Enhanced Memory Formation Research Articles

How Stress Alters Memory in ‘Smart’ Snails

Cognitive ability varies within species, but whether this variation alters the manner in which memory formation is affected by environmental stress is unclear. The great pond snail, Lymnaea stagnalis, is commonly used as model species in studies of learning and memory. The majority of those studies used a single laboratory strain (i.e. the Dutch strain) originating from a wild population in the Netherlands. However, our recent work has identified natural populations that demonstrate significantly enhanced long-term memory (LTM) formation relative to the Dutch strain following operant conditioning of aerial respiratory behaviour. Here we assess how two populations with enhanced memory formation (i.e. ‘smart’ snails), one from Canada (Trans Canada 1: TC1) and one from the U.K. (Chilton Moor: CM) respond to ecologically relevant stressors. In control conditions the Dutch strain forms memory lasting 1–3 h following a single 0.5 h training session in our standard calcium pond water (80 mg/l [Ca2+]), whereas the TC1 and CM populations formed LTM lasting 5+ days following this training regime. Exposure to low environmental calcium pond water (20 mg/l [Ca2+]), which blocks LTM in the Dutch strain, reduced LTM retention to 24 h in the TC1 and CM populations. Crowding (20 snails in 100 ml) immediately prior to training blocks LTM in the Dutch strain, and also did so in TC1 and CM populations. Therefore, snails with enhanced cognitive ability respond to these ecologically relevant stressors in a similar manner to the Dutch strain, but are more robust at forming LTM in a low calcium environment. Despite the two populations (CM and TC1) originating from different continents, LTM formation was indistinguishable in both control and stressed conditions. This indicates that the underlying mechanisms controlling cognitive differences among populations may be highly conserved in L. stagnalis.

Sensory input from the osphradium modulates the response to memory-enhancing stressors in Lymnaea stagnalis

In the freshwater environment species often rely on chemosensory information to modulate behavior. The pond snail, Lymnaea stagnalis, is a model species used to characterize the causal mechanisms of long-term memory (LTM) formation. Chemical stressors including crayfish kairomones and KCl enhance LTM formation (≥24 h) in Lymnaea; however, how these stressors are sensed and the mechanism by which they affect the electrophysiological properties of neurons necessary for memory formation are poorly understood. Here, we assessed whether the osphradium, a primary chemosensory organ in Lymnaea, modulates LTM enhancement. To test this we severed the osphradial nerve proximal to the osphradium, using sham-operated animals as controls, and assessed the behavioral and electrophysiological response to crayfish kairomones and KCl. We operantly conditioned aerial respiratory behavior in intact, sham and osphradially cut animals, and tested for enhanced memory formation after exposure to the chemical stressors. Sham-operated animals displayed the same memory enhancement as intact animals but snails with a severed osphradial nerve did not show LTM enhancement. Extracellular recordings made from the osphradial nerve demonstrate that these stressors evoked afferent sensory activity. Intracellular recordings from right pedal dorsal 1 (RPeD1), a neuron necessary for LTM formation, demonstrate that its electrophysiological activity is altered by input from the osphradium following exposure to crayfish kairomones or KCl in sham and intact animals but no response is seen in RPeD1 in osphradially cut animals. Therefore, sensory input from the osphradium is necessary for LTM enhancement following exposure to these chemical stressors.

