Caudate nucleus‐dependent navigational strategies are associated with increased use of addictive drugs

This study aimed to investigate the relationship between navigational strategies and the use of abused substances in a sample of healthy young adults. Navigational strategies were assessed with the 4‐on‐8 virtual maze (4/8VM), a task previously shown to dissociate between hippocampal‐dependent spatial navigational strategies and caudate nucleus‐dependent stimulus‐response navigational strategies. Spatial strategies involve learning the spatial relationships between the landmarks in an environment, while response learning strategies involve learning a rigid set of stimulus‐response type associations, e.g., see the tree, turn left. We have shown that spatial learners have increased gray matter and fMRI activity in the hippocampus compared with response learners, while response learners have increased gray matter and fMRI activity in the caudate nucleus. We were interested in the prevalence of use of substances of abuse in spatial and response learners because of the evidence that people who score high on traits such as novelty seeking, sensation seeking, reward seeking, and impulsivity, are more cue‐responsive and more likely to use substances of abuse. Since response learners show increased activity and gray matter in the caudate nucleus of the striatum, which is a brain area involved in addiction, we hypothesized that response learners would have a greater use of abused substances than spatial learners. Fifty‐five young adults were tested on the 4/8VM and completed a time‐line follow‐back assessment of drug and alcohol use. We found that response learners had smoked a significantly greater number of cigarettes in their lifetime than spatial learners, were more likely to have used cannabis, and had double the lifetime alcohol consumption. We discuss the possible relationship between substance abuse and response strategies as well as the implications for the hippocampus, risks of neurological and psychiatric disorders, and healthy cognition. © 2013 The Authors. Hippocampus Published by Wiley Periodicals, Inc.     

Evidence for a virtual human analog of a rodent relational memory task: a study of aging and fMRI in young adults

A radial maze concurrent spatial discrimination learning paradigm consisting of two stages was previously designed to assess the flexibility property of relational memory in mice, as a model of human declarative memory. Aged mice and young adult mice with damage to the hippocampus, learned accurately Stage 1 of the task which required them to learn a constant reward location in a specific set of arms (i.e., learning phase). In contrast, they were impaired relative to healthy young adult mice in a second stage when faced with rearrangements of the same arms (i.e., flexibility probes). This mnemonic inflexibility in Stage 2 is thought to derive from insufficient relational processing by the hippocampus during initial learning (Stage 1) which favors stimulus-response learning, a form of procedural learning. This was proposed as a model of the selective declarative and relational memory decline classically described in elderly people. As a first step to examine the validity of this model, we adapted this protocol to humans using a virtual radial-maze. (1) We showed that performance in the flexibility probes in young and older adults positively correlated with performance in a wayfinding task, suggesting that our paradigm assesses relational memory. (2) We demonstrated that older healthy participants displayed a deficit in the performance of the flexibility probes (Stage 2), similar to the one previously seen in aged mice. This was associated with a decline in the wayfinding task. (3) Our fMRI data in young adults confirmed that hippocampal activation during early discrimination learning in Stage 1 correlated with memory flexibility in Stage 2, whereas caudate nucleus activation in Stage 1 negatively correlated with subsequent flexibility. By enabling relational memory assessment in mice and humans, our radial-maze paradigm provides a valuable tool for translational research.     

Factors that influence the relative use of multiple memory systems

Neurobehavioral evidence supports the existence of at least two anatomically distinct “memory systems” in the mammalian brain that mediate dissociable types of learning and memory; a “cognitive” memory system dependent upon the hippocampus and a “stimulus‐response/habit” memory system dependent upon the dorsolateral striatum. Several findings indicate that despite their anatomical and functional distinctiveness, hippocampal‐ and dorsolateral striatal‐dependent memory systems may potentially interact and that, depending on the learning situation, this interaction may be cooperative or competitive. One approach to examining the neural mechanisms underlying these interactions is to consider how various factors influence the relative use of multiple memory systems. The present review examines several such factors, including information compatibility, temporal sequence of training, the visual sensory environment, reinforcement parameters, emotional arousal, and memory modulatory systems. Altering these parameters can lead to selective enhancements of either hippocampal‐dependent or dorsolateral striatal‐dependent memory, and bias animals toward the use of either cognitive or habit memory in dual‐solution tasks that may be solved adequately with either memory system. In many learning situations, the influence of such experimental factors on the relative use of memory systems likely reflects a competitive interaction between the systems. Research examining how various factors influence the relative use of multiple memory systems may be a useful method for investigating how these systems interact with one another. © 2013 Wiley Periodicals, Inc.     

