Neural encoding of objects relevant for navigation and resting state correlations with navigational ability

Objects along a route can help us to successfully navigate through our surroundings. Previous neuroimaging research has shown that the parahippocampal gyrus (PHG) distinguishes between objects that were previously encountered at navigationally relevant locations (decision points) and irrelevant locations (nondecision points) during simple object recognition. This study aimed at unraveling how this neural marking of objects relevant for navigation is established during learning and postlearning rest. Twenty-four participants were scanned using fMRI while they were viewing a route through a virtual environment. Eye movements were measured, and brain responses were time-locked to viewing each object. The PHG showed increased responses to decision point objects compared with nondecision point objects during route learning. We compared functional connectivity between the PHG and the rest of the brain in a resting state scan postlearning with such a scan prelearning. Results show that functional connectivity between the PHG and the hippocampus is positively related to participants' self-reported navigational ability. On the other hand, connectivity with the caudate nucleus correlated negatively with navigational ability. These results are in line with a distinction between egocentric and allocentric spatial representations in the caudate nucleus and the hippocampus, respectively. Our results thus suggest a relation between navigational ability and a neural preference for a specific type of spatial representation. Together, these results show that the PHG is immediately involved in the encoding of navigationally relevant object information. Furthermore, they provide insight into the neural correlates of individual differences in spatial ability.     

Decreased functional magnetic resonance imaging activity in the hippocampus in favor of the caudate nucleus in older adults tested in a virtual navigation task

The neuroimaging literature has shown consistent decreases in functional magnetic resonance imaging (fMRI) activity in the hippocampus of healthy older adults engaged in a navigation task. However, navigation in a virtual maze relies on spatial or response strategies known to depend on the hippocampus and caudate nucleus, respectively. Therefore, since the proportion of people using spatial strategies decreases with normal aging, we hypothesized that it was responsible for the observed decreases in fMRI activity in the hippocampus reported in the literature. The aim of this study was to examine the effects of aging on the hippocampus and caudate nucleus during navigation while taking into account individual navigational strategies. Young (N = 23) and older adults (N = 29) were tested using fMRI on the Concurrent Spatial Discrimination Learning Task, a radial task that dissociates between spatial and response strategies (in Stage 2) after participants reached criteria (in Stage 1). Success on Stage 2 requires that participants have encoded the spatial relationship between the target object and environmental landmarks, that is, the spatial strategy. While older adults required more trials, all participants reached criterion. fMRI results showed that, as a group, young adults had significant activity in the hippocampus as opposed to older adults who instead had significant activity in the caudate nucleus. Importantly, individual differences showed that the older participants who used a spatial strategy to solve the task had significant activity in the hippocampus. These findings suggest that the aging process involves a shift from using the hippocampus toward the caudate nucleus during navigation but that activity in the hippocampus is sustained in a subset of healthy older adults engaged in spatial strategies. © 2013 Wiley Periodicals, Inc.     

Inactivation of the dorsal hippocampus does not affect learning during exploration of a novel environment

The conditioned cue preference (CCP) task was used to study the ability of rats to discriminate between spatial locations. Food-deprived rats explored an eight-arm radial maze with no food present (pre-exposure). On subsequent days, they were alternately confined in one arm of the maze with food and in another arm with no food (training), followed by a preference test with no food present, to determine if they had learned to discriminate between the two arm locations. No injections were given during the two latter phases. With adjacent radial maze arms, rats given three 10-min pre-exposure sessions and four food-pairing trials exhibited a preference for their food-paired arms; rats not pre-exposed did not exhibit this preference. Rats pre-exposed 30 min after dorsal hippocampus injections of muscimol exhibited the preference. With widely separated maze arms, rats given two training trials with no pre-exposure exhibited a preference for the food-paired arm; rats that were given one pre-exposure session did not. Rats pre-exposed 30 min after dorsal hippocampus injections of muscimol did not exhibit the preference. The same intrahippocampal muscimol injections that failed to affect the influence of pre-exposure on CCP learning with both arm configurations impaired win-shift performance, a standard test of spatial learning. These findings suggest that a functional dorsal hippocampus is not required for the (incidental or latent) learning that occurs during unreinforced exploration of a novel environment. The information acquired during this activity subsequently produces a latent learning effect if it is used to discriminate between two ambiguous locations (adjacent arms) or a latent inhibition--like effect if it is used to discriminate between two unambiguous locations (separated maze arms).     

