Scene construction processes in the anterior hippocampus during temporal episodic memory retrieval.

Although the hippocampus has been implicated in both the temporal organization of memories and association of scene elements, some theoretical accounts posit that the role of the hippocampus in episodic memory is largely atemporal. In this study, we set out to explore this discrepancy by identifying hippocampal activity patterns related to scene construction while participants performed a temporal order memory task. Participants in the fMRI scanner were shown a sequence of photographs, each consisting of a central object and a contextual background scene. On each retrieval trial, participants were shown a pair of the original photographs (FULL), objects from the scenes without the background (OBJ), or background contexts without the main foreground object (BACK). In the temporal order judgment (TOJ) task, participants judged the temporal order of the pair of scenes; in the Viewing trials, two identical scenes were shown without any task. First, we found that the anterior hippocampus-particularly the CA1 and subiculum-showed similar patterns of activation between the BACK and OBJ conditions, suggesting that scene construction occurred spontaneously during both TOJ and Viewing. Furthermore, neural markers of scene construction in the anterior hippocampus did not apply to incorrect trials, showing that successful temporal memory retrieval was functionally linked to scene construction. In the cortex, time-processing areas, such as the supplementary motor area and the precuneus, and scene-processing areas, such as the parahippocampal cortex, were activated and functionally connected with the hippocampus. Together, these results support the view that the hippocampus is concurrently involved in scene construction and temporal organization of memory and propose a model of hippocampal episodic memory that takes both processes into account.

Do actions structure auditory memory? Action-based event segmentation effects on sensory responses, pupil dilation and sequential memory.

Our actions shape our everyday experience: what we experience, how we perceive, and remember it are deeply affected by how we interact with the world. Performing an action to deliver a stimulus engages neurophysiological processes which are reflected in the modulation of sensory and pupil responses. We hypothesized that these processes shape memory encoding, parsing the experience by grouping self- and externally generated stimuli into differentiated events. Participants encoded sound sequences, in which either the first or last few sounds were self-generated and the rest externally generated. We tested recall of the sequential order of sounds that had originated from the same (within event) or different sources (across events). Memory performance was not higher for within-event sounds, suggesting that actions did not structure the memory representation. However, during encoding, we observed the expected electrophysiological response attenuation for self-generated sounds, together with increased pupil dilation triggered by actions. Moreover, at the boundary between events, physiological responses to the first sound from the new source were influenced by the direction of the source switch. Our results suggest that introducing actions creates a stronger contextual shift than removing them, even though actions do not directly contribute to memory performance. This study contributes to our understanding of how interacting with sensory input shapes experiences by exploring the relationships between action effects on sensory responses, pupil dilation, and memory encoding. Importantly, it challenges the notion of a meaningful contribution from low-level neurophysiological mechanisms associated with action execution in the modulation of the self-generation effect.

Enactment encoding promotes relative temporal order memory.

Studies have shown that enactment improves memory; however, in daily life, our memories of motor events often exhibit a relative temporal order. Therefore, this study examined whether enactment promotes relative temporal order memory. In Experiment 1, a sequential recall task and a subject-performed task were used to explore whether enactment encoding improved relative temporal order memory. The results showed that the relative temporal order memory of the enactment-encoding group was significantly better than that of the verbal-encoding group, indicating that enactment promoted relative temporal order memory. Since temporal order memory is often affected by spatial cues, in Experiment 2, we further controlled spatial cues and used a 2 (spatial cues: consistent with temporal order, vs. no cues) × 2 (encoding type: verbal vs. enactment) design to explore whether spatial cues influence the effect of enactment encoding on temporal order memory. The results showed that compared with verbal encoding, enactment encoding significantly improved relative temporal order memory. However, no effect of spatial cues on relative temporal order memory was found. Our study confirmed that enactment encoding promotes relative temporal order memory performance independent of spatial cues.

The neurophysiological mechanisms of medial prefrontal-perirhinal cortex circuit mediating temporal order memory decline in early stage of AD rats.

The temporal component of episodic memory has been recognized as a sensitive behavioral marker in early stage of Alzheimer's disease (AD) patients. However, parallel studies in AD animals are currently lacking, and the underlying neural circuit mechanisms remain poorly understood. Using a novel AppNL-G-F knock-in (APP-KI) rat model, the developmental changes of temporal order memory (TOM) and the relationship with medial prefrontal cortex and perirhinal cortex (mPFC-PRH) circuit were determined through in vivo electrophysiology and microimaging technique. We observed a deficit in TOM performance during the object temporal order memory task (OTOMT) in APP-KI rats at 6 month old, which was not evident at 3 or 4 months of age. Alongside behavioral changes, we identified a gradually extensive and aggravated regional activation and functional alterations in the mPFC and PRH during the performance of OTOMT, which occurred prior to the onset of TOM deficits. Moreover, coherence analysis showed that the functional connectivity between the mPFC and PRH could predict the extent of future behavioral performance. Further analysis revealed that the aberrant mPFC-PRH interaction mainly attributed to the progressive deterioration of synaptic transmission, information flow and network coordination from mPFC to PRH, suggesting the mPFC dysfunction maybe the key area of origin underlying the early changes of TOM. These findings identify a pivotal role of the mPFC-PRH circuit in mediating the TOM deficits in the early stage of AD, which holds promising clinical translational value and offers potential early biological markers for predicting AD memory progression.

