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.     

Relevance of stress and female sex hormones for emotion and cognition

There are clear sex differences in incidence and onset of stress-related and other psychiatric disorders in humans. Yet, rodent models for psychiatric disorders are predominantly based on male animals. The strongest argument for not using female rodents is their estrous cycle and the fluctuating sex hormones per phase which multiplies the number of animals to be tested. Here, we will discuss studies focused on sex differences in emotionality and cognitive abilities in experimental conditions with and without stress. First, female sex hormones such as estrogens and progesterone affect emotions and cognition, contributing to sex differences in behavior. Second, females respond differently to stress than males which might be related to the phase of the estrous cycle. For example, female rats and mice express less anxiety than males in a novel environment. Proestrus females are less anxious than females in the other estrous phases. Third, males perform in spatial tasks superior to females. However, while stress impairs spatial memory in males, females improve their spatial abilities, depending on the task and kind of stressor. We conclude that the differences in emotion, cognition and responses to stress between males and females over the different phases of the estrous cycle should be used in animal models for stress-related psychiatric disorders.     

Spatial memory tasks in rodents: what do they model?

The analysis of spatial learning and memory in rodents is commonly used to investigate the mechanisms underlying certain forms of human cognition and to model their dysfunction in neuropsychiatric and neurodegenerative diseases. Proper interpretation of rodent behavior in terms of spatial memory and as a model of human cognitive functions is only possible if various navigation strategies and factors controlling the performance of the animal in a spatial task are taken into consideration. The aim of this review is to describe the experimental approaches that are being used for the study of spatial memory in rats and mice and the way that they can be interpreted in terms of general memory functions. After an introduction to the classification of memory into various categories and respective underlying neuroanatomical substrates, I explain the concept of spatial memory and its measurement in rats and mice by analysis of their navigation strategies. Subsequently, I describe the most common paradigms for spatial memory assessment with specific focus on methodological issues relevant for the correct interpretation of the results in terms of cognitive function. Finally, I present recent advances in the use of spatial memory tasks to investigate episodic-like memory in mice.     

Neurophysiological recordings in freely moving monkeys

Recordings of neuronal activity in freely moving rats are common in experiments where electrical signals are transmitted using cables. Such techniques are not common in monkeys because their prehensile abilities are thought to preclude such techniques. However, analysis of brain mechanisms underlying spatial navigation and cognition require the subject to walk. We have developed techniques for recordings in freely moving monkeys in two different situations: a 5 x 5 m testing laboratory and in a 50 m2 open field environment. Neuronal signals are sent to amplifiers and data acquisition systems using cables or telemetry. These techniques provide high quality recordings of single neurons during behaviors such as foraging, walking, and the performance of memory tasks and thus provide a unique opportunity to study primate behavior in a semi-natural situation.     

Touchscreen-Based Cognitive Tasks Reveal Age-Related Impairment in a Primate Aging Model,the Grey Mouse Lemur (Microcebus murinus)

Mouse lemurs are suggested to represent promising novel non-human primate models for aging research. However, standardized and cross-taxa cognitive testing methods are still lacking. Touchscreen-based testing procedures have proven high stimulus control and reliability in humans and rodents. The aim of this study was to adapt these procedures to mouse lemurs, thereby exploring the effect of age. We measured appetitive learning and cognitive flexibility of two age groups by applying pairwise visual discrimination (PD) and reversal learning (PDR) tasks. On average, mouse lemurs needed 24 days of training before starting with the PD task. Individual performances in PD and PDR tasks correlate significantly, suggesting that individual learning performance is unrelated to the respective task. Compared to the young, aged mouse lemurs showed impairments in both PD and PDR tasks. They needed significantly more trials to reach the task criteria. A much higher inter-individual variation in old than in young adults was revealed. Furthermore, in the PDR task, we found a significantly higher perseverance in aged compared to young adults, indicating an age-related deficit in cognitive flexibility. This study presents the first touchscreen-based data on the cognitive skills and age-related dysfunction in mouse lemurs and provides a unique basis to study mechanisms of inter-individual variation. It furthermore opens exciting perspectives for comparative approaches in aging, personality, and evolutionary research.     

