Hippocampal-medial prefrontal cortex network dynamics predict performance during retrieval in a context-guided object memory task.

Remembering life episodes is a complex process that requires interaction among multiple brain areas. It is thought that contextual information provided by the hippocampus (HPC) can trigger the recall of a past event through the activation of medial prefrontal cortex (mPFC) neuronal ensembles, but the underlying mechanisms remain poorly understood. However, little is known about the coordinated activity between these structures during recall. We performed electrophysiological recordings in behaving rats during the retrieval phase of the object-in-context (OIC) memory task. Context-guided recognition of objects in this task requires the activity of both the mPFC and the ventral HPC (vHPC). Coherence, phase locking, and theta amplitude correlation analysis showed an increase in vHPC-mPFC LFP synchronization in the theta range when animals explore contextually mismatched objects. Moreover, we identified ensembles of putative pyramidal cells in the mPFC that encode specific object­context associations. Interestingly, the increase of vHPC-mPFC synchronization during exploration of the contextually mismatched object and the preference of mPFC incongruent object neurons predicts the animals' performance during the resolution of the OIC task. Altogether, these results identify changes in vHPC-mPFC synchronization and mPFC ensembles encoding specific object­context associations likely involved in the recall of past events.

Persistence of Spatial Memory Induced by Spaced Training Involves a Behavioral-Tagging Process.

Spaced training, which involves long inter-trial intervals, has positive effects on memories. One of the main attributes of long-term memories (LTM) is persistence. Here, to identify the process that promotes LTM persistence by spaced learning, we used the spatial object recognition (SOR) task in rats. The protocol consisted of a first strong training session that induced LTM formation (tested 1 day after training), but not LTM persistence (tested 7 or 14 days after training); and a second weak training session that promoted memory persistence when applied 1 day, but not 7 days, after the first training. We propose that the promotion of memory persistence is based on the Behavioral Tagging (BT) mechanism operating when the memory trace is retrieved. BT involves the setting of a tag induced by learning which gives rise to input selectivity, and the use of plasticity-related proteins (PRPs) to establish the mnemonic trace. We postulate that retraining will mainly retag the sites initially activated by the original learning, where the PRPs needed for memory expression and/or induced by retrieval would be used to maintain a persistent mnemonic trace. Our results suggest that the mechanism of memory expression, but not those of memory reinforcement or reconsolidation, is necessary to promote memory persistence after retraining. The molecular mechanisms involve ERKs1/2 activity to set the SOR learning tag, and the availability of GluA2-containing AMPA receptor. In conclusion, both the synthesis of PRPs and the setting of learning tags are key processes triggered by retraining that allow SOR memory persistence.

AMPA Receptors: A Key Piece in the Puzzle of Memory Retrieval.

Retrieval constitutes a highly regulated and dynamic phase in memory processing. Its rapid temporal scales require a coordinated molecular chain of events at the synaptic level that support transient memory trace reactivation. AMPA receptors (AMPAR) drive the majority of excitatory transmission in the brain and its dynamic features match the singular fast timescales of memory retrieval. Here we provide a review on AMPAR contribution to memory retrieval regarding its dynamic movements along the synaptic compartments, its changes in receptor number and subunit composition that take place in activity dependent processes associated with retrieval. We highlight on the differential regulations exerted by AMPAR subunits in plasticity processes and its impact on memory recall.

Metaplastic regulation of neocortical long-term depression in vivo is sensitive to distinct phases of conditioned taste aversion.

