Double dissociation of function within the hippocampus: a comparison of dorsal, ventral, and complete hippocampal cytotoxic lesions

Rats with complete cytotoxic hippocampal lesions exhibited spatial memory impairments in both the water maze and elevated T maze. They were hyperactive in photocell cages; swam faster in the water maze; and were less efficient on a nonspatial, differential reinforcement of low rates (DRL) task. Performance on both spatial tasks was also impaired by selective dorsal but not ventral lesions; swim speed was increased by ventral but not dorsal lesions. Both partial lesions caused a comparable reduction in DRL efficiency, although these effects were smaller than those of complete lesions. Neither partial lesion induced hyperactivity when rats were tested in photocell cages, although both complete and ventral lesion groups showed increased activity after footshock in other studies (Richmond et al., 1999). These results demonstrate possible functional dissociations along the septotemporal axis of the hippocampus.     

Two forms of spatial memory: a double dissociation between the parietal cortex and the hippocampus in the rat

Two variants of a continuous recognition training procedure were designed in order to query 2 forms of spatial memory. A continuous reinforcement condition (reflecting perceptual memory) and a differential reinforcement condition (reflecting episodic-like memory) were used to test rats on a 12-arm radial maze. After total hippocampal lesions, rats demonstrated intact performance on the continuous reinforcement condition, but impaired performance on the differential reinforcement condition. After parietal lesions, rats demonstrated the reverse pattern of performance: impaired performance on the continuous reinforcement condition and intact performance on the differential reinforcement condition. Thus, a double dissociation appears to exist between parietal cortex and hippocampus for the continuous reinforcement condition (reflecting perceptual memory) versus the differential reinforcement condition (reflecting episodic memory) for spatial location information.     

Dissociation of function within the hippocampus: effects of dorsal, ventral and complete excitotoxic hippocampal lesions on spatial navigation

The present study was designed to assess the possibility that sub-total ventral hippocampal lesions might leave intact a mechanism for only highly accurate navigation, whereas sub-total dorsal hippocampal lesions might leave intact a mechanism only for less precise navigation. Animals with selective dorsal, ventral or complete hippocampal lesions were tested in a water maze, in which the target platform was moved from trial to trial, but always within a defined area, instead of being at a fixed location. Hence, an animal that searched at exactly the point where the platform had been found on a previous trial would be disadvantaged, in comparison with an animal that searched in the right general area. This might favor animals capable of less precise navigation over those with very precise navigational abilities. In subsequent phases of the experiment, we additionally assessed, for comparison, performance with a fixed platform location, reversal learning in the water-maze, and performance on an elevated T-maze. Our results revealed no sign of any qualitative difference between the effects of the selective sub-total lesions when the water maze hidden platform location was varied within the defined area, and the effects in subsequent more conventionally used tests. Ventral hippocampal damage never led to a performance deficit. Dorsal hippocampal damage led to significantly poorer performance in only some test phases, and never led to any sign of improved performance.     

Kindling of the hippocampus induces spatial memory deficits in the rat

Since kindling produces electrophysiological and morphological changes in the brain area stimulated, it may well affect behavioural functions dependent on the kindled area. Using an 8-arm maze, it was found that hippocampal kindling can induce specific memory deficits in spatial tasks. Reference (long-term) memory as well as working (short-term) memory were impaired. The largest impairment was observed during the period in which generalized convulsions occurred. Working memory but not reference memory impairment was reversible. Hippocampal kindling may be a useful experimental model for investigating behavioural deficits correlated with epileptogenesis.     

Valproic acid reduces spatial working memory and cell proliferation in the hippocampus

Valproic acid (VPA) is widely used clinically, as an anticonvulsant and mood stabilizer but is, however, also known to block cell proliferation through its ability to inhibit histone deacetylase enzymes. There have been a number of reports of cognitive impairments in patients taking VPA. In this investigation we examined the relationship between cognition and changes in cell proliferation within the hippocampus, a brain region where continued formation of new neurons is associated with learning and memory. Treatment of rats by i.p. injection of VPA, reduced cell proliferation in the sub granular zone of the dentate gyrus within the hippocampus. This was linked to a significant impairment in their ability to perform a hippocampus-dependent spatial memory test (novel object location). In addition, drug treatment caused a significant reduction in brain-derived neurotrophic factor (BDNF) and Notch 1 but not doublecortin levels within the hippocampus. These results support the idea that VPA may cause cognitive impairment and provide a possible mechanism for this by reducing neurogenesis within the hippocampus.     

