Implication of GluR2 subunit of AMPA receptor in RGS14(414)-mediated memory enhancement

Ongoing quest for finding treatment against memory loss seen in aging and in many neurological and neurodegenerative diseases, so far has been unsuccessful and memory enhancers are seen as a potential remedy against this brain dysfunction. Recently, we showed that gene corresponding to a protein called regulator of G-protein signaling 14 of 414 amino acids (RGS14414) is a robust memory enhancer (Lopez-Aranda et al. 2009: Science). RGS14414-treatment in area V2 of visual cortex caused memory enhancement to such extent that it converted short-term object recognition memory (ORM) of 45min into long lasting long-term memory that could be traced even after many months. Now, through targeting of multiple receptors and molecules known to be involved in memory processing, we found that GluR2 subunit of AMPA receptor might be key to memory enhancement in RGS-animals. RGS14-animals showed a progressive increase in GluR2 protein expression while processing an object information which reached to highest level after 60min of object exposure, a time period required for conversion of short-term ORM into long-term memory in our laboratory set up. Normal rats could retain an object information in brain for 45min (short-term) and not for 60min. However, RGS-treated rats are able to retain the same information for 24h or longer (long-term). Therefore, highest expression of GluR2 subunit seen at 60min suggests that this protein might be key in memory enhancement and conversion to long-term memory in RGS-animals. In addition, we will also discuss the implication of Hebbian plasticity and interaction of brain circuits in memory enhancement.

RGS14 (414)-mediated prevention of an episodic memory loss: a study of molecular mechanism

A large proportion of human populations suffer memory impairments either caused by normal aging or afflicted by diverse neurological and neurodegenerative diseases. Memory enhancers and other drugs tested so far against memory loss have failed to produce therapeutic efficacy in clinical trials and thus, there is a need to find remedy for this mental disorder. In search for cure of memory loss, our laboratory discovered a robust memory enhancer called RGS14(414). A treatment in brain with its gene produces an enduring effect on memory that lasts for lifetime of rats. Therefore, current thesis work was designed to investigate whether RGS14(414) treatment can prevent memory loss and furthermore, explore through biological processes responsible for RGS-mediated memory enhancement. We found that RGS14(414) gene treatment prevented episodic memory loss in rodent models of normal aging and Alzheimer´s disease. A memory loss was observed in normal rats at 18 months of age; however, when they were treated with RGS14(414) gene at 3 months of age, they abrogated this deficit and their memory remained intact till the age of 22 months. In addition to normal aging rats, effect of memory enhancer treatment in mice model of Alzheimer´s disease (AD-mice) produced a similar effect. AD-mice subjected to treatment with RGS14(414) gene at the age of 2 months, a period when memory was intact, showed not only a prevention in memory loss observed at 4 months of age but also they were able to maintain normal memory after 6 months of the treatment. We posit that long-lasting effect on memory enhancement and prevention of memory loss mediated through RGS14(414) might be due to a permanent structural change caused by a surge in neuronal connections and enhanced neuronal remodeling, key processes for long-term memory formation. A neuronal arborization analysis of both pyramidal and non-pyramidal neurons in brain of RGS14(414)-treated rats exhibited robust rise in neurites outgrowth of both kind of cells, and an increment in number of branching from the apical dendrite of pyramidal neurons, reaching to almost three times of the control animals. To further understand of underlying mechanism by which RGS14(414) induces neuronal arborization, we investigated into neurotrophic factors. We observed that RGS14 treatment induces a selective increase in BDNF. Role of BDNF in neuronal arborization, as well as its implication in learning and memory processes is well described. In addition, our results showing a dynamic expression pattern of BDNF during ORM processing that overlapped with memory consolidation further support the idea of the implication of this neurotrophin in formation of long-term memory in RGS-animals. On the other hand, in studies of expression profiling of RGS-treated animals, we have demonstrated that 14-3-3ζ protein displays a coherent relationship to RGS-mediated ORM enhancement. Recent studies have demonstrated that the interaction of receptor for activated protein kinase 1 (RACK1) with 14-3-3ζ is essential for its nuclear translocation, where RACK1-14-3-3ζ complex binds at promotor IV region of BDNF and promotes an increase in BDNF gene transcription. These observations suggest that 14-3-3ζ might regulate the elevated level of BDNF seen in RGS14(414) gene treated animals. Therefore, it seems that RGS-mediated surge in 14-3-3ζ causes elevated BDNF synthesis needed for neuronal arborization and enhanced ORM. The prevention of memory loss might be mediated through a restoration in BDNF and 14-3-3ζ protein levels, which are significantly decreased in aging and Alzheimer’s disease. Additionally, our results demonstrate that RGS14(414) treatment could be a viable strategy against episodic memory loss.