The brain-derived neurotrophic factor Val66Met polymorphism is associated with reduced functional magnetic resonance imaging activity in the hippocampus and increased use of caudate nucleus-dependent strategies in a human virtual navigation task

Multiple memory systems are involved in parallel processing of spatial information during navigation. A series of studies have distinguished between hippocampus-dependent 'spatial' navigation, which relies on knowledge of the relationship between landmarks in one's environment to build a cognitive map, and habit-based 'response' learning, which requires the memorization of a series of actions and is mediated by the caudate nucleus. Studies have demonstrated that people spontaneously use one of these two alternative navigational strategies with almost equal frequency to solve a given navigation task, and that strategy correlates with functional magnetic resonance imaging (fMRI) activity and grey matter density. Although there is evidence for experience modulating grey matter in the hippocampus, genetic contributions may also play an important role in the hippocampus and caudate nucleus. Recently, the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene has emerged as a possible inhibitor of hippocampal function. We have investigated the role of the BDNF Val66Met polymorphism on virtual navigation behaviour and brain activation during an fMRI navigation task. Our results demonstrate a genetic contribution to spontaneous strategies, where 'Met' carriers use a response strategy more frequently than individuals homozygous for the 'Val' allele. Additionally, we found increased hippocampal activation in the Val group relative to the Met group during performance of a virtual navigation task. Our results support the idea that the BDNF gene with the Val66Met polymorphism is a novel candidate gene involved in determining spontaneous strategies during navigation behaviour.     

Disruption of ripple‐associated hippocampal activity during rest impairs spatial learning in the rat

The hippocampus plays a key role in the acquisition of new memories for places and events. Evidence suggests that the consolidation of these memories is enhanced during sleep. At the neuronal level, reactivation of awake experience in the hippocampus during sharp‐wave ripple events, characteristic of slow‐wave sleep, has been proposed as a neural mechanism for sleep‐dependent memory consolidation. However, a causal relation between sleep reactivation and memory consolidation has not been established. Here we show that disrupting neuronal activity during ripple events impairs spatial learning. We trained rats daily in two identical spatial navigation tasks followed each by a 1‐hour rest period. After one of the tasks, stimulation of hippocampal afferents selectively disrupted neuronal activity associated with ripple events without changing the sleep‐wake structure. Rats learned the control task significantly faster than the task followed by rest stimulation, indicating that interfering with hippocampal processing during sleep led to decreased learning. © 2009 Wiley‐Liss, Inc.     

Small lesions of the dorsal or ventral hippocampus subregions are associated with distinct impairments in working memory and reference memory retrieval,and combining them attenuates the acquisition rate of spatial reference memory

The importance of the hippocampus in spatial learning is well established, but the precise relative contributions by the dorsal (septal) and ventral (temporal) subregions remain unresolved. One debate revolves around the extent to which the ventral hippocampus contributes to spatial navigation and learning. Here, separate small subtotal lesions of dorsal hippocampus or ventral hippocampus alone (destroying 18.9 and 28.5% of total hippocampal volume, respectively) spared reference memory acquisition in the water maze. By contrast, combining the two subtotal lesions significantly reduced the rate of acquisition across days. This constitutes evidence for synergistic integration between dorsal and ventral hippocampus in mice. Evidence that ventral hippocampus contributes to spatial/navigation learning also emerged early on during the retention probe test as search preference was reduced in mice with ventral lesions alone or combined lesions. The small ventral lesions also led to anxiolysis in the elevated plus maze and over‐generalization of the conditioned freezing response to a neutral context. Similar effects of comparable magnitudes were seen in mice with combined lesions, suggesting that they were largely due to the small ventral damage. By contrast, small dorsal lesions were uniquely associated with a severe spatial working memory deficit in the water maze. Taken together, both dorsal and ventral poles of the hippocampus contribute to efficient spatial navigation in mice: While the integrity of dorsal hippocampus is necessary for spatial working memory, the acquisition and retrieval of spatial reference memory are modulated by the ventral hippocampus. Although the impairments following ventral damage (alone or in combination with dorsal damage) were less substantial, a wider spectrum of spatial learning, including context conditioning, was implicated. Our results encourage the search for integrative mechanism between dorsal and ventral hippocampus in spatial learning. Candidate neural substrates may include dorsoventral longitudinal connections and reciprocal modulation via overlapping polysynaptic networks beyond hippocampus.     