Metaplasticity refers to the persistent modification, by previous activity, in the ability to induce synaptic plasticity. Accumulated evidence has proposed that metaplasticity contributes to network function and cognitive processes such as learning and memory. In this regard, it has been observed that training in several behavioral tasks modifies the possibility to induce subsequent synaptic plasticity, such as long-term potentiation (LTP) and long-term depression (LTD). For instance, our previous studies have shown that conditioned taste aversion (CTA) training prevents the induction of in vivo LTP in the projection from the basolateral nucleus of the amygdala to the insular cortex (BLA-IC). Likewise, we reported that extinction of CTA allows induction but not maintenance of LTP in the same pathway. Besides, we showed that it is possible to express in vivo low-frequency stimulation LTD in the BLA-IC projection and that its induction prior to CTA training facilitates the extinction of this task. However, until now, little is known about the participation of LTD on metaplastic processes. The present study aimed to analyze whether CTA training modifies the expression of in vivo LTD in the BLA-IC projection. To do so, animals received low-frequency stimulation to induce IC-LTD 48 h after CTA training. Our results show that CTA training occludes the subsequent induction of LTD in the BLA-IC pathway in a retrieval-dependent manner. These findings reveal that CTA elicits a metaplastic regulation of long-lasting changes in the IC synaptic strength, as well as that specific phases of learning differentially take part in adjusting the expression of synaptic plasticity in neocortical regions.

AMPA Receptor Expression Requirement During Long-Term Memory Retrieval and Its Association with mTORC1 Signaling.

Recently, it was reported that mechanistic/mammalian target of rapamycin complex 1 (mTORC1) activity during memory retrieval is required for normal expression of aversive and non-aversive long-term memories. Here we used inhibitory-avoidance task to evaluate the potential mechanisms by which mTORC1 signaling pathway participates in memory retrieval. First, we studied the role of GluA-subunit trafficking during memory recall and its relationship with mTORC1 pathway. We found that pretest intrahippocampal infusion of GluR23É£, a peptide that selectively blocks GluA2-containing AMPA receptor (AMPAR) endocytosis, prevented the amnesia induced by the inhibition of mTORC1 during retrieval. Additionally, we found that GluA1 levels decreased and GluA2 levels increased at the hippocampal postsynaptic density subcellular fraction of rapamycin-infused animals during memory retrieval. GluA2 levels remained intact while GluA1 decreased at the synaptic plasma membrane fraction. Then, we evaluated the requirement of AMPAR subunit expression during memory retrieval. Intrahippocampal infusion of GluA1 or GluA2 antisense oligonucleotides (ASO) 3 h before testing impaired memory retention. The memory impairment induced by GluA2 ASO before retrieval was reverted by GluA23É£ infusion 1 h before testing. However, AMPAR endocytosis blockade was not sufficient to compensate GluA1 synthesis inhibition. Our work indicates that de novo GluA1 and GluA2 AMPAR subunit expression is required for memory retrieval with potential different roles for each subunit and suggests that mTORC1 might regulate AMPAR trafficking during retrieval. Our present results highlight the role of mTORC1 as a key determinant of memory retrieval that impacts the recruitment of different AMPAR subunits.

Stress and long-term memory retrieval: a systematic review

Abstract Introduction The experience of stressful events can alter brain structures involved in memory encoding, storage and retrieval. Here we review experimental research assessing the impact of the stress-related hormone cortisol on long-term memory retrieval. Method A comprehensive literature search was conducted on PubMed, Web of Science and PsycNet databases with the following terms: "stress," "long-term memory," and "retrieval." Studies were included in the review if they tested samples of healthy human participants, with at least one control group, and with the onset of the stress intervention occurring after the encoding phase and shortly (up to one hour) before the final memory test. Results Thirteen studies were included in the qualitative synthesis (N = 962) and were classified according to the time elapsed between stress induction and memory retrieval (stress-retrieval delay), the stress-inducing protocol (stressor), the time of day in which stress induction took place, sex, and age of participants. Most studies induced stress with the Trier Social Stress Test (TSST) between 15 and 25 minutes before the final memory (mostly recall) test and showed significant increases in cortisol levels and memory impairment. Discussion The reviewed studies indicate that stress does impair retrieval, particularly when induced with the TSST, in the afternoon, up to 45 minutes before the onset of the final memory test, in healthy young men. These results may inform future research on the impact of stress-induced cortisol surges on memory retrieval.

How the Brain Represents Language and Answers Questions? Using an AI System to Understand the Underlying Neurobiological Mechanisms.