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.     

Posterior parahippocampal gyrus lesions in the human impair egocentric learning in a virtual environment

Functional imaging studies have shown that the posterior parahippocampal gyrus (PHG) is involved in allocentric (world-centered) object and scene recognition. However, the putative role of the posterior PHG in egocentric (body-centered) spatial memory has received only limited systematic investigation. Thirty-one subjects with pharmacoresistant medial temporal lobe epilepsy (TLE) and temporal lobe removal were compared with 19 matched healthy control subjects on a virtual reality task affording the navigation in a virtual maze (egocentric memory). Lesions of the hippocampus and PHG of TLE subjects were determined by three-dimensional magnetic resonance imaging volumetric assessment. The results indicate that TLE subjects with right-sided posterior PHG lesions were impaired on virtual maze acquisition when compared with controls and TLE subjects with anterior PHG lesions. Larger posterior PHG lesions were significantly related to stronger impairments in virtual maze performance. Our results point to a role of the right-sided posterior PHG for the representation and storage of egocentric information. Moreover, access to both allocentric and egocentric streams of spatial information may enable the posterior PHG to construct a global and comprehensive representation of spatial environments.     

Age-dependent and -independent changes in attention-deficit/hyperactivity disorder (ADHD) during spatial working memory performance

Objectives: Attention-deficit/hyperactivity disorder (ADHD) has been associated with spatial working memory as well as frontostriatal core deficits. However, it is still unclear how the link between these frontostriatal deficits and working memory function in ADHD differs in children and adults. This study examined spatial working memory in adults and children with ADHD, focussing on identifying regions demonstrating age-invariant or age-dependent abnormalities. Methods: We used functional magnetic resonance imaging to examine a group of 26 children and 35 adults to study load manipulated spatial working memory in patients and controls. Results: In comparison to healthy controls, patients demonstrated reduced positive parietal and frontostriatal load effects, i.e., less increase in brain activity from low to high load, despite similar task performance. In addition, younger patients showed negative load effects, i.e., a decrease in brain activity from low to high load, in medial prefrontal regions. Load effect differences between ADHD and controls that differed between age groups were found predominantly in prefrontal regions. Age-invariant load effect differences occurred predominantly in frontostriatal regions. Conclusions: The age-dependent deviations support the role of prefrontal maturation and compensation in ADHD, while the age-invariant alterations observed in frontostriatal regions provide further evidence that these regions reflect a core pathophysiology in ADHD.     

Neural correlates of strategic memory retrieval: differentiating between spatial-associative and temporal-associative strategies

Remembering complex, multidimensional information typically requires strategic memory retrieval, during which information is structured, for instance by spatial- or temporal associations. Although brain regions involved in strategic memory retrieval in general have been identified, differences in retrieval operations related to distinct retrieval strategies are not well-understood. Thus, our aim was to identify brain regions whose activity is differentially involved in spatial-associative and temporal-associative retrieval. First, we showed that our behavioral paradigm probing memory for a set of object-location associations promoted the use of a spatial-associative structure following an encoding condition that provided multiple associations to neighboring objects (spatial-associative condition) and the use of a temporal-associative structure following another study condition that provided predominantly temporal associations between sequentially presented items (temporal-associative condition). Next, we used an adapted version of this paradigm for functional MRI, where we contrasted brain activity related to the recall of object-location associations that were either encoded in the spatial- or the temporal-associative condition. In addition to brain regions generally involved in recall, we found that activity in higher-order visual regions, including the fusiform gyrus, the lingual gyrus, and the cuneus, was relatively enhanced when subjects used a spatial-associative structure for retrieval. In contrast, activity in the globus pallidus and the thalamus was relatively enhanced when subjects used a temporal-associative structure for retrieval. In conclusion, we provide evidence for differential involvement of these brain regions related to different types of strategic memory retrieval and the neural structures described play a role in either spatial-associative or temporal-associative memory retrieval.     

