Cellular and systems reconsolidation in the hippocampus

Cellular theories of memory consolidation posit that new memories require new protein synthesis in order to be stored. Systems consolidation theories posit that the hippocampus has a time-limited role in memory storage, after which the memory is independent of the hippocampus. Here, we show that intra-hippocampal infusions of the protein synthesis inhibitor anisomycin caused amnesia for a consolidated hippocampal-dependent contextual fear memory, but only if the memory was reactivated prior to infusion. The effect occurred even if reactivation was delayed for 45 days after training, a time when contextual memory is independent of the hippocampus. Indeed, reactivation of a hippocampus-independent memory caused the trace to again become hippocampus dependent, but only for 2 days rather than for weeks. Thus, hippocampal memories can undergo reconsolidation at both the cellular and systems levels.     

Estrogen replacement enhances acquisition of a spatial memory task and reduces deficits associated with hippocampal muscarinic receptor inhibition

A delayed matching-to-position (DMP) T-maze task was used to examine the effects of estrogen replacement on spatial learning and memory, as well as the ability of estrogen replacement to reduce performance deficits produced by acute systemic and intrahippocampal muscarinic cholinergic inhibition. Two experiments were performed. In Experiment 1, ovariectomized animals were trained to criterion on the DMP task and then tested with increased intertrial delays and following systemic scopolamine administration. The animals then received either continuous estrogen replacement or sham surgery and were retested beginning 10 days later. In Experiment 2, ovariectomized animals received guide cannulae implanted bilaterally into the hippocampus. Half of these animals also began receiving continuous estrogen replacement. Two months later, the animals were trained on the DMP task and then tested with increased intertrial delays and following systemic as well as intrahippocampal scopolamine administration. Animals received the same test battery 8 months later and were then immediately trained on a reversal task. The results indicate that estrogen-treated animals acquired the DMP task at a significantly faster rate than the ovariectomized, non-estrogen-treated controls. In addition, estrogen replacement significantly reduced deficits in DMP performance produced by intrahippocampal, but not systemic, scopolamine administration. This occurred when animals were tested after 3.5 months, as well as after 12 months, of continuous estrogen replacement. No evidence for an effect of estrogen replacement on spatial working memory or reversal learning was detected. These findings demonstrate that estrogen replacement can enhance acquisition of a spatial memory task and reduce performance deficits associated with hippocampal cholinergic impairment.     

Effect of Radicicol Infusion on the <Emphasis Type="Italic">Src</Emphasis> Tyrosine Kinase Activity of Rat Hippocampus before and after Training in an Inhibitory Avoidance Task

The participation of protein serine/threonine kinases in memory formation and retrieval is well established. In contrast, relatively little is known on the role of protein tyrosine kinases (PTKs). Previous work showed that intra-hippocampal infusion of the Src-PTK inhibitor radicicol inhibits memory acquisition, consolidation, and retrieval of one-trial step-down inhibitory avoidance task. In this study, we investigated the possible interaction between levels of Src-PTK activity in hippocampus and memory acquisition, formation, and retrieval of this task. Radicicol (0.5 μg/ml) was infused into the CA1 region of the hippocampus of rats trained in a one-trial step-down inhibitory avoidance task. Radicicol infused 15 min before training decreased Src-PTK activity, as measured 0, 1.5, and 24 h after training, and impaired memory acquisition of the task. When given immediately after training, there was a decrease in Src-PTK activity 1.5 h, but not 0 or 24 h after training. This treatment depressed memory consolidation. Radicicol infused into CA1 10 min prior to retrieval testing inhibited hippocampal Src-PTK activity, as measured immediately after the test session. The results suggest that Src-PTKs participate in memory acquisition, consolidation, and retrieval processes, but the timing of the role of the enzyme is different in each case.     