Spatial learning and action planning in a prefrontal cortical network model

The interplay between hippocampus and prefrontal cortex (PFC) is fundamental to spatial cognition. Complementing hippocampal place coding, prefrontal representations provide more abstract and hierarchically organized memories suitable for decision making. We model a prefrontal network mediating distributed information processing for spatial learning and action planning. Specific connectivity and synaptic adaptation principles shape the recurrent dynamics of the network arranged in cortical minicolumns. We show how the PFC columnar organization is suitable for learning sparse topological-metrical representations from redundant hippocampal inputs. The recurrent nature of the network supports multilevel spatial processing, allowing structural features of the environment to be encoded. An activation diffusion mechanism spreads the neural activity through the column population leading to trajectory planning. The model provides a functional framework for interpreting the activity of PFC neurons recorded during navigation tasks. We illustrate the link from single unit activity to behavioral responses. The results suggest plausible neural mechanisms subserving the cognitive "insight" capability originally attributed to rodents by Tolman & Honzik. Our time course analysis of neural responses shows how the interaction between hippocampus and PFC can yield the encoding of manifold information pertinent to spatial planning, including prospective coding and distance-to-goal correlates.     

The evolution of intelligence: adaptive specializations versus general process

Darwin argued that between-species differences in intelligence were differences of degree, not of kind. The contemporary ecological approach to animal cognition argues that animals have evolved species-specific and problem-specific processes to solve problems associated with their particular ecological niches: thus different species use different processes, and within a species, different processes are used to tackle problems involving different inputs. This approach contrasts both with Darwin's view and with the general process view, according to which the same central processes of learning and memory are used across an extensive range of problems involving very different inputs. We review evidence relevant to the claim that the learning and memory performance of non-human animals varies according to the nature of the stimuli involved. We first discuss the resource distribution hypothesis, olfactory learning-set formation, and the 'biological constraints' literature, but find no convincing support from these topics for the ecological account of cognition. We then discuss the claim that the performance of birds in spatial tasks of learning and memory is superior in species that depend heavily upon stored food compared to species that either show less dependence upon stored food or do not store food. If it could be shown that storing species enjoy a superiority specifically in spatial (and not non-spatial) tasks, this would argue that spatial tasks are indeed solved using different processes from those used in non-spatial tasks. Our review of this literature does not find a consistent superiority of storing over non-storing birds in spatial tasks, and, in particular, no evidence of enhanced superiority of storing species when the task demands are increased, by, for example, increasing the number of items to be recalled or the duration of the retention period. We discuss also the observation that the hippocampus of storing birds is larger than that of non-storing birds, and find evidence contrary to the view that hippocampal enlargement is associated with enhanced spatial memory; we are, however, unable to suggest a convincing alternative explanation for hippocampal enlargement. The failure to find solid support for the ecological view supports the view that there are no qualitative differences in cognition between animal species in the processes of learning and memory. We also argue that our review supports our contention that speculation about the phylogenetic development and function of behavioural processes does not provide a solid basis for gaining insight into the nature of those processes. We end by confessing to a belief in one major qualitative difference in cognition in animals: we believe that humans alone are capable of acquiring language, and that it is this capacity that divides our intelligence so sharply from non-human intelligence.     

Molecular mechanisms underlying the memory-enhancing effects of estradiol

This article is part of a Special Issue “Estradiol and cognition”.Since the publication of the 1998 special issue of Hormones and Behavior on estrogens and cognition, substantial progress has been made towards understanding the molecular mechanisms through which 17β-estradiol (E₂) regulates hippocampal plasticity and memory. Recent research has demonstrated that rapid effects of E₂ on hippocampal cell signaling, epigenetic processes, and local protein synthesis are necessary for E₂ to facilitate the consolidation of object recognition and spatial memories in ovariectomized female rodents. These effects appear to be mediated by non-classical actions of the intracellular estrogen receptors ERα and ERβ, and possibly by membrane-bound ERs such as the G-protein-coupled estrogen receptor (GPER). New findings also suggest a key role of hippocampally-synthesized E₂ in regulating hippocampal memory formation. The present review discusses these findings in detail and suggests avenues for future study.     

