The impact of flavonoids on spatial memory in rodents: from behaviour to underlying hippocampal mechanisms

Emerging evidence suggests that a group of dietary-derived phytochemicals known as flavonoids are able to induce improvements in memory, learning and cognition. Flavonoids have been shown to modulate critical neuronal signalling pathways involved in processes of memory, and therefore are likely to affect synaptic plasticity and long-term potentiation mechanisms, widely considered to provide a basis for memory. Animal dietary supplementation studies have further shown that flavonoid-rich foods are able to reverse age-related spatial memory and spatial learning impairments. A more accurate understanding of how a particular spatial memory task works and of which aspects of memory and learning can be assessed in each case, are necessary for a correct interpretation of data relating to diet-cognition experiments. Further understanding of how specific behavioural tasks relate to the functioning of hippocampal circuitry during learning processes might be also elucidative of the specific observed memory improvements. The overall goal of this review is to give an overview of how the hippocampal circuitry operates as a memory system during behavioural tasks, which we believe will provide a new insight into the underlying mechanisms of the action of flavonoids on cognition.

Flavonoids as modulators of memory and learning: molecular interactions resulting in behavioural effects

There is considerable interest in the potential of a group of dietary-derived phytochemicals known as flavonoids in modulating neuronal function and thereby influencing memory, learning and cognitive function. The present review begins by detailing the molecular events that underlie the acquisition and consolidation of new memories in the brain in order to provide a critical background to understanding the impact of flavonoid-rich diets or pure flavonoids on memory. Data suggests that despite limited brain bioavailability, dietary supplementation with flavonoid-rich foods, such as blueberry, green tea and Ginkgo biloba lead to significant reversals of age-related deficits on spatial memory and learning. Furthermore, animal and cellular studies suggest that the mechanisms underpinning their ability to induce improvements in memory are linked to the potential of absorbed flavonoids and their metabolites to interact with and modulate critical signalling pathways, transcription factors and gene and/or protein expression which control memory and learning processes in the hippocampus; the brain structure where spatial learning occurs. Overall, current evidence suggests that human translation of these animal investigations are warranted, as are further studies, to better understand the precise cause-and-effect relationship between flavonoid intake and cognitive outputs.

Blueberry supplementation induces spatial memory improvements and region-specific regulation of hippocampal BDNF mRNA expression in young rats

Rationale: Flavonoid-rich foods have been shown to be able to reverse age-related cognitive deficits in memory and learning in both animals and humans. However, to date, there have been only a limited number of studies investigating the effects of flavonoid-rich foods on cognition in young/healthy animals. Objectives: The aim of this study was to investigate the effects of a blueberry-rich diet in young animals using a spatial working memory paradigm, the delayed non-match task, using an eight-arm radial maze. Furthermore, the mechanisms underlying such behavioural effects were investigated. Results: We show that a 7-week supplementation with a blueberry diet (2 % w/w) improves the spatial memory performance of young rats (2 months old). Blueberry-fed animals also exhibited a faster rate of learning compared to those on the control diet. These behavioural outputs were accompanied by the activation of extracellular signal-related kinase (ERK1/2), increases in total cAMP-response element binding protein (CREB) and elevated levels of pro- and mature brain-derived neurotrophic factor (BDNF) in the hippocampus. Changes in hippocampal CREB correlated well with memory performance. Further regional analysis of BDNF gene expression in the hippocampus revealed a specific increase in BDNF mRNA in the dentate gyrus and CA1 areas of hippocampi of blueberry-fed animals. Conclusions: The present study suggests that consumption of flavonoid-rich blueberries has a positive impact on spatial learning performance in young healthy animals, and these improvements are linked to the activation of ERK–CREB– BDNF pathway in the hippocampus.

Location, location, location: development of spatiotemporal sequence learning in infancy

We investigated infants' sensitivity to spatiotemporal structure. In Experiment 1, circles appeared in a statistically defined spatial pattern. At test 11-month-olds, but not 8-month-olds, looked longer at a novel spatial sequence. Experiment 2 presented different color/shape stimuli, but only the location sequence was violated during test; 8-month-olds preferred the novel spatial structure, but 5-month-olds did not. In Experiment 3, the locations but not color/shape pairings were constant at test; 5-month-olds showed a novelty preference. Experiment 4 examined "online learning": We recorded eye movements of 8-month-olds watching a spatiotemporal sequence. Saccade latencies to predictable locations decreased. We argue that temporal order statistics involving informative spatial relations become available to infants during the first year after birth, assisted by multiple cues.