Cyclin-Dependent Kinase 5 Activator p25 Is Generated During Memory Formation and Is Reduced at an Early Stage in Alzheimer's Disease

The cyclin-dependent kinase 5 activator p35 can be cleaved into p25. Formation of p25 has been suggested to contribute to neurodegeneration in Alzheimer's disease (AD). However, overexpression of low levels of p25 in mice enhances memory formation. Therefore, it has been suggested that p25 formation might be an event early in AD to compensate for impairments in synaptic plasticity. Ongoing p25 formation has been hypothesized to contribute to neurodegeneration at the later stages of AD. Here, we tested the early compensation hypothesis by analyzing the levels of p25 and its precursor p35 in AD postmortem samples from different brain regions at different stages of tau pathology, using quantitative Western blots. Furthermore, we studied p35 and p25 during spatial memory formation. By employing quantitative mass spectrometry, we identified proteins downstream of p25, which were then studied in AD samples. We found that p25 is generated during spatial memory formation. Furthermore, we demonstrate that overexpression of p25 in the physiological range increases the expression of two proteins implicated in spine formation, septin 7 and optic atrophy 1. We show that the expression of p35 and p25 is reduced as an early event in AD. Moreover, expression of the p25-regulated protein optic atrophy 1 was reduced in a time course similar to p25 expression. Our findings suggest that p25 generation is a mechanism underlying hippocampal memory formation that is impaired in the early stages of AD. Our findings argue against the previously raised early compensation hypothesis and they propose that p25-mediated neurotoxicity does not occur in AD.

Ventromedial Prefrontal Cortex Activation Is Associated with Memory Formation for Predictable Rewards

During reinforcement learning, dopamine release shifts from the moment of reward consumption to the time point when the reward can be predicted. Previous studies provide consistent evidence that reward-predicting cues enhance long-term memory (LTM) formation of these items via dopaminergic projections to the ventral striatum. However, it is less clear whether memory for items that do not precede a reward but are directly associated with reward consumption is also facilitated. Here, we investigated this question in an fMRI paradigm in which LTM for reward-predicting and neutral cues was compared to LTM for items presented during consumption of reliably predictable as compared to less predictable rewards. We observed activation of the ventral striatum and enhanced memory formation during reward anticipation. During processing of less predictable as compared to reliably predictable rewards, the ventral striatum was activated as well, but items associated with less predictable outcomes were remembered worse than items associated with reliably predictable outcomes. Processing of reliably predictable rewards activated the ventromedial prefrontal cortex (vmPFC), and vmPFC BOLD responses were associated with successful memory formation of these items. Taken together, these findings show that consumption of reliably predictable rewards facilitates LTM formation and is associated with activation of the vmPFC.

Increase in excitability of RPeD11 results in memory enhancement of juvenile and adult Lymnaea stagnalis by predator-induced stress

Memory consolidation following learning is a dynamic process. Thus, long-term memory (LTM) formation can be modulated by many factors, including stress. We examined how predator-induced stress enhances LTM formation in the pond snail Lymnaea stagnalis at both the behavioral and electrophysiological levels. Training snails in crayfish effluent (CE; i.e., water from an aquarium containing crayfish) significantly enhanced LTM. That is, while memory persists for only 3 h in adult control experiments following a single 0.5-h training session in pond water in which the pneumostome receives a contingent tactile stimulus to the pneumostome; when the snails are trained in CE, the memory persists for at least 24 h. In juveniles, the data are more dramatic. Juveniles are unable to form LTM in pond water, but form LTM when trained in CE. Here we examined whether juvenile snails form LTM following a one-trial training procedure (1TT). Following the 1TT procedure (a single-trial aversive operant conditioning training procedure), juveniles do not form LTM, unless trained in CE. Concomitantly, we observe changes in the excitability of RPeD11, a key neuron mediating the whole snail withdrawal response, which may be a neural correlate of enhanced memory formation.

Evidence of STAT5‐dependent and ‐independent routes to CD8 memory formation and a preferential role for IL‐7 over IL‐15 in STAT5 activation

IL-7 and IL-15 have non-redundant roles in promoting development of memory CD8+ T cells. STAT5 is activated by receptors of both cytokines and has also been implicated as a requirement for generation of memory. To determine whether STAT5 activity was required for IL-7 and IL-15-mediated generation of memory, we expressed either wild type (WT) or constitutively active (CA) forms of STAT5a in normal effector cells and then observed their ability to form memory in cytokine replete or deficient hosts. Receptor independent CA-STAT5a significantly enhanced memory formation in the absence of either cytokine but did not mediate complete rescue. Interestingly, WT-STAT5a expression enhanced memory formation in a strictly IL-7 dependent manner, suggesting that IL-7 is a more potent activator of STAT5 than IL-15 in vivo. These data suggest that the non-redundant requirement for IL-7 and IL-15 is mediated through differential activation of both STAT5-dependent and STAT5-independent pathways.