Estrogen treatment effects on cognition, memory and mood in male-to-female transsexuals

Gonadal hormones, particularly estrogens, have been suggested to influence memory and cognitive tasks that show sex differences. Previously, we reported that male-to-female (M-F) transsexuals undergoing estrogen treatment for sex re-assignment scored higher on verbal Paired Associate Learning (PAL) than a transsexual control group awaiting estrogen treatment. The present study used a more robust design to examine further associations between estrogen and cognition. We assessed additional aspects of memory, including visual, spatial, object and location memory, other cognitive abilities that show reliable sex differences, including verbal and visual-spatial abilities, and mood variables that could mediate associations between estrogen and cognition. In addition to comparing groups of individuals on and off estrogen, we used two repeated measures designs (AB and BA). The AB group was tested prior to hormone treatment and then again after treatment had begun; the BA group was tested while on estrogen treatment and then again when hormones had been withdrawn prior to surgery. Few changes in memory or cognition were observed, and changes that were observed were not consistent across study designs. The lack of significant effects did not relate to mood changes or to the sexual orientation of participants. These findings suggest that estrogen treatment associated with sex change for M-F transsexuals has little or no influence on sex-typed aspects of cognition or memory.     

Modulating Cognition Using Transcranial Direct Current Stimulation of the Cerebellum

Numerous studies have emerged recently that demonstrate the possibility of modulating, and in some cases enhancing, cognitive processes by exciting brain regions involved in working memory and attention using transcranial electrical brain stimulation. Some researchers now believe the cerebellum supports cognition, possibly via a remote neuromodulatory effect on the prefrontal cortex. This paper describes a procedure for investigating a role for the cerebellum in cognition using transcranial direct current stimulation (tDCS), and a selection of information-processing tasks of varying task difficulty, which have previously been shown to involve working memory, attention and cerebellar functioning. One task is called the Paced Auditory Serial Addition Task (PASAT) and the other a novel variant of this task called the Paced Auditory Serial Subtraction Task (PASST). A verb generation task and its two controls (noun and verb reading) were also investigated. All five tasks were performed by three separate groups of participants, before and after the modulation of cortico-cerebellar connectivity using anodal, cathodal or sham tDCS over the right cerebellar cortex. The procedure demonstrates how performance (accuracy, verbal response latency and variability) could be selectively improved after cathodal stimulation, but only during tasks that the participants rated as difficult, and not easy. Performance was unchanged by anodal or sham stimulation. These findings demonstrate a role for the cerebellum in cognition, whereby activity in the left prefrontal cortex is likely dis-inhibited by cathodal tDCS over the right cerebellar cortex. Transcranial brain stimulation is growing in popularity in various labs and clinics. However, the after-effects of tDCS are inconsistent between individuals and not always polarity-specific, and may even be task- or load-specific, all of which requires further study. Future efforts might also be guided towards neuro-enhancement in cerebellar patients presenting with cognitive impairment once a better understanding of brain stimulation mechanisms has emerged.     

Decision Rules and Group Rationality: Cognitive Gain or Standstill?

Recent research in group cognition points towards the existence of collective cognitive competencies that transcend individual group members’ cognitive competencies. Since rationality is a key cognitive competence for group decision making, and group cognition emerges from the coordination of individual cognition during social interactions, this study tests the extent to which collaborative and consultative decision rules impact the emergence of group rationality. Using a set of decision tasks adapted from the heuristics and biases literature, we evaluate rationality as the extent to which individual choices are aligned with a normative ideal. We further operationalize group rationality as cognitive synergy (the extent to which collective rationality exceeds average or best individual rationality in the group), and we test the effect of collaborative and consultative decision rules in a sample of 176 groups. Our results show that the collaborative decision rule has superior synergic effects as compared to the consultative decision rule. The ninety one groups working in a collaborative fashion made more rational choices (above and beyond the average rationality of their members) than the eighty five groups working in a consultative fashion. Moreover, the groups using a collaborative decision rule were closer to the rationality of their best member than groups using consultative decision rules. Nevertheless, on average groups did not outperformed their best member. Therefore, our results reveal how decision rules prescribing interpersonal interactions impact on the emergence of collective cognitive competencies. They also open potential venues for further research on the emergence of collective rationality in human decision-making groups.     