A virtual reality-based FMRI study of reward-based spatial learning

Although temporo-parietal cortices mediate spatial navigation in animals and humans, the neural correlates of reward-based spatial learning are less well known. Twenty-five healthy adults performed a virtual reality fMRI task that required learning to use extra-maze cues to navigate an 8-arm radial maze and find hidden rewards. Searching the maze in the spatial learning condition compared to the control conditions was associated with activation of temporo-parietal regions, albeit not including the hippocampus. The receipt of rewards was associated with activation of the hippocampus in a control condition when using the extra-maze cues for navigation was rendered impossible by randomizing the spatial location of cues. Our novel experimental design allowed us to assess the differential contributions of the hippocampus and other temporo-parietal areas to searching and reward processing during reward-based spatial learning. This translational research will permit parallel studies in animals and humans to establish the functional similarity of learning systems across species; cellular and molecular studies in animals may then inform the effects of manipulations on these systems in humans, and fMRI studies in humans may inform the interpretation and relevance of findings in animals.     

Recurrent seizures induce a reversible impairment in a spatial hidden goal task

A major question concerning the learning and memory deficits characteristic of epilepsy is the relative importance of the initial insult that leads to recurrent, unprovoked seizures versus the seizures themselves. A related issue is whether seizure‐induced cognitive decline is permanent or reversible when convulsions cease. To address these problems, adult rats were extensively trained in the “spatial accuracy task,” a dry‐land analog of the Morris water maze. This task allows the rat's estimate of the location of a hidden goal zone to be repeatedly measured within each behavioral session. One aim was to measure, in well‐trained animals, the time course of any cognitive impairment caused by a daily flurothyl‐induced generalized seizure over 11 days. A second aim was to look for possible recovery during 9 subsequent days with no seizures. We saw a cumulative degradation in spatial performance during the seizure days and reversal of the deficit after seizures were stopped such that performance returned to baseline. Interestingly, the rate of learning to an asymptote, the rate of performance decline during one‐per‐day seizures and the rate of relearning during the recovery period were all similar. Given that the hippocampus plays an important role in spatial memory and that it is the brain structure most vulnerable to abnormal excitation the implication is that the hippocampus remains essential for precise spatial navigation even after prolonged training in locating a fixed goal zone. Clinically, this finding questions the assumption that patients who experience seizures should return to a baseline cognitive level within hours. © 2009 Wiley‐Liss, Inc.     

Negative correlation between grey matter in the hippocampus and caudate nucleus in healthy aging

Neurobiological changes that occur with aging include a reduction in function and volume of the hippocampus. These changes were associated with corresponding memory deficits in navigation tasks. However, navigation can involve different strategies that are dependent on the hippocampus and caudate nucleus. The proportion of people using hippocampus‐dependent spatial strategies decreases across the lifespan. As such, the decrease in spatial strategies, and corresponding increase in caudate nucleus‐dependent response strategies with age, may play a role in the observed neurobiological changes in the hippocampus. Furthermore, we previously showed a negative correlation between grey matter in the hippocampus and caudate nucleus/striatum in mice, young adults, and in individuals diagnosed with Alzheimer's disease. As such, we hypothesized that this negative relationship between the two structures would be present during normal aging. The aim of the current study was to investigate this gap in the literature by studying the relationship between grey matter in the hippocampus and caudate nucleus of the striatum, in relation to each other and to navigation strategies, during healthy aging. Healthy older adults (N = 39) were tested on the Concurrent Spatial Discrimination Learning Task (CSDLT), a virtual radial task that dissociates between spatial and response strategies. A regression of strategies against structural MRIs showed for the first time in older adults that the response strategy was associated with higher amounts of grey matter in the caudate nucleus. As expected, the spatial strategy correlated with grey matter in the hippocampus, which was negatively correlated with grey matter in the caudate nucleus. Interestingly, a sex difference emerged showing that among older adult response learners, women have the least amount of grey matter in the hippocampus, which is a known risk for Alzheimer's disease. This difference was absent among spatial learners. These results are discussed in the context of the putative protective role of spatial memory against grey matter loss in the hippocampus, especially in women.     

