Role of CA3 and CA1 subregions of the dorsal hippocampus on temporal processing of objects

Previous research in the dorsal CA1 and dorsal CA3 subregions of the hippocampus has been shown to play an important role in mediating temporal order memory for spatial location information. What is not known is whether the dorsal CA3 and dorsal CA1 subregions of the hippocampus are also involved in temporal order for visual object information. Rats with dorsal CA1, dorsal CA3 or control lesions were tested in a temporal order task for visual objects using an exploratory paradigm. The results indicated that the controls and the dorsal CA3 lesioned rats preferred the first rather then the last object they had explored previously, indicating good memory for temporal order of object presentation. In contrast, rats with dorsal CA1 lesions displayed a profound deficit in remembering the order of the visual object presentations in that they preferred the last object rather than the first. All three groups of rats preferred a novel object compared to a previously explored object suggesting normal detection of visual object novelty. The results suggest that only the dorsal CA1, but not dorsal CA3, region is critical for processing temporal information for visual objects without affecting the detection of new visual objects.     

Electrolytic lesions of dorsal CA3 impair episodic-like memory in rats

Episodic memory is the ability to recollect one's past experiences occurring in an unique spatial and temporal context. In non-human animals, it is expressed in the ability to combine "what", "where" and "when" factors to form an integrated memory system. During the search for its neural substrates, the hippocampus has attracted a lot of attentions. Yet, it is not yet possible to induce a pure episodic-like memory deficit in animal studies without being confounded by impairments in the spatial cognition. Here, we present a lesion study evidencing direct links between the hippocampus CA3 region and the episodic-like memory in rats. In a spontaneous object exploration task, lesioned rats showed no interaction between the temporal and spatial elements in their memory associated with the objects. In separate tests carried out subsequently, the same animals still expressed abilities to process spatial, temporal, and object recognition memory. In conclusions, our results support the idea that the hippocampus CA3 has a particular status in the neural mechanism of the episodic-like memory system. It is responsible for combining information from different modules of cognitive processes.     

Differential induction of c-Jun and Fos-like proteins in rat hippocampus and dorsal striatum after training in two water maze tasks

Research examining the neuroanatomical bases of memory in mammals suggests that the hippocampus and dorsal striatum are parts of independent memory systems that mediate "cognitive" and stimulus-response "habit" memory, respectively. At the molecular level, increasing evidence indicates a role for immediate early gene (IEG) expression in memory formation. The present experiment examined whether acquisition of cognitive and habit memory result in differential patterns of IEG protein product expression in these two brain structures. Adult male Long-Evans rats were trained in either a hippocampal-dependent spatial water maze task, or a dorsal striatal-dependent cued water maze task. Ninety minutes after task acquisition, brains were removed and processed for immunocytochemical procedures, and the number of cells expressing Fos-like immunoreactivity (Fos-like-IR) and c-Jun-IR in sections from the dorsal hippocampus and the dorsal striatum were counted. In the dorsal hippocampus of rats trained in the spatial task, there were significantly more c-Jun-IR pyramidal cells in the CA1 and CA3 regions, relative to rats that had acquired the cued task, yoked controls (free-swim), or na?ve (home cage) rats. Relative to rats receiving cued task training and control conditions, increases in Fos-like IR were also observed in the CA1 region of rats trained in the spatial task. In rats that had acquired the cued task, patches of c-Jun-IR were observed in the posteroventral striatum; no such patches were evident in rats trained in the spatial task, yoked-control rats, or na?ve rats. The results demonstrate that IEG protein product expression is up-regulated in a task-dependent and brain structure-specific manner shortly after acquisition of cognitive and habit memory tasks.     