Forgetting, reminding, and remembering: the retrieval of lost spatial memory

Retrograde amnesia can occur after brain damage because this disrupts sites of storage, interrupts memory consolidation, or interferes with memory retrieval. While the retrieval failure account has been considered in several animal studies, recent work has focused mainly on memory consolidation, and the neural mechanisms responsible for reactivating memory from stored traces remain poorly understood. We now describe a new retrieval phenomenon in which rats' memory for a spatial location in a watermaze was first weakened by partial lesions of the hippocampus to a level at which it could not be detected. The animals were then reminded by the provision of incomplete and potentially misleading information—an escape platform in a novel location. Paradoxically, both incorrect and correct place information reactivated dormant memory traces equally, such that the previously trained spatial memory was now expressed. It was also established that the reminding procedure could not itself generate new learning in either the original environment, or in a new training situation. The key finding is the development of a protocol that definitively distinguishes reminding from new place learning and thereby reveals that a failure of memory during watermaze testing can arise, at least in part, from a disruption of memory retrieval.     

Pretraining but not Preexposure to the Task Apparatus Prevents the Memory Impairment Induced by Blockade of Protein Synthesis,PKA or MAP Kinase in Rats

Adult male Wistar rats were trained and tested in a step-down inhibitory avoidance task (0.4 mA footshock, 24 h training-test interval). Fifteen minutes before or 0, 1.5 or 3 hours after training, animals received a 0.8 l intrahippocampal infusion of the protein synthesis inhibitor anisomycin (80 g), the PKA inhibitor Rp-cAMP (0.05 g), the MAPK kinase inhibitor PD 098059 (50 M solution) or vehicle (phosphate buffer in saline, pH 7.4). Anisomycin, Rp-cAMP and PD 098059 impaired retention test performance in animals injected at different times, prior and after training. Pretraining with a low footshock intensity (0.2 mA) 24 h before training prevented the amnestic effect of all drugs studied. However, simple preexposure to the inhibitory avoidance apparatus did not alter the amnestic effects of all drugs. The results suggest that memory processing requires hippocampal mechanisms dependent on protein synthesis, PKA and MAPK kinase at different times after training. These findings suggest that weak training must be sufficient to produce some lasting cellular expression of the experience so that the enhancement of consolidation of a previously acquired memory is not dependent on protein synthesis, PKA or MAPK.     

A Potential Spatial Working Memory Training Task to Improve Both Episodic Memory and Fluid Intelligence

One current challenge in cognitive training is to create a training regime that benefits multiple cognitive domains, including episodic memory, without relying on a large battery of tasks, which can be time-consuming and difficult to learn. By giving careful consideration to the neural correlates underlying episodic and working memory, we devised a computerized working memory training task in which neurologically healthy participants were required to monitor and detect repetitions in two streams of spatial information (spatial location and scene identity) presented simultaneously (i.e. a dual n-back paradigm). Participants’ episodic memory abilities were assessed before and after training using two object and scene recognition memory tasks incorporating memory confidence judgments. Furthermore, to determine the generalizability of the effects of training, we also assessed fluid intelligence using a matrix reasoning task. By examining the difference between pre- and post-training performance (i.e. gain scores), we found that the trainers, compared to non-trainers, exhibited a significant improvement in fluid intelligence after 20 days. Interestingly, pre-training fluid intelligence performance, but not training task improvement, was a significant predictor of post-training fluid intelligence improvement, with lower pre-training fluid intelligence associated with greater post-training gain. Crucially, trainers who improved the most on the training task also showed an improvement in recognition memory as captured by d-prime scores and estimates of recollection and familiarity memory. Training task improvement was a significant predictor of gains in recognition and familiarity memory performance, with greater training improvement leading to more marked gains. In contrast, lower pre-training recollection memory scores, and not training task improvement, led to greater recollection memory performance after training. Our findings demonstrate that practice on a single working memory task can potentially improve aspects of both episodic memory and fluid intelligence, and that an extensive training regime with multiple tasks may not be necessary.     

The role of protein synthesis in memory reconsolidation in different time periods after fear conditioning in mice

We have studied the role of protein synthesis in reconsolidation of memory, activated by reminder at different time period after initial acquisition. Mice were trained in a single-trial fear conditioning task and then subjected to reminder, preceded by injection of protein synthesis inhibitor cycloheximide. It was found that this procedure impaired later memory retrieval if applied at 3, 6 and 24 h as well as 14 and 30 days after initial training. This data suggests that reactivated memory is followed by protein synthesis-dependent reconsolidation both at short (3-6 h) and long (14-30 days) intervals after initial acquisition.     