Learning associations between places and visual cues without learning to navigate: neither fornix nor entorhinal cortex is required

Rats with fornix transection, or with cytotoxic retrohippocampal lesions that removed entorhinal cortex plus ventral subiculum, performed a task that permits incidental learning about either allocentric (Allo) or egocentric (Ego) spatial cues without the need to navigate by them. Rats learned eight visual discriminations among computer-displayed scenes in a Y-maze, using the constant-negative paradigm. Every discrimination problem included two familiar scenes (constants) and many less familiar scenes (variables). On each trial, the rats chose between a constant and a variable scene, with the choice of the variable rewarded. In six problems, the two constant scenes had correlated spatial properties, either Alto (each constant appeared always in the same maze arm) or Ego (each constant always appeared in a fixed direction from the start arm) or both (Allo + Ego). In two No-Cue (NC) problems, the two constants appeared in randomly determined arms and directions. Intact rats learn problems with an added Allo or Ego cue faster than NC problems; this facilitation provides indirect evidence that they learn the associations between scenes and spatial cues, even though that is not required for problem solution. Fornix and retrohippocampal-lesioned groups learned NC problems at a similar rate to sham-operated controls and showed as much facilitation of learning by added spatial cues as did the controls; therefore, both lesion groups must have encoded the spatial cues and have incidentally learned their associations with particular constant scenes. Similar facilitation was seen in subgroups that had short or long prior experience with the apparatus and task. Therefore, neither major hippocampal input-output system is crucial for learning about allocentric or egocentric cues in this paradigm, which does not require rats to control their choices or navigation directly by spatial cues.

Using learning networks to understand complex systems: a case study of biological, geophysical and social research in the Amazon

Developing high-quality scientific research will be most effective if research communities with diverse skills and interests are able to share information and knowledge, are aware of the major challenges across disciplines, and can exploit economies of scale to provide robust answers and better inform policy. We evaluate opportunities and challenges facing the development of a more interactive research environment by developing an interdisciplinary synthesis of research on a single geographic region. We focus on the Amazon as it is of enormous regional and global environmental importance and faces a highly uncertain future. To take stock of existing knowledge and provide a framework for analysis we present a set of mini-reviews from fourteen different areas of research, encompassing taxonomy, biodiversity, biogeography, vegetation dynamics, landscape ecology, earth-atmosphere interactions, ecosystem processes, fire, deforestation dynamics, hydrology, hunting, conservation planning, livelihoods, and payments for ecosystem services. Each review highlights the current state of knowledge and identifies research priorities, including major challenges and opportunities. We show that while substantial progress is being made across many areas of scientific research, our understanding of specific issues is often dependent on knowledge from other disciplines. Accelerating the acquisition of reliable and contextualized knowledge about the fate of complex pristine and modified ecosystems is partly dependent on our ability to exploit economies of scale in shared resources and technical expertise, recognise and make explicit interconnections and feedbacks among sub-disciplines, increase the temporal and spatial scale of existing studies, and improve the dissemination of scientific findings to policy makers and society at large. Enhancing interaction among research efforts is vital if we are to make the most of limited funds and overcome the challenges posed by addressing large-scale interdisciplinary questions. Bringing together a diverse scientific community with a single geographic focus can help increase awareness of research questions both within and among disciplines, and reveal the opportunities that may exist for advancing acquisition of reliable knowledge. This approach could be useful for a variety of globally important scientific questions.

A role for hippocampal PSA-NCAM and NMDA-NR2B receptor function in flavonoid-induced spatial memory improvements in young rats

The increase in incidence and prevalence of neurodegenerative diseases highlights the need for a more comprehensive understanding of how food components may affect neural systems. In particular, flavonoids have been recognized as promising agents capable of influencing different aspects of synaptic plasticity resulting in improvements in memory and learning in both animals and humans. Our previous studies highlight the efficacy of flavonoids in reversing memory impairments in aged rats, yet little is known about the effects of these compounds in healthy animals, particularly with respect to the molecular mechanisms by which flavonoids might alter the underlying synaptic modifications responsible for behavioral changes. We demonstrate that a 3-week intervention with two dietary doses of flavonoids (Dose I: 8.7 mg/day and Dose II: 17.4 mg/day) facilitates spatial memory acquisition and consolidation (24 recall) (p < 0.05) in young healthy rats. We show for the first time that these behavioral improvements are linked to increased levels in the polysialylated form of the neural adhesion molecule (PSA-NCAM) in the dentate gyrus (DG) of the hippocampus, which is known to be required for the establishment of durable memories. We observed parallel increases in hippocampal NMDA receptors containing the NR2B subunit for both 8.7 mg/day (p < 0.05) and 17.4 mg/day (p < 0.001) doses, suggesting an enhancement of glutamate signaling following flavonoid intervention. This is further strengthened by the simultaneous modulation of hippocampal ERK/CREB/BDNF signaling and the activation of the Akt/mTOR/Arc pathway, which are crucial in inducing changes in the strength of hippocampal synaptic connections that underlie learning. Collectively, the present data supports a new role for PSA-NCAM and NMDA-NR2B receptor on flavonoid-induced improvements in learning and memory, contributing further to the growing body of evidence suggesting beneficial effects of flavonoids in cognition and brain health.