Spontaneous navigational strategies and performance in the virtual town

The 4-on-8 virtual maze provides evidence for variability in spontaneous strategy use during navigation. Functional magnetic resonance imaging (MRI) confirmed that these spatial and response strategies rely on the hippocampus and caudate nucleus memory systems, respectively. We asked whether the spontaneous use of a particular navigational strategy was associated with a particular ability to navigate in one's environment. We tested 30 young participants on the 4-on-8 virtual maze and we assessed their way finding ability in a virtual town. As expected, spatial learners performed well in the virtual town and the response learners, who never used external landmarks and relied purely on an egocentric strategy, performed poorly. Interestingly, a group who used the most efficient response strategy based on external landmarks in the 4-on-8 virtual maze, switched to the most efficient spatial strategy in the virtual town. Our data suggest that the best navigators are those who appropriately use spatial or response strategies depending on the demands of the task.     

Role of low‐ and high‐frequency oscillations in the human hippocampus for encoding environmental novelty during a spatial navigation task

The hippocampus plays a key role in the encoding and retrieval of information related to novel environments during spatial navigation. However, the neural basis for these processes in the human hippocampus remains unknown because it is difficult to directly measure neural signals in the human hippocampus. This study investigated hippocampal neural oscillations involved in encoding novel environments during spatial navigation in a virtual environment. Seven epileptic patients with implanted intracranial hippocampal depth electrodes performed three sessions of virtual environment navigation. Each session consisted of a navigation task and a location‐recall task. The navigation task consisted of eight blocks, and in each block, the participant navigated to the location of four different objects and was instructed to remember the location of the objects. After the eight blocks were completed, a location‐recall task was performed for each of the four objects. Intracranial electroencephalography data were monitored during the navigation tasks. Theta (5–8 Hz) and delta (1–4 Hz) oscillations were lower in the first block (novel environment) than in the eighth block (familiar environment) of the navigation task, and significantly increased from block one to block eight. By contrast, low‐gamma (31–50 Hz) oscillations were higher in the first block than in the eighth block of the navigation task, and significantly decreased from block one to block eight. Comparison of sessions with high recall performance (low error between identified and actual object location) and low recall performance revealed that high‐gamma (51–100 Hz) oscillations significantly decreased from block one to block eight only in sessions with high recall performance. These findings suggest that delta, theta, and low‐gamma oscillations were associated with encoding of environmental novelty and high‐gamma oscillations were important for the successful encoding of environmental novelty. © 2014 Wiley Periodicals, Inc.     

Disrupted allocentric but preserved egocentric spatial learning in transgenic mice with impaired glucocorticoid receptor function

Spatial and non-spatial learning of mice with an incorporated antisense RNA complementary to a fragment of cDNA coding for the glucocorticoid receptor (GR) were evaluated in allocentric and egocentric radial maze and water maze tasks, and in spontaneous object recognition and sensorimotor learning paradigms. Mice with impaired GR function did not acquire two maze paradigms based on allocentric spatial navigation, radial maze non-matching to position and water maze spatial discrimination learning. Comparison of performance in spaced and massed trials indicated that this may be due to a general inability to store information into allocentric reference memory or in retrieval processes. However, both groups of animals learned the rules of an egocentric radial maze task at similar rates and there was no difference in their ability to recognise objects once animals had equal opportunity to explore the sample objects. Sensorimotor performance was impaired in transgenic animals, but it is suggested that this is due to non-specific factors rather than to disrupted sensorimotor learning per se. These results are consistent with a disruption of hippocampal function. Histological examination of the hippocampus revealed no obvious structural abnormalities in transgenic animals. Therefore, the data suggest that functional underactivity of GRs at the level of the hippocampus induces a deficit in allocentric navigation while sparing egocentric navigation and object recognition.     