Inactivation of the Anterior Cingulate Reveals Enhanced Reliance on Cortical Networks for Remote Spatial Memory Retrieval after Sequential Memory Processing

One system consolidation model suggests that as time passes, ensembles of cortical neurons form strong connections to represent remote memories. In this model, the anterior cingulate cortex (ACC) serves as a cortical region that represents remote memories. However, there is debate as to whether remote spatial memories go through this systems consolidation process and come to rely on the ACC. The present experiment examined whether increasing the processing demand on the hippocampus, by sequential training on two spatial tasks, would more fully engage the ACC during retrieval of a remote spatial memory. In this scenario, inactivation of the ACC at a remote time point was hypothesized to produce a severe memory deficit if rats had been trained on two, sequential spatial tasks. Rats were trained on a water maze (WM) task only or a WM task followed by a radial arm maze task. A WM probe test was given recently or remotely to all rats. Prior to the probe test, rats received an injection of saline or muscimol into the ACC. A subtle deficit in probe performance was found at the remote time point in the group trained on only one spatial task and treated with muscimol. In the group trained on two spatial tasks and treated with muscimol, a subtle deficit in probe performance was noted at the recent time point and a substantial deficit in probe performance was observed at the remote time point. c-Fos labeling in the hippocampus revealed more labeling in the CA1 region in all remotely tested groups than recently tested groups. Findings suggest that spatial remote memories come to rely more fully on the ACC when hippocampal processing requirements are increased. Results also suggest continued involvement of the hippocampus in spatial memory retrieval along with a progressive strengthening of cortical connections as time progresses.     

Over-reinforcement protects against memory deficits induced by muscarinic blockade of the striatum

It has been shown that blockade of muscarinic receptors of the anterior striatum (AS) induces significant impairments in the retrieval of stored information of a passive avoidance task, trained with conventional parameters of footshock, and that the same blockade is ineffective in altering short-term memory of this task. The results of the present experimental series showed that in conditions of over-reinforcement, microinjections of scopolamine into the AS shortly after training or before retention testing of passive avoidance, do not produce memory deficits when retention is assessed 30 min, 24 h or 48 h after training. It is suggested that after an enhanced learning experience (over-reinforcement) striatal cholinergic activity is not involved in short- and long-term memory functions.     

Effects of demanding foraging conditions on cache retrival accuracy in food-caching mountain chickadees (Poecile gambeli)

Birds rely, at least in part, on spatial memory for recovering previously hidden caches but accurate cache recovery may be more critical for birds that forage in harsh conditions where the food supply is limited and unpredictable. Failure to find caches in these conditions may potentially result in death from starvation. In order to test this hypothesis we compared the cache recovery behaviour of 24 wild-caught mountain chickadees (Poecile gambeli), half of which were maintained on a limited and unpredictable food supply while the rest were maintained on an ad libitum food supply for 60 days. We then tested their cache retrieval accuracy by allowing birds from both groups to cache seeds in the experimental room and recover them 5 hours later. Our results showed that birds maintained on a limited and unpredictable food supply made significantly fewer visits to non-cache sites when recovering their caches compared to birds maintained on ad libitum food. We found the same difference in performance in two versions of a one-trial associative learning task in which the birds had to rely on memory to find previously encountered hidden food. In a non-spatial memory version of the task, in which the baited feeder was clearly marked, there were no significant differences between the two groups. We therefore concluded that the two groups differed in their efficiency at cache retrieval. We suggest that this difference is more likely to be attributable to a difference in memory (encoding or recall) than to a difference in their motivation to search for hidden food, although the possibility of some motivational differences still exists. Overall, our results suggest that demanding foraging conditions favour more accurate cache retrieval in food-caching birds.     