Disconnection analysis of CA3 and DG in mediating encoding but not retrieval in a spatial maze learning task

The dentate gyrus (DG) subregion of the hippocampus has been shown to be involved in encoding but not retrieval in a spatial maze task (modified Hebb-Williams maze). The first experiment in this study examined whether a lesion to the CA3 would contribute to a similar encoding deficit. A DG group was included in order to replicate previous results. Relative to controls, animals receiving CA3 lesions were impaired in encoding, not retrieval, on the modified Hebb-Williams maze--similar to a group that received DG lesions. This suggests the possibility that CA3 and DG are working together to mediate encoding processes. The second experiment in this study was designed to test the interaction between CA3 and DG using a disconnection paradigm. Animals with contralateral lesions (CA3 lesioned in one hemisphere, DG lesioned in the other hemisphere) showed a significant disruption effect on encoding, but not retrieval, when compared with animals with ipsilateral lesions (CA3 and DG lesioned in the same hemisphere, leaving the other hemisphere intact). This suggests an interaction between CA3 and DG in supporting encoding but not retrieval processes in a spatial maze learning task.     

Memory for frequency in rats: role of the hippocampus and medial prefrontal cortex

On a radial arm maze rats were tested for frequency memory of specific spatial locations, a task that presumably involves the coding of temporal information. On any trial during the study phase rats were allowed to visit three different spatial locations only once and one spatial location twice. During the test phase the rats were given a choice between a spatial location that had been visited once and spatial location that had been visited twice. The rats were reinforced for selecting the twice-visited spatial location. The number of spatial locations between a repetition (lag) was varied from one to three. After extensive training rats displayed memory for frequency only for a lag of three spatial locations, i.e., they displayed a repetition lag effect. Animals then received control, medial prefrontal cortex, or hippocampal lesions. Upon subsequent retests control rats continued to display frequency memory, but animals with medial prefrontal cortex or hippocampal lesions displayed a marked impairment. These data support the idea that both the hippocampus and medial prefrontal cortex code temporal order information.     

NMDA signaling in CA1 mediates selectively the spatial component of episodic memory

Recent studies focusing on the memory for temporal order have reported that CA1 plays a critical role in the memory for the sequences of events, in addition to its well-described role in spatial navigation. In contrast, CA3 was found to principally contribute to the memory for the association of items with spatial or contextual information in tasks focusing on spatial memory. Other studies have shown that NMDA signaling in the hippocampus is critical to memory performance in studies that have investigated spatial and temporal order memory independently. However, the role of NMDA signaling separately in CA1 and CA3 in memory that combines both spatial and temporal processing demands (episodic memory) has not been examined. Here we investigated the effect of the deletion of the NR1 subunit of the NMDA receptor in CA1 or CA3 on the spatial and the temporal aspects of episodic memory, using a behavioral task that allows for these two aspects of memory to be evaluated distinctly within the same task. Under these conditions, NMDA signaling in CA1 specifically contributes to the spatial aspect of memory function and is not required to support the memory for temporal order of events.     

Evidence for the substantia nigra pars compacta as an essential component of a memory system independent of the hippocampal memory system

The aim of the present study was to test if the nigrostriatal pathway is an essential component for a water maze cued task learning and if it works independently of the hippocampal memory system. This hypothesis was tested using an animal model of Parkinson's disease in which male Wistar rats were lesioned in the substantia nigra pars compacta (SNc) by the intranigral infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), thus causing a partial depletion of striatal dopamine. SNc-lesioned and sham-operated animals were implanted bilaterally with guide cannulae above the dorsal hippocampus in order to be tested after the administration of 0.4 microl 2% lidocaine or saline into this structure. The animals were tested in a spatial or in a cued version of the water maze, memory tasks previously reported to model hippocampal-dependent spatial/relational and striatal-dependent S-R learning, respectively. Hippocampal inactivation, but not SNc lesion, impaired learning and memory in the spatial version of the water maze. An opposite situation was observed with the cued version. No significant interaction was observed between the SNc lesion and hippocampal inactivation conditions affecting scores in the spatial or in the cued version of the water maze. These results suggest that the nigrostriatal pathway is an essential part of the memory system that processes S-R learning and that it works independently of the hippocampal memory system that processes spatial/relational memories.     