Prenatal stress changes learning strategies in adulthood

It is well known that stressful experiences may shape hippocampus‐dependent learning and memory processes. However, although most studies focused on the impact of stress at the time of learning or memory testing, very little is known about how stress during critical periods of brain development affects learning and memory later in life. In this study, we asked whether prenatal stress exposure may influence the engagement of hippocampus‐dependent spatial learning strategies and caudate nucleus‐dependent response learning strategies in later life. To this end, we tested healthy participants whose mothers had experienced major negative life events during their pregnancy in a virtual navigation task that can be solved by spatial and response strategies. We found that young adults with prenatal stress used rigid response learning strategies more often than flexible spatial learning strategies compared with participants whose mothers did not experience major negative life events during pregnancy. Individual differences in acute or chronic stress do not account for these findings. Our data suggest that the engagement of hippocampal and nonhippocampal learning strategies may be influenced by stress very early in life. © 2012 Wiley Periodicals, Inc.     

Dissociation of function between the dorsal and the ventral hippocampus in spatial learning abilities of the rat: a within-subject, within-task comparison of reference and working spatial memory

Lesions restricted to the dorsal, but not the ventral, hippocampus severely impair the formation of spatial memory. This dissociation was first demonstrated using the water maze task. The present study investigated whether the dorsal and the ventral hippocampus are involved differentially in spatial reference and spatial working memory using a four-baited/four-unbaited version of the eight-arm radial maze task. This test allows the concurrent evaluation of reference and working memory with respect to the same set of spatial cues, and thereby enables a within-subjects within-task comparison between the two forms of memory functions. Rats with N-methyl-d-aspartic acid-induced excitotoxic lesions of the dorsal hippocampus, ventral hippocampus or both were compared with sham and unoperated controls. We showed that dorsal lesions were as effective as complete lesions in severely disrupting both reference and working spatial memory, whereas rats with ventral lesions performed at a level comparable with controls. These results lend further support to the existence of a functional dissociation between the dorsal and the ventral hippocampus, with the former being preferentially involved in spatial learning.     

Selective deficit in spatial memory strategies contrast to intact response strategies in patients with schizophrenia spectrum disorders tested in a virtual navigation task

Spatial memory is impaired among persons with schizophrenia (SCZ). However, different strategies may be used to solve most spatial memory and navigation tasks. This study investigated the hypothesis that participants with schizophrenia‐spectrum disorders (SSD) would demonstrate differential impairment during acquisition and retrieval of target locations when using a hippocampal‐dependent spatial strategy, but not a response strategy, which is more associated with caudate function. Healthy control (CON) and SSD participants were tested using the 4‐on‐8 virtual maze (4/8VM), a virtual navigation task designed to differentiate between participants' use of spatial and response strategies. Consistent with our predictions, SSD participants demonstrated a differential deficit such that those who navigated using a spatial strategy made more errors and took longer to locate targets. In contrast, SSD participants who spontaneously used a response strategy performed as well as CON participants. The differential pattern of spatial‐memory impairment in SSD provides only indirect support for underlying hippocampal dysfunction. These findings emphasize the importance of considering individual strategies when investigating SSD‐related memory and navigation performance. Future cognitive intervention protocols may harness SSD participants' intact ability to navigate using a response strategy and/or train the deficient ability to navigate using a spatial strategy to improve navigation and memory abilities in participants with SSD. © 2013 Wiley Periodicals, Inc.     

The functional role of human right hippocampal/parahippocampal theta rhythm in environmental encoding during virtual spatial navigation