Maps of space in human frontoparietal cortex

Prefrontal cortex (PFC) and posterior parietal cortex (PPC) are neural substrates for spatial cognition. We here review studies in which we tested the hypothesis that human frontoparietal cortex may function as a priority map. According to priority map theory, objects or locations in the visual world are represented by neural activity that is proportional to their attentional priority. Using functional magnetic resonance imaging (fMRI), we first identified topographic maps in PFC and PPC as candidate priority maps of space. We then measured fMRI activity in candidate priority maps during the delay periods of a covert attention task, a spatial working memory task, and a motor planning task to test whether the activity depended on the particular spatial cognition. Our hypothesis was that some, but not all, candidate priority maps in PFC and PPC would be agnostic with regard to what was being prioritized, in that their activity would reflect the location in space across tasks rather than a particular kind of spatial cognition (e.g., covert attention). To test whether patterns of delay period activity were interchangeable during the spatial cognitive tasks, we used multivariate classifiers. We found that decoders trained to predict the locations on one task (e.g., working memory) cross-predicted the locations on the other tasks (e.g., covert attention and motor planning) in superior precentral sulcus (sPCS) and in a region of intraparietal sulcus (IPS2), suggesting that these patterns of maintenance activity may be interchangeable across the tasks. Such properties make sPCS in frontal cortex and IPS2 in parietal cortex viable priority map candidates, and suggest that these areas may be the human homologs of the monkey frontal eye field (FEF) and lateral intraparietal area (LIP).     

Investigating physical cognition in rooks, Corvus frugilegus

Although animals (particularly tool-users) are capable of solving physical tasks in the laboratory , the degree to which they understand them in terms of their underlying physical forces is a matter of contention. Here, using a new paradigm, the two-trap tube task, we report the performance of non-tool-using rooks. In contrast to the low success rates of previous studies using trap-tube problems , seven out of eight rooks solved the initial task, and did so rapidly. Instead of the usual, conceptually flawed control, we used a series of novel transfer tasks to test for understanding. All seven transferred their solution across a change in stimuli. However, six out of seven were unable to transfer to two further tasks, which did not share any one visual constant. One female was able to solve these further transfer tasks. Her result is suggestive evidence that rooks are capable of sophisticated physical cognition, if not through an understanding of unobservable forces , perhaps through rule abstraction. Our results highlight the need to investigate cognitive mechanisms other than causal understanding in studying animal physical cognition.     

Using Fiberless,Wearable fNIRS to Monitor Brain Activity in Real-world Cognitive Tasks

Functional Near Infrared Spectroscopy (fNIRS) is a neuroimaging technique that uses near-infrared light to monitor brain activity. Based on neurovascular coupling, fNIRS is able to measure the haemoglobin concentration changes secondary to neuronal activity. Compared to other neuroimaging techniques, fNIRS represents a good compromise in terms of spatial and temporal resolution. Moreover, it is portable, lightweight, less sensitive to motion artifacts and does not impose significant physical restraints. It is therefore appropriate to monitor a wide range of cognitive tasks (e.g., auditory, gait analysis, social interaction) and different age populations (e.g., new-borns, adults, elderly people). The recent development of fiberless fNIRS devices has opened the way to new applications in neuroscience research. This represents a unique opportunity to study functional activity during real-world tests, which can be more sensitive and accurate in assessing cognitive function and dysfunction than lab-based tests. This study explored the use of fiberless fNIRS to monitor brain activity during a real-world prospective memory task. This protocol is performed outside the lab and brain haemoglobin concentration changes are continuously measured over the prefrontal cortex while the subject walks around in order to accomplish several different tasks.     