Behavioral characterization of a transection of dorsal CA3 subcortical efferents: comparison with scopolamine and physostigmine infusions into dorsal CA3

Cholinergic projections from the medial septum and diagonal band of Broca into the hippocampus have long been implicated in learning and memory. Projections from CA3 to neurons in the medial septum and the diagonal band of Broca have been anatomically characterized. The present experiments were designed to evaluate interactions between the dorsal CA3 subcortical efferents and the cholinergic efferents from the medial septum and diagonal band of Broca for spatial and nonspatial (visual object) novelty detection in the rat. In Experiment 1, physostigmine and scopolamine (both 0.4 microL at 30 microM) were infused into dorsal CA3 and animals were tested on a spatial and nonspatial (visual object) novelty detection paradigm. Scopolamine infusions into dorsal CA3 caused deficits for both spatial and nonspatial (visual object) novelty detection. Physostigmine infusions into dorsal CA3 enhanced both spatial and nonspatial (visual object) novelty detection. These data support models proposing that acetylcholine may control the dynamics for encoding, consolidation, and retrieval in the hippocampus. In Experiment 2, a selective transection of dorsal CA3 efferents in the fimbria resulted in deficits for spatial and nonspatial (visual object) novelty detection. These deficits were similar to the deficits caused by scopolamine infusions into dorsal CA3. These data demonstrate that dorsal CA3 and the medial septum/diagonal band of Broca interact, and that dorsal CA3 influences cholinergic inputs into the hippocampus to facilitate encoding.     

记忆过程中海马CA1区神经元的集群放电特征

观察空间工作记忆过程中海马CA1区神经元群的放电特征。应用多通道神经元集群放电记录技术, 同步观察和记录清醒大鼠在执行延迟选择任务时的行为轨迹以及海马CA1区神经元的放电活动。发现：海马CA1区位置细胞的位置野是在学习过程中逐渐形成并可消退; 部分位置细胞的放电对未来目标定向性行为具有预测作用; 在空间工作记忆过程中, 神经元放电之间的相关性加强, 神经元之间以及神经元与局部场电位之间存在相位编码方式。结果提示海马CA1区神经元参与对空间信息的初级编码和加工, 并为未来行为决策提供有效信息, 而且海马对信息的加工是通过局部神经网络进行, 时间编码可能是海马信息加工的重要方式之一。     

Reversible hippocampal lesions disrupt water maze performance during both recent and remote memory tests

Conventional lesion methods have shown that damage to the rodent hippocampus can impair previously acquired spatial memory in tasks such as the water maze. In contrast, work with reversible lesion methods using a different spatial task has found remote memory to be spared. To determine whether the finding of spared remote spatial memory depends on the lesion method, we reversibly inactivated the hippocampus with lidocaine either immediately (0-DAY) or 1 mo (30-DAY) after training in a water maze. For both the 0-DAY and 30-DAY retention tests, rats that received lidocaine infusions exhibited impaired performance. In addition, when the 0-DAY group was retested 2 d later, (when the drug was no longer active), the effect was reversed. That is, rats that had previously received lidocaine performed as well as control rats did. These findings indicate that the rodent hippocampus is important for both recent and remote spatial memory, as assessed in the water maze. What determines whether remote spatial memory is preserved or impaired following disruption of hippocampal function appears to be the type of task used to assess spatial memory, not the method used to disrupt the hippocampus.     