Predicting episodic and spatial memory performance from hippocampal resting‐state functional connectivity: Evidence for an anterior–posterior division of function

fMRI studies have identified distinct resting‐state functional connectivity (RSFC) networks associated with the anterior and posterior hippocampus. However, the functional relevance of these two networks is still largely unknown. Hippocampal lesion studies and task‐related fMRI point to a role for the anterior hippocampus in nonspatial episodic memory and the posterior hippocampus in spatial memory. We used Relevance Vector Regression (RVR), a machine‐learning method that enables predictions of continuous outcome measures from multivariate patterns of brain imaging data, to test the hypothesis that patterns of whole‐brain RSFC associated with the anterior hippocampus predict episodic memory performance, while patterns of whole‐brain RSFC associated with the posterior hippocampus predict spatial memory performance. Magnetic resonance imaging and memory assessment took place at two separate occasions. The anterior and posterior RSFC largely corresponded with previous findings, and showed no effect of laterality. Supporting the hypothesis, RVR produced accurate predictions of episodic performance from anterior, but not posterior, RSFC, and accurate predictions of spatial performance from posterior, but not anterior, RSFC. In contrast, a univariate approach could not predict performance from resting‐state connectivity. This supports a functional dissociation between the anterior and posterior hippocampus, and indicates a multivariate relationship between intrinsic functional networks and cognitive performance within specific domains, that is relatively stable over time.     

Catecholamine alterations in basal ganglia after hippocampal lesions

Rats were given sham, cortical, or hippocampal lesions and sacrificed 7 or 28 days following surgery. Levels of norepinephrine, dopamine, and the major dopamine metabolites, 3, 4-dihydroxyphenylacetic acid and homovanillic acid (HVA), were assayed in 3 brain regions. At day 7 there was a decrease in dopamine utilization and a decrease in norepinephrine levels in the nucleus accumbens after hippocampal damage but both of these measures returned to normal levels by day 28. In the neostriatum HVA levels decreased at day 7 after hippocampal damage. The utilization of dopamine in the neostriatum was decreased at day 28 in animals that received neocortical lesions but this was not observed in animals with hippocampal destruction. No effects of any lesion at any day were found in the olfactory tubercle region, the third brain region analyzed. It is thought that the removal of hippocampal and neocortical input to the basal ganglia influences catecholamine function reflected in the loss and subsequent recovery of dopamine utilization.     

Evidence for a relationship between place-cell spatial firing and spatial memory performance.

The rat hippocampus contains place cells whose firing is location-specific. Although many properties of place cells have been uncovered, little is known about their actual contribution to the animal's spatial performance. In this study, we addressed this issue by recording place cells while rats solved a continuous spatial alternation task in which they had to alternate between the two arms of a Y-maze to get a food reward in the third (goal) arm. By manipulating the information available to the animals, we induced the cells to establish their fields in locations that were out of register relative to their standard position, thus making them inconsistent with the learned spatial task. When this happened, the rats' performance in the alternation task was markedly decreased. In addition, the nature of the behavioral errors during inconsistent field placements also changed dramatically in a way that was highly indicative of the rats' spatial disorientation. These results suggest that there is a functional relationship between the spatial firing patterns of place cells and the spatial behavior of the rat, thus strengthening the idea that these cells are part of a navigational system.     

Photoperiod interacts with food restriction in performance in the Barnes maze in female California mice

Food restriction has been reported to have positive effects on cognition. This study examines how another environmental factor, daylength, can alter the impact of food restriction on the brain and behavior. Female California mice (Peromyscus californicus), housed on either long days (16 h of light and 8 h of darkness) or short days (8 h of light and 16 h of darkness), were restricted to 80% of their normal baseline food intake or provided with food ad libitum. Testing in a Barnes maze revealed that the effects of food restriction depended on photoperiod, and that these effects differed for acquisition vs. reversal learning. During acquisition testing, food restriction increased latency to finding the target hole in short‐day mice but not in long‐day mice. In reversal testing, food restriction decreased latency to finding the target hole in long‐day mice but not in short‐day mice. Latency to finding the hole was positively and independently correlated with both errors and time spent freezing, suggesting that changes in both spatial learning and anxiety‐like behavior contributed to performance. Short days increased hippocampal expression of the synaptic protein, synapsin I, which was reversed by food restriction. Short days also reduced plasma corticosterone levels, but diet had no effect. There was no effect of diet or photoperiod on hippocampal expression of the glial marker, glial fibrillary acidic protein. The present findings suggest that, in female California mice, the differential effects of food restriction on acquisition and reversal learning are photoperiod‐dependent. These results justify further testing of the relationship between food restriction and hippocampal synapsin I in the context of spatial learning.     

