Assessing episodic memory in rodents using spontaneous object recognition tasks.

Models of episodic memory are successfully established using spontaneous object recognition tasks in rodents. In this review, we present behavioral techniques devised to investigate this type of memory, emphasizing methods based on associations of places and temporal order of items explored by rats and mice. We also provide a review on the areas and circuitry of the medial temporal lobe underlying episodic-like memory, considering that a large number of neurobiology data derived from these protocols. Although spontaneous recognition tasks are commonplace in this field, there is need for careful evaluation of factors affecting animal performance. Such as the ongoing development of tools for investigating the neural basis of memory, efforts should be put in the refinement of experimental designs, in order to provide reliable behavioral evidence of this complex mnemonic system.

Post-learning caffeine administration improves 'what-when' and 'what-where' components of episodic-like memory in rats.

Episodic-like memory (ELM) consists in the capacity of nonhuman animals to remember 'where' and 'when' a specific episode occurred ('what'). Previous studies have showed that Wistar rats can form an ELM, but not after a 24 h retention delay. On the other hand, it has been demonstrated that caffeine can improve episodic memory consolidation in humans. Therefore, we verified whether acute post-sample caffeine administration could improve ELM consolidation in Wistar rats, as well if it could be related to neurochemical changes in the prefrontal cortex and hippocampus - regions related to episodic-like memory processing. 46 Male Wistar Rats, approximately 3 months-old, were divided into four groups as follows: untreated (n = 11), saline (n = 11), caffeine 10 mg ∕kg i.p (n = 12); caffeine 15 mg∕kgi.p (n = 12) and tested in WWWhen/ELM task. The animals treated with caffeine in different dosages (10 mg/kg and 15 mg/kg) discriminated temporally and spatially the objects, respectively. These groups also showed a dopamine renewal rate in the hippocampus, suggesting that there was an increase in the turnover compared with the groups with no caffeine administration. We can conclude that caffeine leads to an improvement in the consolidation of the temporal ('what-when') and spatial ('what-where') aspects of episodic-like memory.

Anticonvulsant Activity of trans-Anethole in Mice.

Epilepsy is a chronic neurological disorder affecting 1-2% of world population, and one-third of patients are refractory to pharmacological treatment. This fact has stimulated research for new antiepileptic drugs and natural products have been an important source. trans-Anethole (TAN) is a phenylpropanoid, component of some essential oils, extracted from plants, and its effects have been little studied. Therefore, this study is aimed at investigating the TAN effect in classic seizure models and evaluate the electroencephalographic (EEG) profile of animals treated with this substance. For this, Swiss male mice (Mus musculus) were used, and the lethal dose was evaluated and subsequently submitted to the test maximal electroshock (MES), the pentylenetetrazole- (PTZ) induced seizure test, and the EEG profile. Initially, the LD50 for TAN was estimated in 1000 mg/kg (i.p.) dose and there was no sign of acute toxicity or death. In the MES test, TAN 300, i.p. (12.00 ± 2.9 s) and 400 mg/kg, i.p. (9.00 ± 4.4 s) doses was able to decrease tonic seizures duration induced by electric discharge (0.5 mA, 150 pulses/s, for 0.5 s). In the PTZ test (75 mg/kg, i.p.), TAN 400 mg/kg, i.p. increased the latency to myoclonic jerks (80.0 (56.0-134.0)), the latency totonic-clonic seizures (900.0 (861.0-900.0) and decrease seizure duration (0.0 (0.0-10.0)). No deaths were found in this groups compared to vehicle. EEG analysis showed an amplitude decrease of waves (ratio of baseline) in TAN 300 (1.82 ± 0.23) and 400 mg/kg (1.06 ± 0.16) groups. In this way, TAN at 400 mg/kg was able to inhibit and/or attenuate seizures by increasing the time for the onset of spasms and convulsions, as reducing the duration of seizures. The EEG profile corroborate with this results showing a reduction in the amplitude of waves compared to the PTZ group. Thus, TAN showed an anticonvulsant effect in all experimental models performed, behavioral and electroencephalographic.

Theta and gamma oscillations in the rat hippocampus support the discrimination of object displacement in a recognition memory task.