Interacting noradrenergic and corticosteroid systems shift human brain activation patterns during encoding

Emotionally arousing experiences are usually well retained, an effect that depends on the release of adrenal stress hormones. Animal studies have shown that corticosterone and noradrenaline – representing the two main stress hormone systems – act in concert to enhance memory formation by actions involving the amygdala, hippocampus and prefrontal cortex (PFC). Here we test whether interactions between these two stress hormone systems also affect human memory formation as well as the associated pattern of brain activation. To this end, forty-eight male human subjects received hydrocortisone, yohimbine or both before presentation of emotional and neutral pictures. Activity in the amygdala, hippocampus and PFC was monitored with functional Magnetic Resonance Imaging (fMRI) during encoding of these stimuli, when hormonal levels were elevated. Memory performance was tested 1 week later. We investigated whether an increased level of one of the two hormone systems would lead to differential effects compared to the combined application of the drugs on brain activation and memory performance. We report that the application of cortisol led to an overall enhancing effect on recognition memory, with no significant additional effect of yohimbine. However, during encoding the brain switched from amygdala/hippocampus activation with either hormone alone, to a strong deactivation of prefrontal areas under the influence of the combination of both exogenous hormones. Although we did not find evidence that exogenous stimulation of the noradrenergic and corticosteroid systems led to significant interaction effects on memory performance in this experiment, we conclude that stress hormone levels during encoding did differentially determine the activation pattern of the brain circuits here involved.

Age-related memory impairments due to reduced blood glucose responses to epinephrine

Increases in blood glucose levels are an important component of the mechanisms by which epinephrine enhances memory formation. The present experiments addressed the hypothesis that a dysfunction in the blood glucose response to circulating epinephrine contributes to age-related memory impairments. Doses of epinephrine and glucagon that significantly increased blood glucose levels in young adult rats were far less effective at doing so in 2-year-old rats. In young rats, epinephrine and glucose were about equally effective in enhancing memory and in prolonging post-training release of acetylcholine in the hippocampus. However, glucose was more effective than epinephrine in enhancing both memory and acetylcholine release in aged rats. These results suggest that an uncoupling between circulating epinephrine and glucose levels in old rats may lead to an age-related reduction in the provision of glucose to the brain during training. This in turn may contribute to age-related changes in memory and neural plasticity.

Meaningful learning: Students’ perceptions of a new form of case seminar in pathology

Background: Student-centred activities have been developed in a pathology course for medical students.Aim: This study reports on students’ perceptions of a new form of case seminar as a way to learn pathology.Method: The seminar was evaluated through open-ended questionnaires and the data was analysed with a qualitative content analysis approach.Results: All students reported that the case seminar was a positive learning experience. Four aspects of importance for learning were identified: motivational, knowledge construction, contextual and collaborative aspects. The motivational aspects concerned an increase in interest and motivation to learn, while the knowledge construction aspects included enhancing memory formation and facilitation of understanding. The case seminar also seems to help the students relate the textbook knowledge to a real world context and future profession, which can be described as the contextual aspects of learning. According to the students in our study, the work in small groups resulted in positive collaborative aspects of learning.Conclusions: The new case seminar could be an effective teaching and learning activity. It can be used in a traditional course as a complement to lectures and does not require a major change in the course design. It is also well suited for integrated curricula.