The ventral hippocampus is necessary for expressing a spatial memory

Current views posit the dorsal hippocampus (DHipp) as contributing to spatial memory processes. Conversely, the ventral hippocampus (VHipp) modulates stress, emotions and affects. Arguments supporting this segregation include differences in (i) connectivity: the DHipp is connected with the entorhinal cortex which receives visuospatial neocortical inputs; the VHipp is connected with both the amygdala and hypothalamus, (ii) electrophysiological characteristics: there is a larger proportion of place cells in the DHipp than in the VHipp, and an increasing dorsoventral gradient in the size of place fields, suggesting less refined spatial coding in the VHipp, and (iii) consequences of lesions: spatial memory is altered after DHipp lesions, less dramatically, sometimes not, after VHipp lesions. Using reversible inactivation, we report in rats, that lidocaine infusions into the DHipp or VHipp right before a probe trial impair retrieval performance in a water-maze task. This impairment was found at two post-acquisition delays compatible with recent memory (1 and 5 days). Pre-training blockade of the VHipp did not prevent task acquisition and drug-free retrieval, on the contrary to pre-training blockade of DHipp, which altered performance in a subsequent drug-free probe trial. Complementary experiments excluded possible locomotor, sensorimotor, motivational or anxiety-related biases from data interpretation. Our conclusion is that a spatial memory can be acquired with the DHipp, less efficiently with the VHipp, and that the retrieval of such a memory and/or the expression of its representation engages the dorsoventral axis of the hippocampus when the task has been learnt with an entirely functional hippocampus.     

Single unit activity in the rat hippocampus during a spatial memory task

Summary Single unit activity was recorded from complex spike cells in the hippocampus of the rat while the animal was performing a spatial memory task. The task required the animal to choose the correct arm of a 4 arm plus-shaped maze in order to obtain reward. The location of the goal arm was varied from trial to trial and was identified by 6 controlled spatial cues which were distributed around the enclosure and which were rotated in step with the goal. On some trials these spatial cues were present throughout the trial (spatial reference memory trials) while on other trials they were present during the first part of the trial but were removed before the rat was allowed to choose the goal (spatial working memory trials). On these latter trials the animal had to remember the location of the cues and/or goal during the delay in order to choose correctly. 55 units were recorded during sufficient reference memory trials for the relationship between their firing pattern and different spatial aspects of the environment to be determined. 33 units had fields with significant relations to the controlled cues while 16 had significant relations to the static background cues, those cues in the environment which did not change position from trial to trial. Of 43 units which could be tested for their relation to the shape of the maze arms themselves, 15 showed such a relationship. Therefore the place units can be influenced by different aspects of the spatial environment but those related to the task requirement appear to be more potent. Interaction effects between the different spatial factors also influenced the firing pattern of some units. Of particular interest was the interaction between the controlled cues and the static background cues found in some cells since this might shed some light on how the hippocampus enables the rat to solve the memory task. 30 units with place fields related to the controlled cues were recorded during successful performance on spatial working memory trials as well as during spatial reference memory trials. The place fields of 90% of these units were maintained during the retention phase of the memory trials. During the recording of some units, other types of trial were given as well. On control trials, the cues were removed before the rat was placed on the maze. These trials provided controls for the potential influence of information left behind by the controlled cues and for the influence of the animal's behaviour on the unit activity. They also provided information about the unit firing in the absence of the controlled spatial cues and about the animal's choice of goal under these circumstances. During control trials, the units typically maintained their place fields but these fields had no relation to the experimenter-defined goal. The rat's choice of goal arm at the end of the trial, however, continued to show the usual spatial relationship to the fields. The data from these control trials, taken together with the interaction between the controlled cues and the static background cues seen in some of the cells and the characteristic mistakes made by each rat, suggest that the animal enters the task on each trial with an expected or preferred orientation of the controlled spatial cues relative to the background cues and that it must reorient its cognitive map of the environment or search for a different map when the actual orientation of the controlled cues departs from this default condition. Detour trials differed from working memory trials in that the animal was not immediately allowed to choose the goal at the end of the retention period but was forced to enter a non-goal arm instead. These trials ruled out the possibility that the animal was remembering the specific turn required to reach the goal and demonstrated that the place fields for the entire maze are set up as a result of exposure to the controlled spatial cues in any one of the start arms. Overall, the results provide strong support for the cognitive map theory of hippocampal function. In particular, they demonstrate that the representations of places within an environment are connected together to form a map, that the orientation of this map relative to an environment can be changed from trial to trial, and that this orientation is remembered following the removal of the controlled spatial cues.     