The home-range concept in rodents revised

The paradigm regarding the ecology of populations of small rodents has had several basic theses: (1) the individual has a home range or is a migrant; (2) factors regulating population parameters (including density) include spatio-social relations between individuals; and (3) the phenomena observed on trial plots with a system of live traps are the same as those beyond the plot. However, the home-range concept in small rodents is open to criticism in that: (1) observations point to much greater ranges of spatial activity in these animals than has been shown hitherto in plot-based studies with systems of live traps; (2) there is great variability in the directions and extent of the spatial activity of small rodents; (3) observations suggest that what is regarded as the area of spatial activity of an individual has limited information content since the ‘tenant’ makes use of the area via tracks and trails along which it moves. Transfers of studies on odour-related information in small rodents from the laboratory to natural populations confirm the significance of odours in the life of these animals and in integrating their populations. It is possible that the need to leave information in the environment (informational conditioning) provokes considerable locomotory and spatial activity in small rodents. Live traps with bait (food) limit the spatial activity of animals. The set of traps in which an individual is caught thus represents not home range but trap range. A new paradigm for the ecology of small rodents should comprise the propositions that: (1) the function of olfactory information is the integration of a population into an ecological system; (2) the maintenance of odour-mediated conditioning in the environment is one of the reasons for locomotor and spatial activity; (3) the patchy distribution of food in the environment (including study plots with traps) gives rise to changes in the use made of space by individuals; (4) the phenomena observed on research plots with live traps containing bait are different to those ongoing at the same time outside these areas. Such a paradigm requires reinterpretation of research results obtained hitherto as well as the application of new research methods.     

Lithium treatment alleviates impaired cognition in a mouse model of fragile X syndrome

Fragile X syndrome (FXS) is caused by suppressed expression of fragile X mental retardation protein (FMRP), which results in intellectual disability accompanied by many variably manifested characteristics, such as hyperactivity, seizures and autistic‐like behaviors. Treatment of mice that lack FMRP, Fmr1 knockout (KO) mice, with lithium has been reported to ameliorate locomotor hyperactivity, prevent hypersensitivity to audiogenic seizures, improve passive avoidance behavior and attenuate sociability deficits. To focus on the defining characteristic of FXS, which is cognitive impairment, we tested if lithium treatment ameliorated impairments in four cognitive tasks in Fmr1 KO mice, tested if the response to lithium differed in adolescent and adult mice and tested if therapeutic effects persisted after discontinuation of lithium administration. Fmr1 KO mice displayed impaired cognition in the novel object detection task, temporal ordering for objects task and coordinate and categorical spatial processing tasks. Chronic lithium treatment of adolescent (from 4 to 8 weeks of age) and adult (from 8 to 12 weeks of age) mice abolished cognitive impairments in all four cognitive tasks. Cognitive deficits returned after lithium treatment was discontinued for 4 weeks. These results show that Fmr1 KO mice exhibit severe impairments in these cognitive tasks, that lithium is equally effective in normalizing cognition in these tasks whether it is administered to young or adult mice and that lithium administration must be continued for the cognitive improvements to be sustained. These findings provide further evidence that lithium administration may be beneficial for individuals with FXS .     

The exploratory behaviour of rats in the hole-board apparatus: Is head-dipping a valid measure of neophilia?

The exploratory behaviour of laboratory rodents is of interest within a number of areas of behavioural pharmacology. However, how best to measure exploratory behaviour in rodents remains a contentious issue. Many unconditioned tests, such as the open field, potentially confound general locomotor activity with exploration. The hole-board apparatus appears to avoid this confound, as head-dipping into holes in the floor is assumed to be a valid measure of the subject's attraction towards novelty (neophilia). This study aimed to investigate whether head-dipping should be considered a valid measure of neophilia by comparing performance of adult male and female Lister hooded rats on the hole-board task (a) over repeated sessions and (b) when novel objects were absent or present underneath the holes. The results show that head-dipping initially decreased across repeated exposures, while time spent in the aversive central area increased. No change in head-dipping was seen in response to objects being placed underneath the holes. Rather than being a measure of neophilia, these results support the hypothesis that head-dipping represents an escape response, which declines as the subject becomes less fearful. These results are compared with previous studies of repeated exposure to other novel environments.     