To understand the computations that underlie high-level cognitive processes we propose a framework of mechanisms that could in principle implement START, an AI program that answers questions using natural language. START organizes a sentence into a series of triplets, each containing three elements (subject, verb, object). We propose that the brain similarly defines triplets and then chunks the three elements into a spatial pattern. A complete sentence can be represented using up to 7 triplets in a working memory buffer organized by theta and gamma oscillations. This buffer can transfer information into long-term memory networks where a second chunking operation converts the serial triplets into a single spatial pattern in a network, with each triplet (with corresponding elements) represented in specialized subregions. The triplets that define a sentence become synaptically linked, thereby encoding the sentence in synaptic weights. When a question is posed, there is a search for the closest stored memory (having the greatest number of shared triplets). We have devised a search process that does not require that the question and the stored memory have the same number of triplets or have triplets in the same order. Once the most similar memory is recalled and undergoes 2-level dechunking, the sought for information can be obtained by element-by-element comparison of the key triplet in the question to the corresponding triplet in the retrieved memory. This search may require a reordering to align corresponding triplets, the use of pointers that link different triplets, or the use of semantic memory. Our framework uses 12 network processes; existing models can implement many of these, but in other cases we can only suggest neural implementations. Overall, our scheme provides the first view of how language-based question answering could be implemented by the brain.

M1 muscarinic receptors are necessary for retrieval of remote context fear memory.

Several studies have investigated the transition of consolidation of recent memory to remote memory in aversively motivated tasks, such as contextual fear conditioning (CFC) and inhibitory avoidance (IA). However, the mechanisms that serve the retrieval of remote memories, has not yet been fully understood. Some evidences suggest that the central cholinergic system appears be involved in the modulation of these processes. Therefore, the present study aimed to investigate the effects of a pre-test administration of dicyclomine, a high-affinity M1 muscarinic receptor antagonist, on the retrieval of remote memories in fear conditioning and IA tasks. Male Wistar rats were trained, and after 1 or 28days, the rats received dicyclomine (16 or 32mg/kg, intraperitoneally, i.p.) and were tested in CFC, tone fear conditioning (TFC) and IA tasks. At both time intervals, 32mg/kg dicyclomine induced impairment of CFC. In TFC task only the performance of the rats 28days after training was impaired. The IA task was not affected in any of the studied intervals. These findings suggest a differential contribution of muscarinic receptors on recent and remote memories retrieval revealing a more generalized role in remote memory.

Selective neuronal degeneration in the retrosplenial cortex impairs the recall of contextual fear memory.

The retrosplenial cortex (RSC) is one of the largest cortical areas in rodents, and is subdivided in two main regions, A29 and A30, according to their cytoarchitectural organization and connectivities. However, very little is known about the functional activity of each RSC subdivision during the execution of complex cognitive tasks. Here, we used a well-established fear learning protocol that induced long-lasting contextual fear memory and showed that during evocation of the fear memory, the expression of early growth response gene 1 was up-regulated in A30, and in other brain areas implicated in fear and spatial memory, however, was down-regulated in A29, including layers IV and V. To search for the participation of A29 on fear memory, we triggered selective degeneration of neurons within cortical layers IV and V of A29 by using a non-invasive protocol that takes advantage of the vulnerability that these neurons have MK801-toxicity and the modulation of this neurodegeneration by testosterone. Application of 5 mg/kg MK801 in intact males induced negligible neuronal degeneration of A29 neurons and had no impact on fear memory retrieval. However, in orchiectomized rats, 5 mg/kg MK801 induced overt degeneration of layers IV-V neurons of A29, significantly impairing fear memory recall. Degeneration of A29 neurons did not affect exploratory or anxiety-related behavior nor altered unconditioned freezing. Importantly, protecting A29 neurons from MK801-toxicity by testosterone preserved fear memory recall in orchiectomized rats. Thus, neurons within cortical layers IV-V of A29 are critically required for efficient retrieval of contextual fear memory.

Acute restraint stress and corticosterone transiently disrupts novelty preference in an object recognition task.