The effect of negative and positive emotionality on associative memory: an FMRI study

In general, emotion is known to enhance memory processes. However, the effect of emotion on associative memory and the underling neural mechanisms remains largely unexplored. In this study, we explored brain activation during an associative memory task that involved the encoding and retrieval of word and face pairs. The word and face pairs consisted of either negative or positive words with neutral faces. Significant hippocampal activation was observed during both encoding and retrieval, regardless of whether the word was negative or positive. Negative and positive emotionality differentially affected the hemodynamic responses to encoding and retrieval in the amygdala, with increased responses during encoding negative word and face pairs. Furthermore, activation of the amygdala during encoding of negative word and neutral face pairs was inversely correlated with subsequent memory retrieval. These findings suggest that activation of the amygdala induced by negative emotion during encoding may disrupt associative memory performance.     

Deployment of Spatial Attention towards Locations in Memory Representations. An EEG Study

Recalling information from visual short-term memory (VSTM) involves the same neural mechanisms as attending to an actually perceived scene. In particular, retrieval from VSTM has been associated with orienting of visual attention towards a location within a spatially-organized memory representation. However, an open question concerns whether spatial attention is also recruited during VSTM retrieval even when performing the task does not require access to spatial coordinates of items in the memorized scene. The present study combined a visual search task with a modified, delayed central probe protocol, together with EEG analysis, to answer this question. We found a temporal contralateral negativity (TCN) elicited by a centrally presented go-signal which was spatially uninformative and featurally unrelated to the search target and informed participants only about a response key that they had to press to indicate a prepared target-present vs. -absent decision. This lateralization during VSTM retrieval (TCN) provides strong evidence of a shift of attention towards the target location in the memory representation, which occurred despite the fact that the present task required no spatial (or featural) information from the search to be encoded, maintained, and retrieved to produce the correct response and that the go-signal did not itself specify any information relating to the location and defining feature of the target.     

Movement-related theta rhythm in humans: coordinating self-directed hippocampal learning

The hippocampus is crucial for episodic or declarative memory and the theta rhythm has been implicated in mnemonic processing, but the functional contribution of theta to memory remains the subject of intense speculation. Recent evidence suggests that the hippocampus might function as a network hub for volitional learning. In contrast to human experiments, electrophysiological recordings in the hippocampus of behaving rodents are dominated by theta oscillations reflecting volitional movement, which has been linked to spatial exploration and encoding. This literature makes the surprising cross-species prediction that the human hippocampal theta rhythm supports memory by coordinating exploratory movements in the service of self-directed learning. We examined the links between theta, spatial exploration, and memory encoding by designing an interactive human spatial navigation paradigm combined with multimodal neuroimaging. We used both non-invasive whole-head Magnetoencephalography (MEG) to look at theta oscillations and Functional Magnetic Resonance Imaging (fMRI) to look at brain regions associated with volitional movement and learning. We found that theta power increases during the self-initiation of virtual movement, additionally correlating with subsequent memory performance and environmental familiarity. Performance-related hippocampal theta increases were observed during a static pre-navigation retrieval phase, where planning for subsequent navigation occurred. Furthermore, periods of the task showing movement-related theta increases showed decreased fMRI activity in the parahippocampus and increased activity in the hippocampus and other brain regions that strikingly overlap with the previously observed volitional learning network (the reverse pattern was seen for stationary periods). These fMRI changes also correlated with participant's performance. Our findings suggest that the human hippocampal theta rhythm supports memory by coordinating exploratory movements in the service of self-directed learning. These findings directly extend the role of the hippocampus in spatial exploration in rodents to human memory and self-directed learning.     

Key Features of Human Episodic Recollection in the Cross-Episode Retrieval of Rat Hippocampus Representations of Space