Sleep-Effects on Implicit and Explicit Memory in Repeated Visual Search

In repeated visual search tasks, facilitation of reaction times (RTs) due to repetition of the spatial arrangement of items occurs independently of RT facilitation due to improvements in general task performance. Whereas the latter represents typical procedural learning, the former is a kind of implicit memory that depends on the medial temporal lobe (MTL) memory system and is impaired in patients with amnesia. A third type of memory that develops during visual search is the observers’ explicit knowledge of repeated displays. Here, we used a visual search task to investigate whether procedural memory, implicit contextual cueing, and explicit knowledge of repeated configurations, which all arise independently from the same set of stimuli, are influenced by sleep. Observers participated in two experimental sessions, separated by either a nap or a controlled rest period. In each of the two sessions, they performed a visual search task in combination with an explicit recognition task. We found that (1) across sessions, MTL-independent procedural learning was more pronounced for the nap than rest group. This confirms earlier findings, albeit from different motor and perceptual tasks, showing that procedural memory can benefit from sleep. (2) Likewise, the sleep group compared with the rest group showed enhanced context-dependent configural learning in the second session. This is a novel finding, indicating that the MTL-dependent, implicit memory underlying contextual cueing is also sleep-dependent. (3) By contrast, sleep and wake groups displayed equivalent improvements in explicit recognition memory in the second session. Overall, the current study shows that sleep affects MTL-dependent as well as MTL-independent memory, but it affects different, albeit simultaneously acquired, forms of MTL-dependent memory differentially.     

Appetitive position discrimination in the T-maze

This protocol details a method to perform appetitively motivated tasks in rodents to test cognitive ability. When testing cognition in animals, the simplest paradigms can potentially yield quick results with minimal investment from the experimenter. Although appetitively motivated tasks are generally learnt more slowly than aversively motivated ones, they may be essential for distinguishing the effects of a treatment on learning from its effects on aversive motivation per se. For example, if a treatment improves learning in both types of paradigm, this is better evidence that it affects cognition rather than sensorimotor processes. Rats and mice easily learn position discriminations in a T-maze, especially if multiple cues, such as different objects and floor textures in the goal arms, are provided. To start, the rodent is placed in the maze and it chooses an arm. This Trial 1, however, is the only one on which this arm will be rewarded. From now on, it must always choose the other arm. The rule is simple: for example, always turn left into the arm with diagonal black stripes on the walls and gravel glued to the floor. High levels of correct responding can be achieved within 20-40 trials. The test may therefore be particularly useful with animals of low cognitive ability, such as transgenic mice derived from some 129 or SJL strains. Once the animals are habituated, each trial should take approximately 1 min. Thus, to test ten animals for 40 trials would take around 7 h.     

Digit ratio predicts sense of direction in women

The relative length of the second-to-fourth digits (2D:4D) has been linked with prenatal androgen in humans. The 2D:4D is sexually dimorphic, with lower values in males than females, and appears to correlate with diverse measures of behavior. However, the relationship between digit ratio and cognition, and spatial cognition in particular, has produced mixed results. In the present study, we hypothesized that spatial tasks separating cue conditions that either favored female or male strategies would examine this structure-function correlation with greater precision. Previous work suggests that males are better in the use of directional cues than females. In the present study, participants learned a target location in a virtual landscape environment, in conditions that contained either all directional (i.e., distant or compass bearing) cues, or all positional (i.e., local, small objects) cues. After a short delay, participants navigated back to the target location from a novel starting location. Males had higher accuracy in initial search direction than females in environments with all directional cues. Lower digit ratio was correlated with higher accuracy of initial search direction in females in environments with all directional cues. Mental rotation scores did not correlate with digit ratio in either males or females. These results demonstrate for the first time that a sex difference in the use of directional cues, i.e., the sense of direction, is associated with more male-like digit ratio.