No Evidence of Memory Processing During Propofol-Remifentanil Target-Controlled Infusion Anesthesia With Bispectral Index Monitoring in Cardiac Surgery

Auditory information presented during anesthesia can activate memory. Surgical stimulation may enhance memory formation. The authors' hypothesis is that implicit memory processing is not preserved during unconsciousness, even in the presence of a surgical stimulus. A double-blind randomized controlled trial. A single-institution, university hospital. Thirty-eight adults undergoing cardiac surgery. Patients were randomized to continuously hear either disc A or B during surgery. On each disc, 20 different words were recorded. Implicit and explicit memory were tested. The study design was that each group served as a control for the other. The responses from both groups on both lists allowed the authors to compare the likeliness of correctly identifying the words from a list whether it was heard while under anesthesia or not. During the interview, no patient had explicit recall as investigated by the free recall test, and no one reported dreaming. As for implicit memory processing, the difference between the mean rate of correct answers on the word-stem completion test for the disc the patients heard (3.42% for disc A and 13.15% for disc B) or did not hear (3.15% for disc A and 14.73% for disc B) was not statistically significant (p = 0.95 for A and p = 0.42 for B). Explicit and implicit memory were not detectable in patients anesthetized with an effect-site target-controlled infusion of propofol and remifentanil with bispectral index monitoring. These results suggest that there is no memory processing under anesthesia in the surgical setting.

Associations evoked during memory encoding recruit the context‐network

An extensive cortical network consisting of structures in the medial temporal lobe (hippocampus and parahippocampal cortex), lateral parietal cortex, retrosplenial cortex, and medial prefrontal cortex has recently attracted attention in cognitive neuroscience research, linking the network to both episodic memory and spatial processing. It has been suggested that its function may be best characterized as supporting the processing of contextual associations (context network). In this study, we explored whether the role of this network in contextual processing extends to associations that are evoked in a spontaneous manner. In a novel memory encoding task, participants indicated whether they encoded pictures (objects and novel faces) based on an evoked association or based on a perceptual feature. Memory encoding with subjective associations enhanced memory formation relative to feature-based encoding, and this effect was more pronounced for rapidly evoked associations. Functional magnetic resonance imaging during encoding yielded significant activations in all regions of the context network, i.e., medial prefrontal cortex, lateral parietal cortex, retrosplenial cortex, and posterior medial temporal lobe for the associative vs. feature-based comparisons. The low number of misses did not permit the analysis of a subsequent memory contrast. Our data suggest that the context network, which includes the posterior hippocampus and parahippocampal cortex, might support the linkage of external stimuli to long-term memory representations.

Enhancing memory formation by altering protein phosphorylation balance

In Lymnaea, aerial respiration can be operantly conditioned and depending on the training procedure employed two forms of memory can result: intermediate-term (ITM) and long-term memory (LTM). ITM, which persists for 3 h, is dependent on de novo protein synthesis whilst LTM, which persists for at least 24 h, is dependent on both de novo protein synthesis and altered gene activity. A single 0.5 h training session (i.e. ITM-training) leaves behind a residual molecular memory trace, which a second bout of ITM-training can activate and boost it to a LTM. Here we extend this finding to show that either inhibiting protein phosphatase activity with okadaic acid (1 μM), or increasing protein kinase C (PKC) activity and therefore protein phosphorylation with bryostatin (0.25 ng/mL) treatment prior to ITM-training, results in a LTM. However, following right pedal dorsal 1 (RPeD1) soma ablation neither of these treatments are effective in producing LTM following ITM-training, indicating transcription is a necessity. These findings suggest that the balance between phosphorylation and dephosphorylation in neurons is a key factor for LTM formation.