Neurophysiological studies focus on memory retrieval as a reproduction of what was experienced and have established that neural discharge is replayed to express memory. However, cognitive psychology has established that recollection is not a verbatim replay of stored information. Recollection is constructive, the product of memory retrieval cues, the information stored in memory, and the subject''s state of mind. We discovered key features of constructive recollection embedded in the rat CA1 ensemble discharge during an active avoidance task. Rats learned two task variants, one with the arena stable, the other with it rotating; each variant defined a distinct behavioral episode. During the rotating episode, the ensemble discharge of CA1 principal neurons was dynamically organized to concurrently represent space in two distinct codes. The code for spatial reference frame switched rapidly between representing the rat''s current location in either the stationary spatial frame of the room or the rotating frame of the arena. The code for task variant switched less frequently between a representation of the current rotating episode and the stable episode from the rat''s past. The characteristics and interplay of these two hippocampal codes revealed three key properties of constructive recollection. (1) Although the ensemble representations of the stable and rotating episodes were distinct, ensemble discharge during rotation occasionally resembled the stable condition, demonstrating cross-episode retrieval of the representation of the remote, stable episode. (2) This cross-episode retrieval at the level of the code for task variant was more likely when the rotating arena was about to match its orientation in the stable episode. (3) The likelihood of cross-episode retrieval was influenced by preretrieval information that was signaled at the level of the code for spatial reference frame. Thus key features of episodic recollection manifest in rat hippocampal representations of space.     

Cognitive Behavioral Performance of Untreated Depressed Patients with Mild Depressive Symptoms

This study evaluated the working memory performance of 18 patients experiencing their first onset of mild depression without treatment and 18 healthy matched controls. The results demonstrated that working memory impairment in patients with mild depression occurred when memorizing the position of a picture but not when memorizing the pictures themselves. There was no significant difference between the two groups in the emotional impact on the working memory, indicating that the attenuation of spatial working memory was not affected by negative emotion; however, cognitive control selectively affected spatial working memory. In addition, the accuracy of spatial working memory in the depressed patients was not significantly reduced, but the reaction time was significantly extended compared with the healthy controls. This finding indicated that there was no damage to memory encoding and function maintenance in the patients but rather only impaired memory retrieval, suggesting that the extent of damage to the working memory system and cognitive control abilities was associated with the corresponding depressive symptoms. The development of mild to severe depressive symptoms may be accompanied by spatial working memory damage from the impaired memory retrieval function extending to memory encoding and memory retention impairments. In addition, the impaired cognitive control began with an inadequate capacity to automatically process internal negative emotions and further extended to impairment of the ability to regulate and suppress external emotions. The results of the mood-congruent study showed that the memory of patients with mild symptoms of depression was associated with a mood-congruent memory effect, demonstrating that mood-congruent memory was a typical feature of depression, regardless of the severity of depression. This study provided important information for understanding the development of cognitive dysfunction.     

Evidence for hippocampal role in place avoidance other than merely memory storage

Spatial navigation is used as a popular animal model of higher cognitive functions in people. The data suggest that the hippocampus is important for both storing spatial memories and for performing spatial computations necessary for navigation. Animals use multiple behavioral strategies to solve spatial tasks often using multiple memory systems. We investigated how inactivation of the rat hippocampus affects performance in a place avoidance task to determine if the role of the hippocampus in this task could be attributed to memory storage/retrieval or to the computations needed for navigation. Injecting tetrodotoxin (TTX) into both hippocampi impaired conditioned place avoidance, but after injecting only one hippocampus, the rats learned the place avoidance as well as without any injections. Retention of the place avoidance learned with one hippocampus was not impaired when the injection was switched to the hippocampus that had not been injected during learning. The result suggests that during learning, the hippocampus did not store the place avoidance memory.     

Rats answer an unexpected question after incidental encoding

A fundamental aspect of episodic memory is that retrieval of information can occur when encoding is incidental and memory assessment is unexpected. These features are difficult to model in animals because behavioral training likely gives rise to well-learned expectations about the sequence of events. Thus, the possibility remains that animals may solve an episodic memory test by using well-learned semantic rules without remembering the episode at memory assessment. Here we show that rats can answer an unexpected question after incidental encoding in a hippocampal-dependent manner, consistent with the use of episodic memory. Rats were initially trained to report about a recent event (food versus no food) and separately searched for food where there was no expectation of being asked about the presence of food. To test episodic memory, we gave rats the opportunity to incidentally encode the presence or absence of food and unexpectedly asked them to report about the recent event. Temporary inactivation of the CA3 region of the hippocampus with bilateral infusions of lidocaine selectively eliminated the ability of rats to answer the unexpected, but not the expected, question. Our studies suggest that rats remember an earlier episode after incidental encoding based upon hippocampal-dependent episodic memory.     