Behavioral functions of the CA3 subregion of the hippocampus

From a behavioral perspective, the CA3a,b subregion of the hippocampus plays an important role in the encoding of new spatial information within short-term memory with a duration of seconds and minutes. This can easily be observed in tasks that require rapid encoding, novelty detection, one-trial short-term or working memory, and one-trial cued recall primarily for spatial information. These are tasks that have been assumed to reflect the operations of episodic memory and require interactions between CA3a,b and the dentate gyrus via mossy fiber inputs into the CA3a,b. The CA3a,b is also important for encoding of spatial information requiring multiple trials including the acquisition of arbitrary and relational associations. These tasks tend to be non-episodic and can be mediated by arbitrary and conjunctive operations. All these tasks are assumed to operate within an autoassociative network function of the CA3 region. The output from CA3a,b via the fimbria and the medial and lateral perforant path inputs play a supporting role in the neural circuit that supports the operation of these tasks. The CA3a,b also plays a role in sequential processing of information in cooperation with CA1 based on the Schaffer collateral output from CA3a,b to CA1. The CA3a,b also supports retrieval of short-term memory information based on a spatial pattern completion process. Finally, CA3c may, in cooperation with the dentate gyrus, serve an important role in processing the geometry of the environment.     

Involvement of the hippocampal CA3-region in acquisition and in memory consolidation of spatial but not in object information in mice

This study investigates the implication of the hippocampal CA3-region in the different phases of learning and memory in spatial and non-spatial tasks. For that purpose, we performed focal injections of diethyldithiocarbamate (DDC) into the CA3-region of the dorsal hippocampus. The DDC chelates most of the heavy metals in the brain which blocks selectively and reversibly the synapses containing heavy metals, i.e., the mossy fibres synaptic buttons and synapses of the dendrites of pyramidal cells. The effects of temporal inactivation of the CA3-region was examined in a non-associative task, the spatial open-field, designed to estimate the ability of mice to react to spatial changes, and in the object recognition task, designed to estimate the ability of mice to identify a familiar object. The results show that DDC induced a specific impairment on learning and memory consolidation in the spatial open-field but had no effect on recall in this task. In the object recognition task, DDC did not induce any impairment in the different phases of learning and memory. These data demonstrate that the hippocampal CA3-region is specifically implicated in spatial information processing and seems to be involved not only in acquisition but also in consolidation of spatial information.     

Perirhinal cortex lesions produce retrograde amnesia for spatial information in rats: consolidation or retrieval?

Several lines of evidence in humans and experimental animals suggest that the hippocampus is critical for the formation and retrieval of spatial memory. However, although the hippocampus is reciprocally connected to adjacent cortices within the medial temporal lobe and they, in turn, are connected to the neocortex, little is known regarding the function of these cortices in memory. Here, using a reference spatial memory task in the radial maze, we show that neurotoxic perirhinal cortex lesions produce a profound retrograde amnesia when learning-surgery intervals of 1 or 50 d are used (Experiment 1). With the aim of dissociating between consolidation and retrieval processes, we injected lidocaine either daily after training (Experiment 2) or before a retention test once the learning had been completed (Experiment 3). Results show that reversible perirhinal inactivation impairs retrieval but not consolidation. However, the same procedure followed in Experiment 2 disrupted consolidation when the lidocaine was injected into the dorsal hippocampus. The results of Experiment 4 rule out the possibility that the deficit in retrieval is due to a state-dependent effect. These findings demonstrate the differential contribution of various regions of the medial temporal lobe to memory, suggesting that the perirhinal cortex plays a key role in the retrieval of spatial information for a long period of time.     

Locomotor, avoidance,and maze behavior in rats with selective disruption of hippocampal output.

