentiation could be behaviorally reinforced by drinking 15 min after tetanization. However, in fimbria-fornix-lesioned animals long-term potentiation-reinforcement by drinking was not detected. This result indicates that the effect of behavioral-motivational stimuli to reinforce long-term potentiation is mediated by subcortical, heterosynaptic afferents.

Effect of LTP-reinforcing paradigms on neurotransmitter release in the dentate gyrus of young and aged rats.

Long-term potentiation (LTP) is considered a cellular correlate of memory processing. A short-lasting early-LTP can be prolonged into a late-L TP (>4h) by stimulation of the basolateral amygdala (BLA) or motivational behavioral stimuli in young, but not in aged, cognitively impaired rats. We measured the changes in transmitter release-induced by BLA or behavioral reinforcement-in young and aged cognitively impaired rats, after implanting a microdialysis cannula at the dentate gyrus. Samples were taken under baseline conditions and during stimulation of BLA. Rats were water deprived and tested again next day, taking samples after allowing access to water. Higher concentrations of choline, HIAA, aspartate, glutamate, and glycine were found in baseline samples from young animals compared to aged. In young animals, BLA stimulation increased the levels of ACh and reduced norepinephrine and serotonine, while behavioral reinforcement reduced the levels of glutamate and glycine. These effects were absent among aged rats, suggesting that this reduced neurochemical response might be linked to the impaired LTP-reinforcement reported previously.

[Comparative study of bilateral lesions in the entorhinal cortex and in the fimbria fornix]. / Estudio comparativo de la lesión bilateral de corteza entorrinal y de la fimbria-fórnix.

INTRODUCTION: Numerous reports show that lesions to hippocampus afferents, such as the entorhinal cortex (EC) and the fimbria fornix (FF), exert an effect on memory in rodents. There are, however, no long term comparative studies that show which of these lesions could be most useful as a model for studies into neuroplasticity. MATERIAL AND METHODS: Young male Sprague Dawley rats were used. Bilateral electrolytic lesion was caused to the EC or the FF was damaged by transection. One, four or 12 weeks later the animals were evaluated in a Morris water maze, first with an invisible platform and then with the platform within view. The results from the two groups were compared to each other and to those obtained from healthy controls and subjects with false lesions by means of a variance analysis. RESULTS: In the test with an invisible platform, both types of lesion gave rise to serious, irreparable involvement of the spatial memory of the animals, at least up to 12 weeks after the lesion. The test with the visible platform revealed significant differences between animals with lesion to the EC evaluated at 12 weeks, which suggests the development of some visual or motor deterioration in these animals. CONCLUSIONS: Although both lesions gave rise to behavioural deterioration that was irreversible in the long term in rodents, the lesion to the FF seems to be a better model for evaluating specific effects on learning and memory, since the lesion to the EC apparently triggers additional sensory and motor involvement.

Behavioral reinforcement of long-term potentiation in rat dentate gyrus in vivo is protein synthesis-dependent.

A transient, protein synthesis-independent long-term potentiation (early-LTP, <4 h) can be reinforced into a maintained protein synthesis-dependent late-LTP (>4 h) by specific electrical stimulation of limbic structures (J. Neurosci. 21 (2001) 3697). Similarly, LTP-modulation can be obtained by behavioral stimuli with strong motivational content. However, the requirement of protein synthesis during behavioral reinforcement has not been shown so far. Thus, we have studied here this specific question using a behavioral reinforcement protocol, i.e. allowing water-deprived animals to drink 15 min after induction of early-LTP. This procedure transformed early-LTP into late-LTP. Anisomycin, a reversible protein synthesis inhibitor, abolished behavioral LTP-reinforcement. These results demonstrate that behavioral reinforcement depends on protein synthesis.