Multiregional 1H-MRSI of the hippocampus,thalamus, and basal ganglia in schizophrenia

Background: The hippocampus, thalamus and basal ganglia are among the brain regions of major interest in schizophrenia. Aims: The purpose of this study was to corroborate previous findings of reduced N-acetylaspartate in the hippocampal and thalamic regions and to investigate possible metabolite changes in the putamen in schizophrenia. Method: MRSI study of the thalamus, basal ganglia, and hippocampus in 13 schizophrenic patients under stable medication and age-matched healthy controls. Results A decrease of the N-acetylaspartate signal was found in the hippocampal region and the thalamus but not in the putamen of patients compared to controls. No significant group differences in the signals from creatine and phosphocreatine, and choline-containing compounds were found in the hippocampal region and the putamen but the signal from choline-containing compounds was decreased in the thalamus of patients. Conclusion: Metabolic processes in the basal ganglia of schizophrenic patients seem to be opposite the hippocampal and thalamus findings. Received: 6 August 2002 / Accepted: 5 December 2002 Correspondence to Dr. Gabriele Ende     

Neuronal activity in the hippocampus during delayed non-match to sample performance in rats: evidence for hippocampal processing in recognition memory.

Neuronal activity in the CA1 of rats was explored with regard to functional correlates of performance in an odor-guided continuous delayed non-match to sample task. Although different CA1 cells fired in association with each identifiable trial event, these analyses focused on cells that fired selectively during the period of odor cue sampling and response generation. The firing patterns of many of these cells reflected the match or non-match comparison between current and previous odor cues independent of the particular stimuli that composed those comparisons. Such cells were more prevalent in sessions when performance was highly accurate. Hippocampal cells did not demonstrate stimulus-evoked firing that persisted through the memory delay, nor did they fire differentially to session-novel vs. repeated odor presentations. These results suggest that the hippocampus contributes to recognition memory by processing comparisons between current information and representations of previous stimuli stored in parahippocampal and neocortical structures.     

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.     

Decortication abolishes place but not cue learning in rats

The experiments examined whether decorticate rats are able to acquire a place learning strategy, as compared with a cue learning strategy, to successfully navigate from one place to another and whether the hippocampus, in the absence of the neocortex, contributes to successful performance. Decorticate rats, with or without hippocampectomy, were unable to locate an “invisible” platform submerged at a fixed place in a tank of cool water (made opaque by milk), rather they scrabbled at the edges of the tank and failed even to initiate search strategies. They were able to learn to swim directly to the platform if it was visible. Their ability to find the hidden platform was not enhanced by presurgical experience or two-stage ablations with training before and after ablations. When pretrained on the cue task and tested on the place task, they learned to inhibit scrabbling at the tank edges and “search” in a haphazard fashion for the hidden platform, but they never learned to swim directly toward it. When decorticate rats, trained on the cue task, received superior colliculus or basal ganglia removal in a second operation, cue learning was abolished. Hippocampal removal after decortication left performance on the cue task unaffected. The results demonstrate: (1) the integrity of the neocortex is essential for place learning; (2) the brainstem, including superior colliculus and basal ganglia, is sufficient for cue learning; and (3) in the absence of the neocortex the hippocampus plays no role in guiding either type of navigation. It is concluded that sensorimotor subsystems of the forebrain play a special role as detector-response systems for guiding behaviour in response to constellations of distal stimuli, whereas subcortical structures are sufficient for navigation to a single stimulus.     

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.     