Episodic memory depends on the recollection of spatial and temporal aspects of past experiences in which the hippocampus plays a critical role. Studies on hippocampal lesions in rodents have shown that dentate gyrus (DG) and CA3 are necessary to detect object displacement in memory tasks. However, the understanding of real-time oscillatory activity underlying memory discrimination of subtle and pronounced displacements remains elusive. Here, we chronically implanted microelectrode arrays in adult male Wistar rats to record network oscillations from DG, CA3, and CA1 of the dorsal hippocampus while animals executed an object recognition task of high and low spatial displacement tests (HD: 108 cm, and LD: 54 cm, respectively). Behavioral analysis showed that the animals discriminate between stationary and displaced objects in the HD but not LD conditions. To investigate the hypothesis that theta and gamma oscillations in different areas of the hippocampus support discrimination processes in a recognition memory task, we compared epochs of object exploration between HD and LD conditions as well as displaced and stationary objects. We observed that object exploration epochs were accompanied by strong rhythmic activity in the theta frequency (6-12 Hz) band in the three hippocampal areas. Comparison between test conditions revealed higher theta band power and higher theta-gamma phase-amplitude coupling in the DG during HD than LD conditions. Similarly, direct comparison between displaced and stationary objects within the HD test showed higher theta band power in CA3 during exploration of displaced objects. Moreover, the discrimination index between displaced and stationary objects directly correlated with CA1 gamma band power in epochs of object exploration. We thus conclude that theta and gamma oscillations in the dorsal hippocampus support the successful discrimination of object displacement in a recognition memory task.

Stress, memory, and implications for major depression.

The stress response comprises a phylogenetically conserved set of cognitive, physiological, and behavioral responses that evolved as a survival strategy. In this context, the memory of stressful events would be adaptive as it could avoid re-exposure to an adverse event, otherwise the event would be facilitated in positively stressful or non-distressful conditions. However, the interaction between stress and memory comprises complex responses, some of them which are not yet completely understood, and which depend on several factors such as the memory system that is recruited, the nature and duration of the stressful event, as well as the timing in which this interaction takes place. In this narrative review, we briefly discuss the mechanisms of the stress response, the main memory systems, and its neural correlates. Then, we show how stress, through the action of its biochemical mediators, influences memory systems and mnemonic processes. Finally, we make use of major depressive disorder to explore the possible implications of non-adaptive interactions between stress and memory to psychiatric disorders, as well as possible roles for memory studies in the field of psychiatry.

Rats recognize spatial and temporal attributes in a new object recognition memory task with multiple trials.

BACKGROUND: Episodic-like memory tasks based on the spontaneous exploration of objects are commonly applied in one-trial protocols. However, multiple-trial designs are known to reduce animal numbers and data variance, providing faster accumulation of data. NEW METHOD: In this study, we devised a new object recognition memory task for rats that carry out multiple trials per session. We developed three types of continual trial tasks: a longer protocol, a shorter protocol, and a protocol in which the experimental session was divided into two days. RESULTS: In our design, rats expressed temporal and spatial memory, but not what-where-when content integration. We found that shorter protocols were more efficient to evaluate memory capabilities. COMPARISON WITH EXISTING METHODS: To the best of our knowledge, it is the first object recognition task with multiple trials that simultaneously assess the temporal and spatial aspects of episodic-like memory. CONCLUSIONS: We suggest that our task is suitable for the simultaneous measurements of brain functions related to spatial and temporal attributes in rats.

Conspecific Presence Improves Episodic-Like Memory in Rats.

A number of studies have provided evidence that animals, including rats, remember past episodes. However, few experiments have addressed episodic-like memory from a social perspective. In the present study, we evaluated Wistar rats in the WWWhen/ELM task as single setups and in dyads, applying a long retention interval. We also investigated behaviors that could subserve the emergence of this type of memory. We found that only rats tested in the social setting were able to recollect an integrated episodic-like memory that lasted 24 h. Additionally, rats in dyads presented higher levels of exploration during the task. When exposed to the testing environment, the dyads exhibited affiliative behavior toward each other and presented fewer anxiety-like responses. Our findings indicate that the presence of a conspecific could act as a facilitating factor in memory evaluations based on spontaneous exploration of objects and provide empirical support for applying more naturalistic settings in investigations of episodic-like memory in rats.