Estudio comparativo de la lesión bilateral de corteza entorrinal y de la fimbria-fórnix / Comparative study of bilateral lesions in the entorhinal cortex and inthe fimbria-fornix

Introducción. Numerosos comunicados muestran que la lesión de aferentes al hipocampo, como la corteza entorrinal (CE) y la fimbria-fórnix (FF), afectan a la memoria en roedores; sin embargo, no existen estudios comparativos a largo plazo que demuestren cuál de esas lesiones pudiera ser más útil como modelo para estudios de neuroplasticidad. Material y métodos. Se utilizaron ratas macho jóvenes de la variedad Sprague Dawley. Se provocó una lesión electrolítica bilateral de la CE o una lesión por transección de la FF. Después de una, cuatro o doce semanas, los animales se evaluaron en el laberinto acuático de Morris, primero con plataforma no visible y después con plataforma visible. Los resultados de los grupos se compararon entre sí y con los de controles sanos y falsas lesionadas mediante un análisis de varianza. Resultados. En la prueba con plataforma no visible, ambos tipos de lesión provocaron una afectación grave e irreversible de la memoria espacial de los animales, al menos hasta doce semanas después de la lesión. La prueba con plataforma visible mostró diferencias significativas entre los animales con lesión de la CE evaluados a las 12 semanas, lo que sugiere el desarrollo de algún deterioro visual o motor en estos animales. Conclusiones. Aunque ambas lesiones provocan un deterioro conductual no reversible a largo plazo en los roedores, la lesión de la FF parece un mejor modelo para evaluar efectos específicos sobre el aprendizaje y la memoria, ya que la lesión de la CE, aparentemente, provoca afectaciones sensoriales o motoras adicionales (AU)

Introduction. Numerous reports show that lesions to hippocampus afferents, such as the entorhinal cortex (EC) and the fimbria-fornix (FF), exert an effect on memory in rodents. There are, however, no long term comparative studies that show which of these lesions could be most useful as a model for studies into neuroplasticity. Material and methods. Young male Sprague Dawley rats were used. Bilateral electrolytic lesion was caused to the EC or the FF was damaged by transection. One, four or 12 weeks later the animals were evaluated in a Morris water maze, first with an invisible platform and then with the platform within view. The results from the two groups were compared to each other and to those obtained from healthy controls and subjects with false lesions by means of a variance analysis. Results. In the test with an invisible platform, both types of lesion gave rise to serious, irreparable involvement of the spatial memory of the animals, at least up to 12 weeks after the lesion. The test with the visible platform revealed significant differences between animals with lesion to the EC evaluated at 12 weeks, which suggests the development of some visual or motor deterioration in these animals. Conclusions. Although both lesions gave rise to behavioural deterioration that was irreversible in the long term in rodents, the lesion to the FF seems to be a better model for evaluating specific effects on learning and memory, since the lesion to the EC apparently triggers additional sensory and motor involvement (AU)

The amygdala is part of the behavioural reinforcement system modulating long-term potentiation in rat hippocampus.

Long-term potentiation (LTP) in the dentate gyrus can be modulated and prolonged by emotional/motivational influences when concurrently activated. A similar effect on LTP can be obtained by stimulating the amygdala, suggesting that this limbic structure might be part of the neural system involved in behavioural reinforcement. To confirm this we have performed a series of experiments in which the basolateral amygdala was either temporary inactivated by injection of lidocaine or permanently lesioned electrolytically. Both manipulations completely blocked the reinforcing effect of a motivational stimulus (drinking after 24-h deprivation) on LTP at the perforant pathway-dentate gyrus synapses, whilst leaving intact the non-reinforced potentiation. These results demonstrate that the basolateral amygdala is a key structure within the system involved in the modulatory interaction between the affective status of the animal and the mechanisms of functional plasticity.

El glutatión en la función cognitiva y la neurodegeneración / Glutathione in cognitive function and neurodegeneration

Objetivo. Reseñar las principales evidencias acerca del papel del glutatión en la función cognitiva y los procesos de plasticidad sináptica, así como su participación en los eventos neurodegenerativos y neurotróficos modelados en roedores. Desarrollo. El tripéptido glutatión y las enzimas relacionadas con éste participan en el mantenimiento de la homeostasis oxidante de las células aeróbicas. El daño oxidativo a los componentes neuronales se presenta en la base molecular de la neurodegeneración y el envejecimiento cerebral. En los eventos de plasticidad neuronal, mediadores de las funciones de aprendizaje y memoria, participan biomoléculas cuya actividad se modula por las variaciones en el estado redox del medio. El bajo contenido de glutatión provoca un déficit en los mecanismos de plasticidad sináptica hipocampal, tanto a largo como a corto plazo, que se acompañan y probablemente causan un deterioro en la adquisición, pero no en la consolidación, de la información espacial. Por otra parte, los resultados de varios estudios sugieren que los efectos beneficiosos del tratamiento con factores neurotróficos pueden mediarse por una modulación de las defensas antioxidantes. Así, el factor de crecimiento nervioso estimula a la glutatión reductasa y restaura la actividad aumentada de la glutatión peroxidasa en animales con déficit cognitivo. Conclusión. Existe un vínculo estrecho entre el metabolismo del glutatión y los procesos de aprendizaje y memoria. En este vínculo, los mecanismos preservadores de la homeostasis oxidante cerebral pueden participar, a la vez, como moduladores de la función cognitiva y como dianas de los eventos degenerativos y neurotróficos (AU)