The neuronal monocarboxylate transporter MCT2: its regulation by BDNF and its role in learning and memory

Glucose has been considered the major, if not the exclusive, energy substrate for the brain. But under certain physiological and pathological conditions other substrates, namely monocarboxylates (lactate, pyruvate and ketone bodies), can contribute significantly to satisfy brain energy demands. These monocarboxylates need to be transported across the blood-brain barrier or out of astrocytes into the extracellular space and taken up into neurons. It has been shown that monocarboxylates are transported by a family of proton-linked transporters called monocarboxylate transporters (MCTs). In the central nervous system, MCT2 is the predominant neuronal isoform and little is known about the regulation of its expression. Noradrenaline (NA), insulin and IGF-1 were previously shown to enhance the expression of MCT2 in cultured cortical neurons via a translational mechanism. Here we demonstrate that the well known brain neurotrophic factor BDNF enhances MCT2 protein expression in cultured cortical neurons and in synaptoneurosome preparations in a time- and concentrationdependent manner without affecting MCT2 mRNA levels. We observed that BDNF induced MCT2 expression by activation of MAPK as well as PI3K/Akt/mTOR signaling pathways. Furthermore, we investigated the possible post-transcriptional regulation of MCT2 expression by a neuronal miRNA. Then, we demonstrated that BDNF enhanced MCT2 expression in the hippocampus in vivo, in parallel with some post-synaptic proteins such as PSD95 and AMPA receptor GluR2/3 subunits, and two immediate early genes Arc and Zif268 known to be expressed in conditions related to synaptic plasticity. In the last part, we demonstrated in vivo that a downregulation of hippocampal MCT2 via silencing with an appropriate lentiviral vector in mice caused an impairment of working memory without reference memory deficit. In conclusion, these results suggest that regulation of neuronal monocarboxylate transporter MCT2 expression could be a key event in the context of synaptic plasticity, allowing an adequate energy substrate supply in situations of altered synaptic efficacy. - Le glucose représente le substrat énergétique majeur pour le cerveau. Cependant, dans certaines conditions physiologiques ou pathologiques, le cerveau a la capacité d'utiliser des substrats énergéiques appartenant à la classe des monocarboxylates (lactate, pyruvate et corps cétoniques) afin de satisfaire ses besoins énergétiques. Ces monocarboxylates doivent être transportés à travers la barrière hématoencéphalique mais aussi hors des astrocytes vers l'espace extracellulaire puis re-captés par les neurones. Leur transport est assuré par une famillle de transporteurs aux monocarboxylates (MCTs). Dans le système nerveux central, les neurones expriment principalement l'isoforme MCT2 mais peu d'informations sont disponibles concernant la régulation de son expression. Il a été montré que la noradrénaline, l'insuline et l'IGF-1 induisent l'expression de MCT2 dans des cultures de neurones corticaux par un mécanisme traductionnel. Dans cette étude nous démontrons dans un premier temps que le facteur neurotrophique BDNF augmente l'expression de MCT2 à la fois dans des cultures de neurones corticaux et dans les préparations synaptoneurosomales selon un décours temporel et une gamme de concentrations propre. Aucun changement n'a été observé concernant les niveaux d'ARNm de MCT2. Nous avons observé que le BDNF induisait l'expression de MCT2 par l'activation simultanée des voies de signalisation MAPK et PI3K/Akt/mTOR. De plus, nous nous sommes intéressés à une potentielle régulation par les micro-ARNs de la synthèse de MCT2. Ensuite, nous avons démontré que le BDNF induit aussi l'expression de MCT2 dans l'hippocampe de la souris en parallèle avec d'autres protéines post-synaptiques telles que PSD95 et GluR2/3 et avec deux « immediate early genes » tels que Arc et Zif268 connus pour être exprimés dans des conditions de plasticité synaptique. Dans un dernier temps, nous avons démontré qu'une diminution d'expression de MCT2 induite par le biais d'un siRNA exprimé via un vecteur lentiviral dans l'hippocampe de souris générait des déficits de mémoire de travail sans affecter la mémoire de référence. En conclusion, ces résultats nous suggèrent que le transporteur aux monocarboxylates neuronal MCT2 serait essentiel pour l'apport énergétique du lactate pour les neurones dans des conditions de haute activité neuronale comme c'est le cas pendant les processus de plasticité synaptique.