Aposematic colouration enhances memory formation in domestic chicks trained in a weak passive avoidance learning paradigm

The one-trial passive avoidance learning task is commonly used in avian research to explore anatomical, cellular and molecular parameters of learning and memory. Many factors are known to influence the effectiveness and/or duration of such learning events. Combinations of novel odours, such as pyrazine, and aposematic colours, such as brig ht yellow or red, have been shown to induce a long-lasting aversion to food crumbs in ‘visual’ predators, including birds such as the domestic chick (1). The aim of this study was to (a) examine whether visual complexity played a role in the generation of an aversive response to a novel visual stimulus and (b) to establish whether the duration of memory of an aversive experience could be modified by altering the visual properties of the stimulus. In the first experiment, naïve domestic chicks were trained on a weakly aversive one-trial passive avoidance bead task, in which chicks were allowed to peck at a bead coated with a 10% solution of the bitter-tasting and odorous substance methylanthranilate (MeA). The chicks were trained with (allowed to peck) one of four differently coloured beads dipped in 10% MeA. Chrome, black, yellow or black-and-yellow striped beads were used. ‘Recall’ of the aversive bead was examined by presenting the (clean) training bead 24 h after training and monitoring avoidance to it compared to a ‘neutral’ white bead. A high proportion (63%) of chicks trained with the black and yellow striped bead avoided it 24 h after training, whereas little or no avoidance was seen in response to chrome, yellow or black beads. In a second experiment naïve domestic chicks were all trained once only with a black and yellow striped bead coated in a 10% MeA solution, but this time, were tested 24 h later, once only, with either a black, a yellow or a black and yellow striped bead. Nearly 60% of chicks tested with a black and yellow striped bead showed avoidance of the bead, whereas only 23% of those tested with a black bead and 14% tested with a yellow bead showed avoidance. These results confirm the importance of complex warning colouration, when paired with a novel olfactory cue and a bitter taste, in avoidance learning. We conclude that the chicks’ response to monochromatic colours (e.g. yellow or black) is not affected by their previous experience with a conspicuously patterned stimulus (yellow and black stripes). Moreover, it suggests a predisposition for chicks to attend to aversive cues associated with ‘naturalistic’ high contrast colour cue combinations such as black and yellow.

Role of β-Adrenoceptors in Memory Consolidation: β3-Adrenoceptors Act on Glucose Uptake and β2-Adrenoceptors on Glycogenolysis

Noradrenaline, acting via beta(2)- and beta(3)-adrenoceptors (AR), enhances memory formation in single trial-discriminated avoidance learning in day-old chicks by mechanisms involving changes in metabolism of glucose and/or glycogen. Earlier studies of memory consolidation in chicks implicated beta(3)- rather than beta(2)-ARs in enhancement of memory consolidation by glucose, but did not elucidate whether stimulation of glucose uptake or of glycolysis was responsible. This study examines the role of glucose transport in memory formation using central injection of the nonselective facilitative glucose transporter (GLUT) inhibitor cytochalasin B, the endothelial/astrocytic GLUT-1 inhibitor phloretin and the Na(+)/energy-dependent endothelial glucose transporter (SGLT) inhibitor phlorizin. Cytochalasin B inhibited memory when injected into the mesopallium (avian cortex) either close to or between 25 and 45 min after training, whereas phloretin and phlorizin only inhibited memory at 30 min. This suggested that astrocytic/endothelial (GLUT-1) transport is critical at the time of consolidation, whereas a different transporter, probably the neuronal glucose transporter (GLUT-3), is important at the time of training. Inhibition of glucose transport by cytochalasin B, phloretin, or phlorizin also interfered with beta(3)-AR-mediated memory enhancement 20 min posttraining, whereas inhibition of glycogenolysis interfered with beta(2)-AR agonist enhancement of memory. We conclude that in astrocytes (1) activities of both GLUT-1 and SGLT are essential for memory consolidation 30 min posttraining; (2) neuronal GLUT-3 is essential at the time of training; and (3) beta(2)- and beta(3)-ARs consolidate memory by different mechanisms; beta(3)-ARs stimulate central glucose transport, whereas beta(2)-ARs stimulate central glycogenolysis.