Objective. To review the main findings on the glutathione role in cognitive function and synaptic plasticity processes, as well as, its involvement in neurotrophic and neurodegenerative events in rodents. Development. The tripeptide glutathione and its related enzymes participate in the maintenance of oxidant homeostasis in aerobic cells. Oxidative damage to neuronal components underlies the molecular basis of neurodegeneration and brain aging. Several biomolecules with redox-dependent activity are involved in the neuronal plasticity events that have a role in learning and memory functions. The maintenance of normal glutathione level is important for acquisition, but not consolidation, of spatial memory. Glutathione unavailability induces failures in hippocampal synaptic plasticity mechanisms, which are possibly related to a spatial memory deficit. On the other hand, several studies have suggested that the beneficial effects of neurotrophic treatments are mediated by the modulation of antioxidant defense mechanisms. In fact, nerve growth factor treatment to cognitively impaired rats stimulates glutathione reductase and can prevent the increases in glutathione peroxidase activity, pointing these enzymes as possible intracellular targets of neurotrophin actions on oxidant homeostasis. Conclusion. There is a closed link between glutathione metabolism and oxidant homeostasis, which is expressed in learning and synaptic plasticity deficits in conditions of low glutathione content, as well as, in neurodegeneration-induced glutathione metabolism changes that can be prevented by neurotrophic treatment (AU)

[Glutathione in cognitive function and neurodegeneration]. / El glutatión en la función cognitiva y la neurodegeneración.

OBJECTIVE: To review the main findings on the glutathione role in cognitive function and synaptic plasticity processes, as well as, its involvement in neurotrophic and neurodegenerative events in rodents. DEVELOPMENT: The tripeptide glutathione and its related enzymes participate in the maintenance of oxidant homeostasis in aerobic cells. Oxidative damage to neuronal components underlies the molecular basis of neurodegeneration and brain aging. Several biomolecules with redox dependent activity are involved in the neuronal plasticity events that have a role in learning and memory functions. The maintenance of normal glutathione level is important for acquisition, but not consolidation, of spatial memory. Glutathione unavailability induces failures in hippocampal synaptic plasticity mechanisms, which are possibly related to a spatial memory deficit. On the other hand, several studies have suggested that the beneficial effects of neurotrophic treatments are mediated by the modulation of antioxidant defense mechanisms. In fact, nerve growth factor treatment to cognitively impaired rats stimulates glutathione reductase and can prevent the increases in glutathione peroxidase activity, pointing these enzymes as possible intracellular targets of neurotrophin actions on oxidant homeostasis. CONCLUSION: There is a closed link between glutathione metabolism and oxidant homeostasis, which is expressed in learning and synaptic plasticity deficits in conditions of low glutathione content, as well as, in neurodegeneration induced glutathione metabolism changes that can be prevented by neurotrophic treatment

[Interactions between the hippocampus and the amygdala in synaptic plasticity processes. A key to understanding the relations between motivation and memory]. / Interacciones entre el hipocampo y la amígdala en proceso de plasticidad sináptica. Una clave para entender las relaciones entre motivación y memoria.

INTRODUCTION: Memory is initially stored as a transitory change that can become consolidated and converted into a long term memory trace. Consolidation largely depends on the emotional state. It is known that the hippocampus plays a role in the consolidation process of certain types of memory and that the amygdala might modulate the consolidation of the memory traces in other parts of the brain. The interaction between these two structures is crucial in many forms of learning and memory. METHOD: The hippocampus, as well as the amygdala, display a type of synaptic plasticity known as long term potentiation (LTP), which is considered to be a cellular memory mechanism. Recently, it has been reported that the consolidation of the hippocampal LTP may be modulated, like memory, by the emotional state and by the activation of the basolateral amygdala. These findings, taken as a whole, can help to explain how the processes of consolidation of memory take place. At the same time they also constitute a more physiological model of the learning and memory processes, which will provide us with a more accurate understanding of the mechanisms behind the consolidation of the memory.