The Intrahippocampal Infusion Of Crotamine From Crotalus Durissus Terrificus Venom Enhances Memory Persistence In Rats.

Previous research has shown that crotamine, a toxin isolated from the venom of Crotalus durissus terrificus, induces the release of acetylcholine and dopamine in the central nervous system of rats. Particularly, these neurotransmitters are important modulators of memory processes. Therefore, in this study we investigated the effects of crotamine infusion on persistence of memory in rats. We verified that the intrahippocampal infusion of crotamine (1 μg/μl; 1 μl/side) improved the persistence of object recognition and aversive memory. By other side, the intrahippocampal infusion of the toxin did not alter locomotor and exploratory activities, anxiety or pain threshold. These results demonstrate a future prospect of using crotamine as potential pharmacological tool to treat diseases involving memory impairment, although it is still necessary more researches to better elucidate the crotamine effects on hippocampus and memory.

Metabolic Memory Of ß-cells Controls Insulin Secretion And Is Mediated By Camkii.

Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) functions both in regulation of insulin secretion and neurotransmitter release through common downstream mediators. Therefore, we hypothesized that pancreatic ß-cells acquire and store the information contained in calcium pulses as a form of metabolic memory, just as neurons store cognitive information. To test this hypothesis, we developed a novel paradigm of pulsed exposure of ß-cells to intervals of high glucose, followed by a 24-h consolidation period to eliminate any acute metabolic effects. Strikingly, ß-cells exposed to this high-glucose pulse paradigm exhibited significantly stronger insulin secretion. This metabolic memory was entirely dependent on CaMKII. Metabolic memory was reflected on the protein level by increased expression of proteins involved in glucose sensing and Ca(2+)-dependent vesicle secretion, and by elevated levels of the key ß-cell transcription factor MAFA. In summary, like neurons, human and mouse ß-cells are able to acquire and retrieve information.

Long-term social recognition memory in adult male rats: factor analysis of the social and non-social behaviors

A modified version of the intruder-resident paradigm was used to investigate if social recognition memory lasts at least 24 h. One hundred and forty-six adult male Wistar rats were used. Independent groups of rats were exposed to an intruder for 0.083, 0.5, 2, 24, or 168 h and tested 24 h after the first encounter with the familiar or a different conspecific. Factor analysis was employed to identify associations between behaviors and treatments. Resident rats exhibited a 24-h social recognition memory, as indicated by a 3- to 5-fold decrease in social behaviors in the second encounter with the same conspecific compared to those observed for a different conspecific, when the duration of the first encounter was 2 h or longer. It was possible to distinguish between two different categories of social behaviors and their expression depended on the duration of the first encounter. Sniffing the anogenital area (49.9% of the social behaviors), sniffing the body (17.9%), sniffing the head (3%), and following the conspecific (3.1%), exhibited mostly by resident rats, characterized social investigation and revealed long-term social recognition memory. However, dominance (23.8%) and mild aggression (2.3%), exhibited by both resident and intruders, characterized social agonistic behaviors and were not affected by memory. Differently, sniffing the environment (76.8% of the non-social behaviors) and rearing (14.3%), both exhibited mostly by adult intruder rats, characterized non-social behaviors. Together, these results show that social recognition memory in rats may last at least 24 h after a 2-h or longer exposure to the conspecific.

Working memory impairment in multiple sclerosis relapsing-remitting patients with episodic memory deficits

Episodic memory is impaired in multiple sclerosis (MS) patients, possibly because of deficits in working memory (WM) functioning. If so, WM alterations should necessarily be found in patients with episodic memory deficits, but this has not yet been demonstrated. In this study we aimed at determining whether episodic memory deficits in relapsing-remitting MS are found in conjunction with impaired WM. We evaluated 32 MS patients and 32 matched healthy controls. Nineteen of the 32 patients had episodic memory impairment, and as a group only these individuals showed deficits in WM capacity, which may lead to difficulty in encoding, and/or retrieving information from episodic memory.