Load effect on what-where-when memory in younger and older adults.

Episodic memory (EM) is a subsystem responsible for storing and evoking information about the "What", "Where" and "When" elements of an event in an integrated way. This capacity depends of structures with hippocampus and prefrontal cortex. The effect of aging on some capacities mediated by these areas, such as the influence of the number of objects on the coding of EM, remains unexplored. The present study examined the memory recall capacity of young and older adults in an EM task which used the number of 2, 4 and 6 items associated with specific space-temporal contexts. The young adults showed better performance coefficients than the older adults in all tasks, regardless of the load used, for all questions, except the "What" type. The group differences increase with load augmentation, stabilizing from the tasks with 4 items. In short, the EM efficiency, evaluated through What-Where-When Task, depends on the quantity information encoding.

Episodic-like memory impairment induced by sub-anaesthetic doses of ketamine.

Episodic-like memory refers to integration of where and when a certain event (what) happened. The glutamatergic neurotransmission, particularly AMPA and NMDA receptors, in the dorsal hippocampus mediates episodic recall. Ketamine is a non-competitive NMDA antagonist with effect on cognitive performance and plasticity. The goal of this study was to evaluate the acute action of ketamine on behavioural and neurochemical aspects of episodic-like memory (WWWhen/ELM task) through immediate-early gene expression (IEG), c-Fos, in the dorsal hippocampus. Animals received saline 0.9% or ketamine at 8 mg/kg or 15 mg/kg (i.p.) immediately after the second sample. Our data indicate that untreated and saline rats integrate the three elements of episodic-like memory. Conversely, animals treated with ketamine showed impairment of ELM formation. In addition, the highest dose of ketamine increased c-Fos expression in dorsal CA1 subregion when compared to saline rats. Our results indicate that the antagonism of NMDA concurrently impair ELM formation of all three aspects of ELM and increase neuronal activation in dorsal CA1.

CA1 inactivation impairs episodic-like memory in rats.

Episodic memory was initially believed to be unique to humans. However, studies demonstrate that nonhuman species discriminate items based on the triad what, where and when. Here we addressed the role of the dorsal hippocampal subfield CA1 in an integrative what-where-when task in Wistar rats. We performed bilateral inactivation of dorsal CA1 with the GABAA agonist muscimol previously to the task. As expected, sham-operated animals recollected an integrative memory for objects (what), their places (where) and temporal order (when). However, the inactivation of CA1 impaired the performance of the three components of episodic-like memory. In addition, total time of objects exploration and distance traveled were not different between groups, indicating that rats had similar levels of motivation, thus, alterations in exploration does not account for impaired locomotor performance. Altogether, our data provides evidence that CA1 plays an important role in episodic-like memory.

Differential Cortical c-Fos and Zif-268 Expression after Object and Spatial Memory Processing in a Standard or Episodic-Like Object Recognition Task.

Episodic memory reflects the capacity to recollect what, where, and when a specific event happened in an integrative manner. Animal studies have suggested that the medial temporal lobe and the medial pre-frontal cortex are important for episodic-like memory (ELM) formation. The goal of present study was to evaluate whether there are different patterns of expression of the immediate early genes c-Fos and Zif-268 in these cortical areas after rats are exposed to object recognition (OR) tasks with different cognitive demands. Male rats were randomly assigned to five groups: home cage control, empty open field (CTR-OF), open field with one object (CTR-OF + Obj), novel OR task, and ELM task and were killed 1 h after the last behavioral procedure. Rats were able to discriminate the objects in the OR task. In the ELM task, rats showed spatial (but not temporal) discrimination of the objects. We found an increase in the c-Fos expression in the dorsal dentate gyrus (DG) and in the perirhinal cortex (PRh) in the OR and ELM groups. The OR group also presented an increase of c-Fos expression in the medial prefrontal cortex (mPFC). Additionally, the OR and ELM groups had increased expression of Zif-268 in the mPFC. Moreover, Zif-268 was increased in the dorsal CA1 and PRh only in the ELM group. In conclusion, the pattern of activation was different in tasks with different cognitive demands. Accordingly, correlation tests suggest the engagement of different neural networks in the tasks used. Specifically, perirhinal-DG co-activation was detected after the what-where memory retrieval, but not after the novel OR task. Both regions correlated with the respective behavioral outcome. These findings can be helpful in the understanding of the neural networks underlying memory tasks with different cognitive demands.