The hippocampus is coupled with the default network during memory retrieval but not during memory encoding

The brain's default mode network (DMN) is activated during internally-oriented tasks and shows strong coherence in spontaneous rest activity. Despite a surge of recent interest, the functional role of the DMN remains poorly understood. Interestingly, the DMN activates during retrieval of past events but deactivates during encoding of novel events into memory. One hypothesis is that these opposing effects reflect a difference between attentional orienting towards internal events, such as retrieved memories, vs. external events, such as to-be-encoded stimuli. Another hypothesis is that hippocampal regions are coupled with the DMN during retrieval but decoupled from the DMN during encoding. The present fMRI study investigated these two hypotheses by combining a resting-state coherence analysis with a task that measured the encoding and retrieval of both internally-generated and externally-presented events. Results revealed that the main DMN regions were activated during retrieval but deactivated during encoding. Counter to the internal orienting hypothesis, this pattern was not modulated by whether memory events were internal or external. Consistent with the hippocampal coupling hypothesis, the hippocampus behaved like other DMN regions during retrieval but not during encoding. Taken together, our findings clarify the relationship between the DMN and the neural correlates of memory retrieval and encoding.     

A novel melatonin agonist Neu-P11 facilitates memory performance and improves cognitive impairment in a rat model of Alzheimer' disease

Previous studies have shown that melatonin is implicated in modulating learning and memory processing. Melatonin also exerts neuroprotective activities against Aβ-induced injury in vitro and in vivo. Neu-P11 (piromelatine, N-(2-(5-methoxy-1H-indol-3-yl)ethyl)-4-oxo-4H-pyran-2-carboxamide) is a novel melatonin (MT1/MT2) receptor agonist and a serotonin 5-HT1A/1D receptor agonist recently developed for the treatment of insomnia. In the present study we firstly investigated whether Neu-P11 and melatonin enhance memory performance in the novel object recognition (NOR) task in rats, and then assessed whether Neu-P11 and melatonin improve neuronal and cognitive impairment in a rat model of Alzheimer' disease (AD) induced by intrahippocampal Aβ_(1–42) injection. The results showed that a single morning or afternoon administration of Neu-P11 enhanced object recognition memory measured at 4 or 24 h after training. Melatonin was effective in the memory facilitating effects only when administered in the afternoon. Further results showed that intrahippocampal Aβ_(1–42) injection resulted in hippocampal cellular loss, as well as decreased learning ability and memory in the Y maze and NOR tasks in rats. Neu-P11 but not melatonin attenuated cellular loss and cognitive impairment in the rat AD model. The current data suggest that Neu-P11 may serve as a novel agent for the treatment of AD.     

Anterior/Posterior Competitive Deactivation/Activation Dichotomy in the Human Hippocampus as Revealed by a 3D Navigation Task

Anterior/posterior long axis specialization is thought to underlie the organization of the hippocampus. However it remains unclear whether antagonistic mechanisms differentially modulate processing of spatial information within the hippocampus. We used fMRI and a virtual reality 3D paradigm to study encoding and retrieval of spatial memory during active visuospatial navigation, requiring positional encoding and retrieval of object landmarks during the path. Both encoding and retrieval elicited BOLD activation of the posterior most portion of hippocampus, while concurrent deactivations (recently shown to reflect decreases in neural responses) were found in the most anterior regions. Encoding elicited stronger activity in the posterior right than the left hippocampus. The former structure also showed significantly stronger activity for allocentric vs. egocentric processing during retrieval. The anterior vs. posterior pattern mimics, from a functional point, although at much distinct temporal scales, the previous anatomical findings in London taxi drivers, whereby posterior enlargement was found at the cost of an anterior decrease, and the mirror symmetric findings observed in blind people, in whom the right anterior hippocampus was found to be larger, at the cost of a smaller posterior hippocampus, as compared with sighted people. In sum, we found a functional dichotomy whereby the anterior/posterior hippocampus shows antagonistic processing patterns for spatial encoding and retrieval of 3D spatial information. To our knowledge, this is the first study reporting such a dynamical pattern in a functional study, which suggests that differential modulation of neural responses within the human hippocampus reflects distinct roles in spatial memory processing.