Influence of memory in deterministic walks in random media: Analytical calculation within a mean-field approximation

Consider a random medium consisting of N points randomly distributed so that there is no correlation among the distances separating them. This is the random link model, which is the high dimensionality limit (mean-field approximation) for the Euclidean random point structure. In the random link model, at discrete time steps, a walker moves to the nearest point, which has not been visited in the last mu steps (memory), producing a deterministic partially self-avoiding walk (the tourist walk). We have analytically obtained the distribution of the number n of points explored by the walker with memory mu=2, as well as the transient and period joint distribution. This result enables us to explain the abrupt change in the exploratory behavior between the cases mu=1 (memoryless walker, driven by extreme value statistics) and mu=2 (walker with memory, driven by combinatorial statistics). In the mu=1 case, the mean newly visited points in the thermodynamic limit (N >> 1) is just < n >=e=2.72... while in the mu=2 case, the mean number < n > of visited points grows proportionally to N(1/2). Also, this result allows us to establish an equivalence between the random link model with mu=2 and random map (uncorrelated back and forth distances) with mu=0 and the abrupt change between the probabilities for null transient time and subsequent ones.

Chaotic model and memory in single calcium-activated potassium channel kinetics

Ion channels are pores formed by proteins and responsible for carrying ion fluxes through cellular membranes. The ion channels can assume conformational states thereby controlling ion flow. Physically, the conformational transitions from one state to another are associated with energy barriers between them and are dependent on stimulus, such as, electrical field, ligands, second messengers, etc. Several models have been proposed to describe the kinetics of ion channels. The classical Markovian model assumes that a future transition is independent of the time that the ion channel stayed in a previous state. Others models as the fractal and the chaotic assume that the rate of transitions between the states depend on the time that the ionic channel stayed in a previous state. For the calcium activated potassium channels of Leydig cells the R/S Hurst analysis has indicated that the channels are long-term correlated with a Hurst coefficient H around 0.7, showing a persistent memory in this kinetic. Here, we applied the R/S analysis to the opening and closing dwell time series obtained from simulated data from a chaotic model proposed by L. Liebovitch and T. Toth [J. Theor. Biol. 148, 243 (1991)] and we show that this chaotic model or any model that treats the set of channel openings and closings as independent events is inadequate to describe the long-term correlation (memory) already described for the experimental data. (C) 2008 American Institute of Physics.

Mn-doped cubic BN as an atomiclike memory device: A density functional study

We investigate the electronic properties of Mn(B) substitutional doping in cubic boron nitride (BN), for different charge states, using density functional theory (DFT) calculations. We show that the neutral Mn has a nonmagnetic ground state (S=0). Upon charge injection, it is unambiguously shown that the Mn(B)(-) has a high-spin configuration with a strong, localized magnetic moment of 5 mu(Bohr). We developed a simple model, parameterized by the DFT results, that allows us to interpret the rules played by the crystal-field and exchange-correlation splitting in the magnetization process.

Random perturbations of stochastic processes with unbounded variable length memory

We consider binary infinite order stochastic chains perturbed by a random noise. This means that at each time step, the value assumed by the chain can be randomly and independently flipped with a small fixed probability. We show that the transition probabilities of the perturbed chain are uniformly close to the corresponding transition probabilities of the original chain. As a consequence, in the case of stochastic chains with unbounded but otherwise finite variable length memory, we show that it is possible to recover the context tree of the original chain, using a suitable version of the algorithm Context, provided that the noise is small enough.

Role of kinin B1 and B2 receptors in memory consolidation during the aging process of mice

Under physiological conditions, elderly people present memory deficit associated with neuronal loss. This pattern is also associated with Alzheimer`s disease but, in this case, in a dramatically intensified level. Kinin receptors have been involved in neurodegeneration and increase of amyloid-beta concentration, associated with Alzheimer`s disease (AD). Considering these findings, this work evaluated the role of kinin receptors in memory consolidation during the aging process. Male C57BI/6 (wt), knock-out B1 (koB1) or B2 (koB2) mice (3, 6, 12 and 18-month-old - mo; n = 10 per group) were submitted to an acquisition session, reinforcement to learning (24 h later: test 1) and final test (7 days later: test 2), in an active avoidance apparatus, to evaluate memory. Conditioned avoidance responses (CAR, % of 50 trials) were registered. In acquisition sessions, similar CAR were obtained among age matched animals from all strains. However, a significant decrease in CAR was observed throughout the aging process (3mo: 8.8 +/- 2.3%; 6mo: 4.1 +/- 0.6%; 12mo: 2.2 +/- 0.6%, 18mo: 3.6 +/- 0.6%, P < 0.01), indicating a reduction in the learning process. In test 1, as expected, memory retention increased significantly (P < 0.05) in all 3- and 6-month-old animals as well as in 12-month-old-wt and 12-month-old-koB1 (P < 0.01), compared to the training session. However, 12-month-old-koB2 and all 18-month-old animals did not show an increase in memory retention. In test 2, 3- and 6-month-old wt and koB1 mice of all ages showed a significant improvement in memory (P < 0.05) compared to test 1. However, 12-month-old wt and koB2 mice of all ages showed no difference in memory retention. We suggest that, during the aging process, the B1 receptor could be involved in neurodegeneration and memory loss. Nevertheless, the B2 receptor is apparently acting as a neuroprotective factor. (C) 2009 Elsevier Ltd. All rights reserved.