Differential roles of the dorsal hippocampal regions in the acquisition of spatial and temporal aspects of episodic-like memory.

Episodic memory refers to the recollection of what, where and when an event occurred. Computational models suggest that the dentate gyrus (DG) and the CA3 hippocampal subregions are involved in pattern separation and the rapid acquisition of episodes, while CA1 is involved in the formation of a temporal context. Most of the studies performed to test this hypothesis failed to simultaneously address the aspects of episodic memory. Recently, a new task of object recognition was validated in rats. In the first sample trial, the rat is exposed to four copies of an object. In second sample, the rat is exposed to four copies of a different object. In the test trial, two copies of each of the previous objects are presented. One copy of the object used in sample trial one is located in a different place, and it is expected to be the most explored. Our goal was to evaluate whether the pharmacological inactivation of the dorsal DG/CA3 and CA1 subregions could differentially impair the acquisition of the task. Inactivation of the DG/CA3 subregions impaired the spatial discrimination, while the temporal discrimination was preserved. Rats treated with muscimol in CA1 explored all the objects equally well, irrespective of place or presentation time. Our results are consistent with computational models that postulate a role for DG/CA3 in rapid encoding and in spatial pattern separation, and a role for CA1 in the in the formation of the temporal context of events and as well as in detecting spatial novelty.

Extending possible applications of an episodic-like memory task in rats.

Recently, an object recognition episodic-like memory task was proposed in rodents. However, the short retention delay of the task narrows its applications. This study verifies whether this task can be evoked after 24h. Additionally, the effect of a classical amnestic agent (scopolamine) on episodic-like memory consolidation was investigated. Rats showed increased exploration of old over recent objects and spent more time exploring displaced over stationary object. Both old over recent and displaced over stationary objects preferences were abolished by pos-training scopolamine administration (1mg/kg i.p.), indicating impaired spatiotemporal retrieval. In conclusion, the object recognition task that accomplishes the what, where and when components of episodic-like memory in rats can persist for 24h.

Efeito da repetição de itens na codificação da memória episódica / Effect of item repetition on episodic memory codification / Efecto de la repetición del artículo en la codificación de la memoria episódica

A repetição de itens é um mecanismo que pode promover interferência durante a codificação. Para investigar o impacto desse tipo de interferência na memória episódica de longo prazo estabelecemos um procedimento de codificação composto de três testes consecutivos de reconhecimento de palavras no qual se repetiam os distratores utilizados nos testes (contexto difícil) ou não (contexto fácil). Comparamos o desempenho nos dois contextos ao apresentar os estímulos auditivamente e quando a apresentação foi visual. Participaram do estudo 46 universitários e 16 adultos de idade intermediária. O desempenho nos testes imediatos e na evocação de longo prazo foi pior no contexto difícil, independente do tipo de apresentação dos itens ou da idade dos voluntários. Os resultados indicam que a repetição dos itens gerou um efeito de interferência que implicou em prejuízos na memória imediata e de longo prazo. Esse procedimento assemelha-se a situações cotidianas permitindo mais investigações sobre a interferência.(AU)

Item repetition is a mechanism which can cause interference during codification. To investigate the impact of this type of inference in long term episodic memory we established a codification procedure composed of three consecutive word recognition tests in which repeated distractors were used (difficult context), or not (easy context). The score obtained in both contexts was compared when the stimulus was presented auditorily as well as visually. Our subjects were 46 university students and 16 middle aged adults. The score from the immediate and the long term recognition tests was worse in the difficult context, independent of item presentation type or subject age. The results indicate that item repetition generated interference, hindering immediate and long term memory. This process lends itself to everyday situations, allowing further investigation concerning interference.(AU)