β2‐ and β3‐Adrenoceptors activate glucose uptake in chick astrocytes by distinct mechanisms: a mechanism for memory enhancement?

Isoprenaline, acting at beta-adrenoceptors (ARs), enhances memory formation in single trial discriminated avoidance learning in day-old chicks by mechanisms involving alterations in glucose and glycogen metabolism. Earlier studies of memory consolidation in chicks indicated that beta3-ARs enhanced memory by increasing glucose uptake, whereas beta2-ARs enhance memory by increasing glycogenolysis. This study examines the ability of beta-ARs to increase glucose uptake in chick forebrain astrocytes. The beta-AR agonist isoprenaline increased glucose uptake in a concentration-dependent manner, as did insulin. Glucose uptake was increased by the beta2-AR agonist zinterol and the beta3-AR agonist CL316243, but not by the beta1-AR agonist RO363. In chick astrocytes, reverse transcription-polymerase chain reaction studies showed that beta1-, beta2-, and beta3-AR mRNA were present, whereas radioligand-binding studies showed the presence of only beta2- and beta3-ARs. beta-AR or insulin-mediated glucose uptake was inhibited by phosphatidylinositol-3 kinase and protein kinase C inhibitors, suggesting a possible interaction between the beta-AR and insulin pathways. However beta2- and beta3-ARs increase glucose uptake by two different mechanisms: beta2-ARs via a Gs-cAMP-protein kinase A-dependent pathway, while beta3-ARs via interactions with Gi. These results indicate that activation of beta2- and beta3-ARs causes glucose uptake in chick astrocytes by distinct mechanisms, which may be relevant for memory enhancement.

Modulation of Memory Formation by Stimulus Content: Specific Role of the Medial Prefrontal Cortex in the Successful Encoding of Social Pictures

It is unclear whether the involvement of the medial prefrontal cortex (mPFC) during encoding is restricted to the evaluative processing of to-be-encoded stimuli or if it is instead actively engaged during memory formation. The difficulty of assessing the contribution of the mPFC to encoding based on previous neuroimaging studies partly arises from the use of several types of stimuli, such as emotional or social ones. These different types of stimulus content could differently modulate mPFC activity during memory formation and thus partly explain the variable contribution of this region to encoding. Using emotional/neutral and social/nonsocial pictures, we conducted an event-related functional magnetic resonance imaging study using a subsequent memory paradigm as the main analytical strategy. We observed that the brain activity in the dorsal and orbital mPFC is significantly and specifically predictive of the successful encoding of social compared with nonsocial pictures. In contrast, the activity in the amygdala specifically predicts the successful encoding of emotional compared with neutral pictures. The modulation of the mPFC by social information in a memory encoding context could be associated with the initiation of self-referential processes whose contribution is to enhance memory formation.

Stressful stimuli modulate memory formation in Lymnaea stagnalis

Stress has been shown to be a strong modulator of learning and memory in animals. We employ operant training of aerial respiratory behaviour in our model system, the pond snail Lymnaea stagnalis, to show that application of an acute consistent physical stressor enhances memory formation. A single 30 min operant conditioning training session, which normally results in intermediate-term memory (ITM) persisting 3 h, results in long-term memory (LTM) persisting 24 h if immediately preceded or followed by a stressor, for example a 30 s exposure to 25 mM KCl. Other physical stressors (0.3% quinine-HCl or quick cooling and warming) similarly enhance memory formation. The memory is context specific and is not seen after the application of too much or too little stress. The memory can be extinguished by exposing snails to the hypoxic training environment and withholding reinforcing stimuli. The LTM that results from 30 min of training and stressor exposure is dependent on de novo protein synthesis and gene transcription in a single neuron, RPeD1. Because the soma of RPeD1 must be present for memory augmentation by the application of a stressor we are well placed for future investigations to directly determine the specific molecular alterations by which stress primes the formation of LTM.