Relationship between hyponeophagia and adrenal cortex function in farmed foxes

The adrenal cortex function of farmed blue (Alopex lagopus) and silver foxes (Vulpes vulpes) differing in their reaction in the feeding test were assessed. The urine cortisol:creatinine ratio was lower for those animals eating in the feeding test in comparison to those not eating in both species. In addition, eater silver foxes had lower baseline serum cortisol concentration and also lower serum cortisol concentration 2 h after ACTH administration than noneaters. There were no differences in any serum cortisol levels between the eater and noneater blue foxes. The weights of body and adrenals did not differ between confident and fearful animals in either species. The present study demonstrates that animals not eating in the feeding test may have higher fearfulness and be more stressed than animals eating.     

Double dissociation of configural and featural face processing on P1 and P2 components as a function of spatial attention

Face recognition relies on both configural and featural processing. Previous research has shown that P1 is sensitive to configural face processing, but it is unclear whether any component is sensitive to featural face processing; moreover, if there is such a component, its temporal sequence relative to P1 is unknown. Thus, to avoid confounding physical stimuli differences between configural and featural face processing on ERP components, a spatial attention paradigm was employed by instructing participants to attend an image stream (faces and houses) or an alphanumeric character stream. The interaction between attention and face processing type on P1 and P2 components indicates different mechanisms of configural and featural face processing as a function of spatial attention. The steady‐state visual evoked potential (SSVEP) results clearly demonstrated that participants could selectively attend to different streams of information. Importantly, configural face processing elicited a larger posterior P1 (approximately 128 ms) than featural face processing, whereas P2 (approximately 248 ms) was greater for featural than for configural face processing under attended condition. The interaction between attention and face processing type (configural vs. featural) on P1 and P2 components indicates that there are different mechanisms of configural and featural face processing operating as functions of spatial attention. While the P1 result confirms previous findings separating configural and featural face processing, the newly observed P2 finding in the present study extends this separation to a double dissociation. Therefore, configural and featural face processing are modulated differently by spatial attention, and configural face processing precedes featural face processing.     

Episodic memory and the hippocampus: another view

A popular view of the function of the hippocampus maintains that this structure temporarily encodes the neocortical representation of the experience of an episode. It uses the encoding to recreate repeatedly the neocortical representation. It is said that in time the episodic memory becomes consolidated in the neocortex and can be retrieved independent of the hippocampus. This paper is critical of that view and begins by raising four concerns. These include a question of how the hippocampus could encode the rich complexity of neocortical representations in sufficient detail to recreate them. And it observes that some data indicate episodic memories remain dependent on the hippocampus for life. Another view of hippocampal function is presented which addresses these concerns. Basically, this view hypothesizes that the ability to retrieve episodic memories involves the interplay between two modes of hippocampal function. Processes during the theta mode facilitate the development of context memory in the hippocampus and the registration of unique events in the neocortex, but block the influence of context memory upon the neocortex. By contrast, during the non-theta mode, context memory is projected onto the neocortex, creating a contextual framework. It is proposed that the ability to retrieve memory of episodes depends on the development, through contiguity, of associations between the representation of the episode (created during theta) and a contextual framework (evoked during non-theta). From this perspective, the episode does not need to be encoded in the hippocampus, but remains dependent indefinitely on associations formed between the episodic memory in the neocortex and a context memory maintained in hippocampal structures. However, for the associations that enable retrieval to form, the creation of the representation of an episode during theta must be followed quickly by the evocation of a contextual framework. During an extended period of the theta mode as occurs during REM sleep dreaming, these associations cannot usually be formed, resulting in amnesia for most dreams.     