Behavioral correlates of selective disruption of hippocampal output were investigated in a series of five experiments. In two experiments an attempt was made through behavioral investigation to determine whether the CA1 neurons project to the fimbria or to the subiculum. The results supported recent views that the subiculum is the recipient of CA1 axons. Disruption of the CA1 output in the dorsal hippocampus of rats produced increased open-field activity, whereas passive avoidance and spontaneous alternation behaviors remained unchanged. No differentiation was obtained between CA1 damage and neocortical lesions in maze learning. Blocking of the fimbrial CA3 output from the dorsal hippocampus improved passive avoidance performance and impaired active avoidance performance, whereas open-field and spontaneous alternation behaviors were unaffected. Interruption of the CA3 output from the ventral hippocampus improved active avoidance performance and reduced spontaneous alternation behavior. Open-field behavior and passive avoidance performance remained unchanged. Total fimbrial sections increased open-field activity, improved passive and active avoidance, and reduced spontaneous alternation. The results are discussed in terms of functional differentiation between the CA1 and CA3 of the dorsal hippocampus and in terms of functional differences in the fimbrial CA3 output from the dorsal and ventral hippocampus.     

Hippocampal CA1 spiking during encoding and retrieval: relation to theta phase

The hippocampal theta rhythm is a prominent oscillation in the field potential observed throughout the hippocampus as a rat investigates stimuli in the environment. A recent computational model [Hasselmo, M. E., Bodelon, C., & Wyble, B. P. (2002a). A proposed function for hippocampal theta rhythm: separate phases of encoding and retrieval enhance reversal of prior learning. Neural Computation, 14, 793-817. Neuromodulation, theta rhythm and rat spatial navigation. Neural Networks, 15, 689-707] suggested that the theta rhythm allows the hippocampal formation to alternate rapidly between conditions that promote memory encoding (strong synaptic input from entorhinal cortex to areas CA3 and CA1) and conditions that promote memory retrieval (strong synaptic input from CA3 to CA1). That model predicted that the preferred theta phase of CA1 spiking should differ for information being encoded versus information being retrieved. In the present study, the spiking activity of CA1 pyramidal cells was recorded while rats performed either an odor-cued delayed nonmatch-to-sample recognition memory test or an object recognition memory task based on the animal's spontaneous preference for novelty. In the test period of both tasks, the preferred theta phase exhibited by CA1 pyramidal cells differed between moments when the rat inspected repeated (match) and non-repeated (nonmatch) items. Also in the present study, additional modeling work extended the previous model to address the mean phase of CA1 spiking associated with stimuli inducing varying levels of retrieval relative to encoding, ranging from novel nonmatch stimuli with no retrieval to highly familiar repeated stimuli with extensive retrieval. The modeling results obtained here demonstrated that the experimentally observed phase differences are consistent with different levels of CA3 synaptic input to CA1 during recognition of repeated items.     

Hippocampal expression of the orphan nuclear receptor gene hzf-3/nurr1 during spatial discrimination learning

The immediate-early gene hzf-3, also known as nurr1, is a member of the inducible orphan nuclear receptor family and is one candidate in the search for genes associated with learning and memory processes. Here we report that acquisition of a spatial food search task is accompanied by elevated levels of hzf-3 mRNA in the hippocampus. Adult male Long-Evans rats were handled, food-restricted, and allowed to habituate to the maze prior to training. During acquisition, rats were given one training session per day for 5 days. Each training session consisted of five trials in which animals searched the maze for food located in 4 of 16 holes in the floor of the maze. Training resulted in spatial acquisition of the task. Northern blot analysis showed significant increases in hippocampal hzf-3 mRNA 3 h after training in the maze. Next, brains were obtained from Naive, Habituated, Day 1, Day 3, and Day 5 animals and processed for in situ hybridization. The results showed significant increases of hzf-3 mRNA in CA1 and CA3 subregions of the dorsal hippocampus during acquisition of the task. We conclude that expression of the hzf-3 gene in the brain is associated with long-term spatial memory processes. The present results are the first to implicate an orphan nuclear receptor in long-term information storage in the hippocampus.     