Effects of the potential 5-HT 7 receptor agonist AS 19 in an autoshaping learning task

This work aimed to evaluate further the role of 5-HT 7 receptors during memory formation in an autoshaping Pavlovian/instrumental learning task. Post-training administration of the potential 5-HT 7 receptor agonist AS 19 or antagonist SB-269970 enhanced memory formation or had no effect, respectively. The AS 19 facilitatory effect was reversed by SB-269970, but not by the selective 5-HT 1A antagonist WAY100635. Amnesia induced by scopolamine (cholinergic antagonist) or dizocilpine (NMDA antagonist) was also reversed by AS 19. Certainly, reservations regarding the selectivity of AS 19 for 5-HT 7 and other 5-HT receptors in vivo are noteworthy and, therefore, its validity for use in animal models as a pharmacological tool. Having mentioned that, it should be noticed that together these data are providing further support to the notion of the 5-HT 7 receptors role in memory formation. Importantly, this 5-HT 7 receptor agonist AS 19 appears to represent a step forward respect to the notion that potent and selective 5-HT 7 receptor agonists can be useful in the treatment of dysfunctional memory in aged-related decline and Alzheimer's disease.

Effects of glucose and 2-deoxyglucose on memory formation in the chick: interaction with β 3-adrenoceptor agonists

Consolidation of a weakly reinforced memory that would otherwise fade after 30 min can be achieved by central or peripheral injection of the selective β 3-adrenoceptor agonist CL316243 as well as the β 2-adrenoceptor agonist zinterol and the α 1-adrenoceptor antagonist prazosin in the day-old chick. The effect of the β 3-adrenoceptor agonist is mimicked by peripheral or central injection of glucose that is effective in enhancing memory from 25 min before to 25 min after training. Glucose uptake into various cell types has been described following activation of β 3-adrenoceptors and in this paper we demonstrate that activation of β 3-adrenoceptors by CL316243 facilitates the effect of a dose of glucose that does not normally enhance memory, whereas a β 2-adrenoceptor agonist and an α 1-adrenoceptor antagonist have no effect. Administration of the glucose uptake inhibitor 2-deoxyglucose prevented the consolidation of strongly reinforced training. The β 3-adrenoceptor agonist facilitated the effect of a non-amnestic dose of 2-deoxyglucose to inhibit memory. There are two time periods relative to the learning trial where memory is vulnerable to interference by centrally administered 2-deoxyglucose: one related to short-term memory and one at the time of consolidation into long-term memory. Peripheral injection of 2-deoxyglucose is only effective at the time of consolidation. The action of the β 3-adrenoceptor agonist to facilitate the action of 2-deoxyglucose only occurs at the time of consolidation. We suggest that a noradrenergic agonist acting at β 3-adrenoceptors enhances memory formation by facilitation of glucose uptake at the time of memory consolidation. This may represent a novel mechanism that would be beneficial for developing compounds for the facilitation of memory in diseases with cognitive deficits.

CREB and the discovery of cognitive enhancers.

In the past few years, a series of molecular-genetic, biochemical, cellular and behavioral studies in fruit flies, sea slugs and mice have confirmed a long-standing notion that long-term memory formation depends on the synthesis of new proteins. Experiments focused on the cAMP-responsive transcription factor, CREB, have established that neural activity-induced regulation of gene transcription promotes a synaptic growth process that strengthens the connections among active neurons. This process constitutes a physical basis for the engram--and CREB is a "molecular switch" to produce the engram. Helicon Therapeutics has been formed to identify drug compounds that enhance memory formation via augmentation of CREB biochemistry. Candidate compounds have been identified from a high throughput cell-based screen and are being evaluated in animal models of memory formation. A gene discovery program also seeks to identify new genes, which function downstream of CREB during memory formation, as a source for new drug discoveries in the future. Together, these drug and gene discovery efforts promise new class of pharmaceutical therapies for the treatment of various forms of cognitive dysfunction.