Low frequency theta band oscillations (4–8 Hz) are thought to provide a timing mechanism for hippocampal place cell firing and to mediate the formation of spatial memory. In rodents, hippocampal theta has been shown to play an important role in encoding a new environment during spatial navigation, but a similar functional role of hippocampal theta in humans has not been firmly established. To investigate this question, we recorded healthy participants’ brain responses with a 160‐channel whole‐head MEG system as they performed two training sets of a virtual Morris water maze task. Environment layouts (except for platform locations) of the two sets were kept constant to measure theta activity during spatial learning in new and familiar environments. In line with previous findings, left hippocampal/parahippocampal theta showed more activation navigating to a hidden platform relative to random swimming. Consistent with our hypothesis, right hippocampal/parahippocampal theta was stronger during the first training set compared to the second one. Notably, theta in this region during the first training set correlated with spatial navigation performance across individuals in both training sets. These results strongly argue for the functional importance of right hippocampal theta in initial encoding of configural properties of an environment during spatial navigation. Our findings provide important evidence that right hippocampal/parahippocampal theta activity is associated with environmental encoding in the human brain. Hum Brain Mapp 38:1347–1361, 2017. © 2016 Wiley Periodicals, Inc.     

Changes in corticostriatal connectivity during reinforcement learning in humans

Many computational models assume that reinforcement learning relies on changes in synaptic efficacy between cortical regions representing stimuli and striatal regions involved in response selection, but this assumption has thus far lacked empirical support in humans. We recorded hemodynamic signals with fMRI while participants navigated a virtual maze to find hidden rewards. We fitted a reinforcement‐learning algorithm to participants' choice behavior and evaluated the neural activity and the changes in functional connectivity related to trial‐by‐trial learning variables. Activity in the posterior putamen during choice periods increased progressively during learning. Furthermore, the functional connections between the sensorimotor cortex and the posterior putamen strengthened progressively as participants learned the task. These changes in corticostriatal connectivity differentiated participants who learned the task from those who did not. These findings provide a direct link between changes in corticostriatal connectivity and learning, thereby supporting a central assumption common to several computational models of reinforcement learning. Hum Brain Mapp 36:793–803, 2015. © 2014 Wiley Periodicals, Inc .     

Dorsal hippocampus not always necessary in a radial arm maze delayed win‐shift task

Spatial working memory is important for foraging and navigating the environment. However, its neural underpinnings remain poorly understood. The hippocampus, known for its spatial coding and involvement in spatial memory, is widely understood to be necessary for spatial working memory when retention intervals increase beyond seconds into minutes. Here, we describe new evidence that the dorsal hippocampus is not always necessary for spatial working memory for retention intervals of 8 min. Rats were trained to perform a delayed spatial win shift radial arm maze task with an 8‐min delay between study and test phases. We then tested whether bilateral inactivation of the dorsal hippocampus between the study and test phases impaired behavioral performance at test. Inactivation was achieved through a bilateral infusion of lidocaine. Performance following lidocaine was compared to control trials, in which, sterile phosphate buffered saline (PBS) was infused. Test performance did not differ between the lidocaine and PBS conditions, remaining high in each. To explore the possibility that this insensitivity to inactivation was a result of overtraining, a second cohort of animals received substantially less training prior to the infusions. In this second cohort, lidocaine infusions did significantly impair task performance. These data indicate that successful performance of a spatial win‐shift task on the 8‐arm maze need not always be hippocampally dependent.     

Differential lateralization of hippocampal connectivity reflects features of recent context and ongoing demands: An examination of immediate post‐task activity

Neuroimaging studies have shown that task demands affect connectivity patterns in the human brain not only during task performance but also during subsequent rest periods. Our goal was to determine whether ongoing connectivity patterns during rest contain information about both the current rest state, as well as the recently terminated task. Our experimental design consisted of two types of active tasks that were followed by two types of low‐demand rest states. Using this design, we examined whether hippocampal functional connectivity during wakeful rest reflects both features of a recently terminated task and those of the current resting‐state condition. We identified four types of networks: (i) one whose connectivity with the hippocampus was determined only by features of a recently terminated task, (ii) one whose connectivity was determined only by features of the current resting‐state, (iii) one whose connectivity reflected aspects of both the recently terminated task and ongoing resting‐state features, and (iv) one whose connectivity with the hippocampus was strong, but not affected by any external factor. The left and right hippocampi played distinct roles in these networks. These findings suggest that ongoing hippocampal connectivity networks mediate information integration across multiple temporal scales, with hippocampal laterality moderating these connectivity patterns. Hum Brain Mapp 36:519–537, 2015. © 2014 Wiley Periodicals, Inc.