The object recognition task is a procedure based on rodents' natural tendency to explore novel objects which is frequently used for memory testing. However, in some instances novelty preference is replaced by familiarity preference, raising questions regarding the validity of novelty preference as a pure recognition memory index. Acute stress- and corticosterone administration-induced novel object preference disruption has been frequently interpreted as memory impairment; however, it is still not clear whether such effect can be actually attributed to either mnemonic disruption or altered novelty seeking. Seventy-five adult male Wistar rats were trained in an object recognition task and subjected to either acute stress or corticosterone administration to evaluate the effect of stress or corticosterone on an object recognition task. Acute stress was induced by restraining movement for 1 or 4h, ending 30 min before the sample trial. Corticosterone was injected intraperitoneally 10 min before the test trial which was performed either 1 or 24h after the sample trial. Four-hour, but not 1-h, stress induced familiar object preference during the test trial performed 1h after the sample trial; however, acute stress had no effects on the test when performed 24h after sample trial. Systemic administration of corticosterone before the test trial performed either 1 or 24h after the sample trial also resulted in familiar object preference. However, neither acute stress nor corticosterone induced changes in locomotor behaviour. Taken together, such results suggested that acute stress probably does not induce memory retrieval impairment but, instead, induces an emotional arousing state which motivates novelty avoidance.

Posterior parietal cortex and long-term memory: some data from laboratory animals.

The posterior parietal cortex (PPC) was long viewed as just involved in the perception of spatial relationships between the body and its surroundings and of movements related to them. In recent years the PPC has been shown to participate in many other cognitive processes, among which working memory and the consolidation and retrieval of episodic memory. The neurotransmitter and other molecular processes involved have been determined to a degree in rodents. More research will no doubt determine the extent to which these findings can be extrapolated to primates, including humans. In these there appears to be a paradox: imaging studies strongly suggest an important participation of the PPC in episodic memory, whereas lesion studies are much less suggestive, let alone conclusive. The data on the participation of the PPC in episodic memory so far do not permit any conclusion as to what aspect of consolidation and retrieval it handles in addition to those dealt with by the hippocampus and basolateral amygdala, if any.

L-histidine provokes a state-dependent memory retrieval deficit in mice re-exposed to the elevated plus-maze

The effects of L-histidine (LH) on anxiety and memory retrieval were investigated in adult male Swiss Albino mice (weight 30-35 g) using the elevated plus-maze. The test was performed on two consecutive days: trial 1 (T1) and trial 2 (T2). In T1, mice received an intraperitoneal injection of saline (SAL) or LH before the test and were then injected again and retested 24 h later. LH had no effect on anxiety at the dose of 200 mg/kg since there was no difference between the SAL-SAL and LH-LH groups at T1 regarding open-arm entries (OAE) and open-arm time (OAT) (mean ± SEM; OAE: 4.0 ± 0.71, 4.80 ± 1.05; OAT: 40.55 ± 9.90, 51.55 ± 12.10, respectively; P > 0.05, Kruskal-Wallis test), or at the dose of 500 mg/kg (OAE: 5.27 ± 0.73, 4.87 ± 0.66; OAT: 63.93 ± 11.72, 63.58 ± 10.22; P > 0.05, Fisher LSD test). At T2, LH-LH animals did not reduce open-arm activity (OAE and OAT) at the dose of 200 mg/kg (T1: 4.87 ± 0.66, T2: 5.47 ± 1.05; T1: 63.58 ± 10.22; T2: 49.01 ± 8.43 for OAE and OAT, respectively; P > 0.05, Wilcoxon test) or at the dose of 500 mg/kg (T1: 4.80 ± 1.60, T2: 4.70 ± 1.04; T1: 51.55 ± 12.10, T2: 43.88 ± 10.64 for OAE and OAT, respectively; P > 0.05, Fisher LSD test), showing an inability to evoke memory 24 h later. These data suggest that LH does not act on anxiety but does induce a state-dependent memory retrieval deficit in mice.