The ventral hippocampus supports a memory representation of context and contextual fear conditioning: implications for a unitary function of the hippocampus

The authors report that either inactivating the ventral hippocampus (VH) with muscimol prior to context preexposure or injecting anisomycin into the VH after preexposure significantly impaired rats' memory for context. Injecting anisomycin into the VH prior to contextual fear conditioning also greatly reduced long-term memory (48-hr retention test) but had no effect on short-term memory (1-hr retention test) for contextual fear. Together with other results, these data suggest that the memory for a novel context is distributed throughout the longitudinal extent of the hippocampus and that this representation helps to support contextual fear conditioning.     

Serotonin and acetylcholine release response in the rat hippocampus during a spatial memory task.

By using in vivo microdialysis we monitored the extracellular levels of acetylcholine and serotonin in the hippocampus of rats performing a spatial memory task. After rats were trained for 10 consecutive days to master a food-reinforced radial-arm maze task, they were implanted with a microdialysis probe in the dorsal hippocampus. On day 12, rats were tested in the maze and acetylcholine and serotonin outputs were monitored before the test, during the waiting phase and while performing the trials. In trained, food-rewarded rats, hippocampal acetylcholine levels increased during the waiting period (181 +/- 90 of baseline) and further increased during the radial-maze performance to 236 +/- 13% of baseline values, while serotonin levels did not change during the waiting period but increased to 142 +/- 3% during the maze performance. To discriminate whether the increase of acetylcholine and serotonin levels during the testing was associated with memory performance or with food consumption, we monitored hippocampal acetylcholine and serotonin release in rats that were trained, but not food rewarded, or in rats that were not trained, but rewarded only on the test day. In the trained, non-rewarded group, acetylcholine release increased during the waiting phase to 168 +/- 6%, but did not increase further during the task performance. In contrast, no change in serotonin release was observed in this group in any phase of the test. In rats which were not trained, but food rewarded, acetylcholine increased only during the maze period (150 +/- 5%). Serotonin increased gradually and become significant at the end of the trials. (130 +/- 3%). While both neurotransmitters could be implicated in feeding behaviour, only activation of cholinergic neurotransmission appears to be associated with memory function. Our results support the following hypotheses: (i) hippocampal acetylcholine could be involved in attentional and cognitive functions underlying motivational processes; (ii) serotonin could be implicated in non-cognitive processes (i.e. in the control of motor and feeding behaviour). Since serotonin and acetylcholine neurotransmission is simultaneously activated during the spatial memory task, this suggests that these neurotransmitter systems regulate behavioural and cognitive functions.     

The functional cooperation of the hippocampus and anterior thalamus via the fimbria-fornix in spatial memory in rats

This study examined whether the cooperation of the hippocampus, and anterior thalamus via the fimbria-fornix is involved in the spatial memory. We compared the effect of contralateral lesions (Contra) with ipsilateral lesions (Ipsi) of the fimbria-fornix and anterior thalamus on the performance of an object exploration task and the Morris water maze task. If the hippocampus and anterior thalamus take part in a same functional system via fornix, the performance of Contra group will be more disruptive than that of Ipsi group. In the object exploration task, Contra and Ipsi groups did not differ from Control group in the performance of object recognition test. However, the performance of Contra group was significantly impaired in the spatial recognition test, compared with two other groups. In the Morris water maze task, only Contra group showed deficits in spatial learning but not the Ipsi group. These results indicate that contralateral, but not ipsilateral lesion caused deficits in spatial memory, supporting the notion that the functional cooperation of hippocampus and anterior thalamus via fornix is vital for spatial memory.     

The effects of two-stage carotid occlusion on spatial memory and pro-inflammatory markers in the hippocampus of rats

The purpose of this study was to evaluate the effects of cerebral hypoperfusion on cognitive ability, TNFα, IL1β and PGE2 levels in both hippocampi in a modified two-vessel occlusion model. Both common carotid arteries of adult male Wistar rats were permanently occluded with an interval of 1 week between occlusions. Learning and memory were significantly decreased after 1 month. This reduction was not significant after 2 months, which may be attributed to blood flow compensation. The TNFα level was significantly increased after 3 h and 1 day. IL1β was significantly increased after 1 day. After a week there was no significant difference in pro-inflammatory levels. Furthermore, there was no difference between right and left hippocampi. It is possible that TNFα and IL1β elevation initiates pathologic processes that contribute to memory impairment.     