A Golgi analysis of the primate globus pallidus. III. Spatial organization of the striato-pallidal complex

An atlas of transverse sections of the globus pallidus and striatum was established in macaque with reference to ventricular coordinates. The three-dimensional geometry of the striato-pallidal complex was investigated by means of sagittal and horizontal reconstructions. Both a personal case studied with autoradiography and data from literature were used to analyze the distribution of cortical axons into the striatum. One may distinguish two striatal territories: one, somatotopically arranged, sensorimotor territory extending over the major part of the putamen; and the other, an associative territory, comprising the caudate nucleus and antero-medial and postero-inferior parts of the putamen. The striato-pallido-nigral bundle was studied using Golgi, Perls, and Fink-Heimer techniques. The bundle is described in four parts: prepallidal (subdivided into caudato-pallidal and putamino-pallidal subparts), transpallidal, pallido-nigral, and nigral. The tracing of the limit between the caudate (associative) and putaminal (essentially sensorimotor) territories shows that the two components are of roughly the same size in the pallidum. The data were compared with geometry and orientation of the dendritic arborizations of large pallidal neurons analyzed in Yelnik et al. ('84). Each pallidal dendritic disc is able to receive axons from a wide region of the striatum. This leads to a convergence on pallidal neurons of striatal axons from different striatal somatotopic strips and from the sensorimotor and associative territories. This is an indication that the globus pallidus may have an integrative role.     

Spontaneous recovery of deficits in spatial memory and cholinergic potentiation of NMDA in CA1 neurons during chronic lithium treatment.

The therapeutic action of lithium in affective disorders is still unclear. One effect of lithium is to deplete membrane inositol and consequently to exhaust the phosphoinositide (PI) pathway. Under chronic lithium treatment, rats showed persistent performance deficits in an active avoidance task and in a visually cued maze. The same treatment, however, resulted in only a transient deficit in the performance of rats in a spatial memory task. Lithium treatment caused a similarly transient deficit in the ability of acetylcholine to potentiate responses to N-methyl-D-aspartate (NMDA) in neurons of the hippocampal slice. The authors propose that the development of compensatory mechanisms may account for the lack of severe memory impairments during lithium treatment. It is suggested that the effects of lithium on the PI pathway are not sufficient to explain the behavioral consequences of chronic lithium treatment.     

Sleep to find your way: the role of sleep in the consolidation of memory for navigation in humans

Although a large body of evidence indicates that sleep plays an important role in learning and memory processes, the actual existence of a sleep-dependent spatial memory consolidation has been not firmly established. Here, by using a computerized 3D virtual navigation tool, we were able to show that topographical orientation in humans largely benefits from sleep after learning, while 10 h of wakefulness during the daytime do not exert similar beneficial effects. In particular, navigation performance enhancement needs sleep in the first post-training night, and no further improvements were seen after a second night of sleep. On the other hand, sleep deprivation hinders any performance enhancement and exerts a proactive disruption of spatial memory consolidation, since recovery sleep do not revert its effects. Spatial memory performance does not benefit from the simple passage of time, and a period of wakefulness between learning and sleep does not seem to have the role of stabilizing memory traces. In conclusion, our results indicate that spatial performance improvement is observed only when learning is followed by a period of sleep, regardless of the retention interval length.     

Golgi study of the primate substantia nigra. II. Spatial organization of dendritic arborizations in relation to the cytoarchitectonic boundaries and to the striatonigral bundle

The spatial organization of Golgi-stained dendritic arborizations of the substantia nigra was studied in three dimensions by using a video computer system. Dendritic orientation was analyzed in relation to the cytoarchitectonic boundaries and to the direction of the axons of the striato-pallidonigral bundle. All the brains, humans and macaques, were sectioned according to the same ventricular planes. The striatal bundle is made up of dense fascicles of very thin parallel axons. Sixty neurons located in the pars reticulata, lateralis, and compacta were reconstructed from serial sections. In the anterior pars reticulata and lateralis, the dendritic arborizations spread in all directions inside the striatal bundle. Below the pars compacta fringes, the dendrites of pars reticulata neurons extend ventrolaterally in the bundle. Because one nigral arborization can cover the whole thickness of the striatal bundle, we are led to believe that nigral neurons exert a role of convergence of the corticostriatal information similar to that of pallidal neurons (Percheron et al., '84a,b). The pars reticulata neurons appear to receive information mainly from the associative striatal territory. The pars lateralis neurons, conversely, appear to receive information from the sensorimotor territory. The anterior pars compacta neurons are organized in such a way that their ventral dendrites, located inside the pars reticulata, are ventrolaterally oriented, perpendicular to the striatal bundle. Their dorsal dendrites remaining in the pars compacta can receive other input. At more caudal levels, the posterior pars compacta neurons have dendrites radiating outside the striatal bundle.