Behavioral and biochemical effects of glutathione depletion in the rat brain.

Glutathione serves the function of providing reducing equivalents for the maintenance of oxidant homeostasis, and besides it plays roles in intra- and intercellular signaling in the brain. Our purpose was to test the effects of depleting tissue glutathione by diethylmaleate (5.3 mmol/kg, intraperitoneal) on brain antioxidant metabolism, nerve growth factor levels, and cognitive performance in rats. Six hours after the treatment, glutathione level in the hippocampus dropped down to 30% of the mean value of vehicle-treated animals and glutathione peroxidase activity also declined. Twenty-four hours after the injection the values had been partially restored. Moreover, the hippocampal and cortical levels of nerve growth factor protein did not change in response to diethylmaleate treatment. Glutathione depletion did not influence the performance of animals in the step-through passive avoidance test, but impairs acquisition in the Morris water maze when given before training. However, when diethylmaleate was administered after acquisition in the same paradigm, it did not affect the retention tested at the following day. Our results suggest that glutathione status is important during acquisition, but not for retention, of spatial memory in maze tasks and they support the hypothesis of the oxidant/antioxidant equilibrium as a key piece acting in the regulation of brain function.

Mecanismos celulares de la neuroplasticidad / Cellular mechanisms of neuroplasticity

Objetivo. Presentar, de manera unificada, una visión de los principales mecanismos de neuroplasticidad conocidos, destacando su universalidad. Desarrollo. La concepción del sistema nervioso como una entidad inmutable ha sufrido modificaciones sustanciales durante la segunda mitad del siglo XX. La neuroplasticidad, es decir, la capacidad de cambio y reparación del cerebro, se expresa de formas diversas, desde modificaciones funcionales de estructuras ya existentes, hasta la formación por crecimiento y proliferación de nuevas estructuras y neuronas. El presente trabajo aborda los mecanismos celulares y moleculares de los fenómenos neuroplásticos y los clasifica en dos grandes grupos: plasticidad por crecimiento, donde se incluyen los mecanismos de regeneración axonal, colateralización y sinaptogénesis reactiva; y plasticidad funcional, que abarca cambios en la eficacia de la transmisión sináptica como la potenciación a largo plazo y la activación de sinapsis silentes. Se presentan además algunas relaciones de fenómenos neuroplásticos con enfermedades del sistema nervioso, así como ejemplos de factores fisiológicos, físicos y farmacológicos que pueden, en el futuro, convertirse en herramientas terapéuticas para estimular y modular la neuroplasticidad. Conclusiones. Los mecanismos neuroplásticos muestran un alto grado de conservación filogenética y ontogenética, y son importantes tanto en la génesis de trastornos y enfermedades del sistema nervioso, como en su reparación tras sufrir traumatismos y daños muy diversos. La modulación de los mecanismos neuroplásticos por agentes físicos y químicos se vislumbra como una de las más potentes herramientas terapéuticas de la neurología restaurativa (AU)

Synaptic plasticity is impaired in rats with a low glutathione content.

Long-term potentiation (LTP) is a sustained increase in the efficacy of synaptic transmission, based on functional changes involving pre- and postsynaptic mechanisms, and has been considered a cellular model for learning and memory. The sulphurated tripeptide glutathione acts as a powerful antioxidant agent within the nervous system. Recent in vitro studies suggest that the cellular redox status might influence the mechanisms involved in synaptic plasticity. It is not known, however, how glutathione depletion might affect LTP. In the present study, we evaluated the input-output relationships, LTP, and paired-pulse interactions in rats with low glutathione levels induced by systemic injection of diethylmaleate. Our results in anesthetized rats show that the basic synaptic transmission between the perforant pathway and the dentate gyrus granule cells was not affected by glutathione depletion. However, in the same synapses it was not possible to induce prolonged changes in synaptic efficacy (LTP). Paired-pulse facilitation was also absent in the treated animals, suggesting an impairment of short-term synaptic interactions. These findings indicate that low content of glutathione can impair short-term and long-term mechanisms of synaptic plasticity and stress the importance of the redox balance in the normal function of brain circuitry.