Localization of function within the dorsal hippocampus: the role of the CA3 subregion in paired-associate learning

Computational models and electrophysiological data suggest that the CA3 subregion of the hippocampus supports the formation of arbitrary associations; however, no behavioral studies have been conducted to test this hypothesis. Rats with neurotoxin-induced lesions of dorsal dentate gyrus (DG), CA3, or CA1 were tested on object-place and odor-place paired-associate tasks to test whether the mechanism that supports paired-associate learning is localized to the CA3 subregion of the dorsal hippocampus or whether all hippocampal subregions contribute to paired-associate learning. The data indicate that rats with DG or CA1 lesions learned the tasks as well as controls; however, CA3-lesioned rats were impaired in learning the tasks. Thus, the CA3 subregion of the dorsal hippocampus contains a mechanism to support paired-associate learning.     

Role of noradrenergic function in the opiate antagonist facilitation of spatial memory

Animals previously trained to criterion on an eight-arm radial maze task received either bilateral 6-hydroxydopamine lesions of the dorsal noradrenergic bundle (DNB) or control surgery. Following a 3-week recovery period, the animals were trained on the same radial maze in two novel environments. By a within-subjects design, in one of these environments animals received posttraining systemic treatment with the opiate antagonist naloxone; in the other novel environment, they received vehicle injection. In animals that received control surgery, opiate antagonist treatment produced a reliable enhancement of performance. Although the DNB-lesion animals did not differ from the control-surgery animals under the saline treatment condition, denervation of forebrain norepinephrine (NE) was found to prevent the memory enhancing effect of posttraining naloxone administration. These results provide further support that enhanced retention obtained with opiate antagonist administration is dependent upon intact NE function.     

Amplitude spectrum EEG signal evidence for the dissociation of motor and perceptual spatial working memory in the human brain

This study investigated the question whether spatial working memory related to movement plans (motor working memory) and spatial working memory related to spatial attention and perceptual processes (perceptual spatial working memory) share the same neurophysiological substrate or there is evidence for separate motor and perceptual working memory streams of processing. Towards this aim, ten healthy human subjects performed delayed responses to visual targets presented at different spatial locations. Two tasks were attained, one in which the spatial location of the target was the goal for a pointing movement and one in which the spatial location of the target was used for a perceptual (yes or no) change detection. Each task involved two conditions: a memory condition in which the target remained visible only for the first 250 ms of the delay period and a delay condition in which the target location remained visible throughout the delay period. The amplitude spectrum analysis of the EEG revealed that the alpha (8–12 Hz) band signal was smaller, while the beta (13–30 Hz) and gamma (30–45 Hz) band signals were larger in the memory compared to the non-memory condition. The alpha band signal difference was confined to the frontal midline area; the beta band signal difference extended over the right hemisphere and midline central area, and the gamma band signal difference was confined to the right occipitoparietal area. Importantly, both in beta and gamma bands, we observed a significant increase in the movement-related compared to the perceptual-related memory-specific amplitude spectrum signal in the central midline area. This result provides clear evidence for the dissociation of motor and perceptual spatial working memory.     

Movement preparation and working memory: a behavioural dissociation

We can cross temporal sensorimotor contingencies by remembering sensory events or by anticipating motor responses. Here we tested the hypothesis that sensory and motor representations can be accessed according to different temporal dynamics. We predicted that the manipulation of movement representations would lead to a performance independent from the length of a delay interposed between sensory instructions and behavioural responses. Conversely, we expected a delay-dependent performance whenever temporary storage of sensory information was necessary to solve the task. We have measured reaction times and error rate in subjects performing a delayed non-matching to sample task. Task contingencies rather than explicit instructions ensured that either sensory or motor representations were used to cross the delay period on each trial. We tested our hypothesis by manipulating the length of the delays between stimulus presentation and behavioural response. We found that carrying sensory material over temporal gaps affects performance as a non-linear function of time, whereas movement representations remain robust over a wide range of delays. This novel behavioural paradigm might prove effective in dissociating the neural bases of preparatory and mnestic processes in normal human subjects, as well as their disorders in neurological patients.