Cognitive and environmental factors influencing the process of spatial knowledge acquisition within virtual reality environments

As the fidelity of virtual environments (VE) continues to increase, the possibility of using them as training platforms is becoming increasingly realistic for a variety of application domains, including military and emergency personnel training. In the past, there was much debate on whether the acquisition and subsequent transfer of spatial knowledge from VEs to the real world is possible, or whether the differences in medium during training would essentially be an obstacle to truly learning geometric space. In this paper, the authors present various cognitive and environmental factors that not only contribute to this process, but also interact with each other to a certain degree, leading to a variable exposure time requirement in order for the process of spatial knowledge acquisition (SKA) to occur. The cognitive factors that the authors discuss include a variety of individual user differences such as: knowledge and experience; cognitive gender differences; aptitude and spatial orientation skill; and finally, cognitive styles. Environmental factors discussed include: Size, Spatial layout complexity and landmark distribution. It may seem obvious that since every individual's brain is unique - not only through experience, but also through genetic predisposition that a one size fits all approach to training would be illogical. Furthermore, considering that various cognitive differences may further emerge when a certain stimulus is present (e.g. complex environmental space), it would make even more sense to understand how these factors can impact spatial memory, and to try to adapt the training session by providing visual/auditory cues as well as by changing the exposure time requirements for each individual. The impact of this research domain is important to VE training in general, however within service and military domains, guaranteeing appropriate spatial training is critical in order to ensure that disorientation does not occur in a life or death scenario.

Joint multiple dictionary learning for tensor sparse coding

Traditional dictionary learning algorithms are used for finding a sparse representation on high dimensional data by transforming samples into a one-dimensional (1D) vector. This 1D model loses the inherent spatial structure property of data. An alternative solution is to employ Tensor Decomposition for dictionary learning on their original structural form —a tensor— by learning multiple dictionaries along each mode and the corresponding sparse representation in respect to the Kronecker product of these dictionaries. To learn tensor dictionaries along each mode, all the existing methods update each dictionary iteratively in an alternating manner. Because atoms from each mode dictionary jointly make contributions to the sparsity of tensor, existing works ignore atoms correlations between different mode dictionaries by treating each mode dictionary independently. In this paper, we propose a joint multiple dictionary learning method for tensor sparse coding, which explores atom correlations for sparse representation and updates multiple atoms from each mode dictionary simultaneously. In this algorithm, the Frequent-Pattern Tree (FP-tree) mining algorithm is employed to exploit frequent atom patterns in the sparse representation. Inspired by the idea of K-SVD, we develop a new dictionary update method that jointly updates elements in each pattern. Experimental results demonstrate our method outperforms other tensor based dictionary learning algorithms.

Activation of G-protein-coupled receptor 30 is sufficient to enhance spatial recognition memory in ovariectomized rats

In ovariectomized rats, administration of estradiol, or selective estrogen receptor agonists that activate either the alpha or beta isoforms, have been shown to enhance spatial cognition on a variety of learning and memory tasks, including those that capitalize on the preference of rats to seek out novelty. Although the effects of the putative estrogen G-protein-coupled receptor 30 (GPR30) on hippocampus-based tasks have been reported using food-motivated tasks, the effects of activation of GPR30 receptors on tasks that depend on the preference of rats to seek out spatial novelty remain to be determined. Therefore, the aim of the current study was to determine if short-term treatment of ovariectomized rats with G-1, an agonist for GPR30, would mimic the effects on spatial recognition memory observed following short-term estradiol treatment. In Experiment 1, ovariectomized rats treated with a low dose (1mug) of estradiol 48h and 24h prior to the information trial of a Y-maze task exhibited a preference for the arm associated with the novel environment on the retention trial conducted 48h later. In Experiment 2, treatment of ovariectomized rats with G-1 (25mug) 48h and 24h prior to the information trial of a Y-maze task resulted in a greater preference for the arm associated with the novel environment on the retention trial. Collectively, the results indicated that short-term treatment of ovariectomized rats with a GPR30 agonist was sufficient to enhance spatial recognition memory, an effect that also occurred following short-term treatment with a low dose of estradiol.