Differential roles for hippocampal areas CA1 and CA3 in the contextual encoding and retrieval of extinguished fear

Recent studies demonstrate that context-specific memory retrieval after extinction requires the hippocampus. However, the contribution of hippocampal subfields to the context-dependent expression of extinction is not known. In the present experiments, we examined the roles of areas CA1 and CA3 of the dorsal hippocampus in the context specificity of extinction. After pairing an auditory conditional stimulus (CS) with an aversive footshock (unconditional stimulus or US), rats received extinction sessions in which the CS was presented without the US. In Experiment 1, pretraining neurotoxic lesions in either CA1 or CA3 eliminated the context dependence of extinguished fear. In Experiment 2, lesions of CA1 or CA3 were made after extinction training. In this case, only CA1 lesions impaired the context dependence of extinction. Collectively, these results reveal that both hippocampal areas CA1 and CA3 contribute to the acquisition of context-dependent extinction, but that only area CA1 is required for contextual memory retrieval.     

Excitotoxic lesions restricted to the dorsal CA1 field of the hippocampus impair spatial memory and extinction learning in C57BL/6 mice

Recent studies in patients with hippocampal lesions have indicated that the degree of memory impairment is proportional to the extent of damage within the hippocampus. Particularly, patients with damage restricted to the CA1 field demonstrate moderate to severe anterograde amnesia with only slight retrograde amnesia. Comparable results are also seen in other species such as non-human primates and rats; however, the effect of selective damage to CA1 has not yet been characterized in mice. In the present study, we investigated the effects of excitotoxic (NMDA) lesions of dorsal CA1 on several aspects of learning and memory performance in mice. Our data indicate that dorsal CA1 lesioned mice are hyperactive upon exposure to a novel environment, have spatial working memory impairments in the Y-maze spontaneous alternation task, and display deficits in an 8-arm spatial discrimination learning task. Lesioned mice are able to acquire an operant lever-press task but demonstrate extinction learning deficits in this appetitive operant paradigm. Taken together, our results indicate that lesions to dorsal CA1 in mice induce selective learning and memory performance deficits similar to those observed in other species, and extend previous findings indicating that this region of the hippocampus is critically involved in the processing of spatial information and/or the processing of inhibitory responses.     

Hippocampal CA1 kindling but not long-term potentiation disrupts spatial memory performance

Long-term synaptic enhancement in the hippocampus has been suggested to cause deficits in spatial performance. Synaptic enhancement has been reported after hippocampal kindling that induced repeated electrographic seizures or afterdischarges (ADs) and after long-term potentiation (LTP) defined as synaptic enhancement without ADs. We studied whether repeated stimulations that gave LTP or ADs resulted in spatial performance deficits on the radial arm maze (RAM) and investigated the minimal number of ADs required for such deficits. Three experimental groups were run as follows: (1) 5 hippocampal ADs in 1 d (5-AD group), (2) 10 hippocampal ADs in 2 d (10-AD group), and (3) 12 -frequency primed-burst stimulations (PBSs) in 2 d in order to induce LTP without ADs (LTP group). Each experimental group was run together with a control group during the same time period. Rats were first trained in a spatial task on a radial arm maze with four of the eight arms baited, then given control or experimental treatment, and maze performance was tested in the first week (1-4 d) and fourth week (22-25 d) after treatment. Basal dendritic population excitatory postsynaptic potentials (pEPSPs) and medial perforant path (MPP)-evoked dentate gyrus population spike and polysynaptic CA1 excitation were recorded before and after experimental and control treatment. Spatial memory errors, in particular reference memory errors, were significantly higher in the 10-AD kindled group than any other group on the first and fourth week after treatment. Spatial memory errors were not significantly different in the 5-AD and LTP groups as compared with any control groups at any time. Basal dendritic pEPSP in CA1 was enhanced for about 1 wk after 12 PBSs, 10 ADs, or 5 ADs, while the dentate gyrus population spike and CA1 polysynaptic excitation evoked by MPP was increased for up to 4 wk after 10 ADs, but not 12 PBSs. Thus, distributed alteration of multiple synaptic transmission in the entorhinal-hippocampal circuit, but not LTP at the basal dendritic synapses in CA1, may disrupt spatial performance after 10 hippocampal ADs.