Participation of kinin receptors on memory impairment after chronic infusion of human amyloid-beta 1-40 peptide in mice

Chronic infusion of human amyloid-beta 1-40 (A beta) in the lateral ventricle (LV) of rats is associated with memory impairment and increase of kinin receptors in cortical and hippocampal areas. Deletion of kinin B1 or B2 receptors abolished memory impairment caused by an acute single injection of A beta in the LV. As brain tissue and kinin receptors could unlikely react to acute or chronic administration of a similar quantity of A beta, we evaluated the participation of B1 or B2 receptors in memory impairment after chronic infusion of A beta. Male C57BI/6 J (wt), knock-out B1 (koB1) or B2 (koB2) mice (12 weeks of age) previously trained in a two-way shuttle-box and achieving conditioned avoidance responses (CAR, % of 50 trials) were infused with AB (550 pmol, 0.12 mu L/h, 28 days) or vehicle in the LV using a mini-osmotic pump. They were tested before the surgery (TO), 7 and 35 days after the infusion started (T7; T35). In T0, no difference was observed between CAR of the control (Cwt = 59.7 +/- 6.7%; CkoB1 = 46.7 +/- 4.0%; CkoB2 = 64.4 +/- 5.8%) and A beta (A beta wt = 66.0 +/- 3.0%; A beta koB1 = 66.8 +/- 8.2%; A beta koB2 = 58.7 +/- 5.9%) groups. In T7, A beta koB2 showed a significant decrease in CAR (41.0 +/- 8.6%) compared to the control-koB2 (72.8 +/- 2.2%, P <0.05). In T35, a significant decrease (P <0.05) was observed in A beta wt (40.7 +/- 3.3%) and A beta koB2 (41.2 +/- 10.7%) but not in the A beta koB1 (64.0 +/- 14.0%) compared to their control groups. No changes were observed in the controls at T35. We suggest that in chronic infusion of BA, B1 receptors could playan important role in the neurodegenerative process. Conversely, the premature memory impairment of koB2 suggests that it may be a protective factor. (C) 2009 Elsevier Ltd. All rights reserved.

MEMORY TRAINING FOR OLDER ADULTS WITH LOW EDUCATION: MENTAL IMAGES VERSUS CATEGORIZATION

This study aimed to describe the benefits of memory training for older adults with low education. Twenty-nine healthy older adults with zero to two years of formal education participated. Sixteen participants received training based on categorization (categorization group = CATG) and 13 received training based on mental images (imagery group = IMG). One group served as control for the other because they trained with different strategies. Training was offered in eight sessions of 90 minutes. The participants were evaluated pre- and posttraining. IMG improved performance in episodic memory tests and had reduced depressive symptoms. CATG increased the use of categorization but did not increase performance in episodic memory tests. Results suggest that the strategy based on the creation of mental images was more effective for older adults with low formal education.

Relationship Between Cortisol Levels and Memory Performance may be Modulated by the Presence or Absence of Cognitive Impairment: Evidence from Healthy Elderly, Mild Cognitive Impairment and Alzheimer`s Disease Subjects

An inverted U-shape function between cortisol levels and memory performance has been reported in studies on both young animals and humans. Yet little is known about this relationship in normal aging or in older subjects with cognitive impairment. This issue is particularly significant since increased levels of cortisol have been reported in Alzheimer`s disease (AD). The present study examined the association between cortisol levels and visual memory performance in healthy subjects as well as in individuals presenting mild cognitive impairment (MCI) or AD. Salivary cortisol was measured in 40 healthy elderly subjects, 31 individuals with amnestic MCI, and 40 subjects with mild probable AD. Memory performance was evaluated using the Brief Cognitive Screening Battery. Higher cortisol levels were associated with better memory performance in healthy elderly (p = 0.005), while higher cortisol levels were correlated with poorer memory performance in MCI subjects (p = 0.011). No correlation between cortisol and memory was found in the AD group (p > 0.05). These results suggest that the relationship between cortisol levels and memory performance in the aging process could vary according to the presence or absence of cognitive impairment.