Manipulation of α4ßδ GABAA receptors alters synaptic pruning in layer 3 prelimbic prefrontal cortex and impairs temporal order recognition: Implications for schizophrenia and autism.

Temporal order memory is impaired in autism spectrum disorder (ASD) and schizophrenia (SCZ). These disorders, more prevalent in males, result in abnormal dendritic spine pruning during adolescence in layer 3 (L3) medial prefrontal cortex (mPFC), yielding either too many (ASD) or too few (SCZ) spines. Here we tested whether altering spine density in neural circuits including the mPFC could be associated with impaired temporal order memory in male mice. We have shown that α4ßδ GABAA receptors (GABARs) emerge at puberty on spines of L5 prelimbic mPFC (PL) where they trigger pruning. We show here that α4ßδ receptors also increase at puberty in L3 PL (P < 0.0001) and used these receptors as a target to manipulate spine density here. Pubertal injection (14 d) of the GABA agonist gaboxadol, at a dose (3 mg/kg) selective for α4ßδ, reduced L3 spine density by half (P < 0.0001), while α4 knock-out increased spine density âˆ¼ 40 % (P < 0.0001), mimicking spine densities in SCZ and ASD, respectively. In both cases, performance on the mPFC-dependent temporal order recognition task was impaired, resulting in decreases in the discrimination ratio which assesses preference for the novel object: -0.39 ± 0.15, gaboxadol versus 0.52 ± 0.09, vehicle; P = 0.0002; -0.048 ± 0.10, α4 KO versus 0.49 ± 0.04, wild-type; P < 0.0001. In contrast, the number of approaches was unaltered, reflecting unchanged locomotion. These data suggest that altering α4ßδ GABAR expression/activity alters spine density in L3 mPFC and impairs temporal order memory to mimic changes in ASD and SCZ. These findings may provide insight into these disorders.

Opposite effects of emotion and event segmentation on temporal order memory and object-context binding.

Our daily lives unfold continuously, yet our memories are organised into distinct events, situated in a specific context of space and time, and chunked when this context changes (at event boundaries). Previous research showed that this process, termed event segmentation, enhances object-context binding but impairs temporal order memory. Physiologically, peaks in pupil dilation index event segmentation, similar to emotion-induced bursts of autonomic arousal. Emotional arousal also modulates object-context binding and temporal order memory. Yet, these two critical factors have not been systematically studied together. To address this gap, we ran a behavioural experiment using a paradigm validated to study event segmentation and extended it with emotion manipulation. During encoding, we sequentially presented greyscale objects embedded in coloured frames (colour changes defining events), with a neutral or aversive sound. During retrieval, we tested participants' memory of temporal order memory and object-colour binding. We found opposite effects of emotion and event segmentation on episodic memory. While event segmentation enhanced object-context binding, emotion impaired it. On the contrary, event segmentation impaired temporal order memory, but emotion enhanced it. These findings increase our understanding of episodic memory organisation in laboratory settings, and potentially in real life with perceptual changes and emotion fluctuations constantly interacting.

Recency memory is altered in cocaine-withdrawn adolescent rats: Implication of cortical mTOR signaling.

In humans, cocaine abuse during adolescence poses a significant risk for developing cognitive deficits later in life. Among the regions responsible for cognitive processes, the medial prefrontal cortex (mPFC) modulates temporal order information via mechanisms involving the mammalian-target of rapamycin (mTOR)-mediated pathway and protein synthesis regulation. Accordingly, our goal was to study the effect of repeated cocaine exposure during both adolescence and adulthood on temporal memory by studying the mTOR pathway in the mPFC. Adolescent or adult rats underwent repeated cocaine injections for 15 days and, after two weeks of withdrawal, engaged in the temporal order object recognition (TOOR) test. We found that repeated cocaine exposure during adolescence impaired TOOR performance, while control or adult-treated animals showed no impairments. Moreover, activation of the mTOR-S6-eEF2 pathway following the TOOR test was diminished only in the adolescent cocaine-treated group. Notably, inhibition of the mTOR-mediated pathway by rapamycin injection impaired TOOR performance in naïve adolescent and adult animals, revealing this pathway to be a critical component in regulating recency memory. Our data indicate that withdrawal from cocaine exposure impairs recency memory via the dysregulation of protein translation mechanisms, but only when cocaine is administered during adolescence.

Time-course of age-related temporal order memory decline in an object recognition paradigm in mice.

Temporal order memory refers to the ability to remember the order of occurrence of items across time. It is a critical feature of episodic memory that is often tested in rodents using spontaneous object recognition paradigms. However, impact of aging over performances of temporal order memory decline is barely known. Herein, we characterized here the effect of normal aging on the temporal order memory performances in NMRI mice between 3 and 19months of age, with an inter-session interval of 24h.We found that temporal order memory was impaired as soon as7 months of age. These results provide strong evidence that temporal order memory is particularly vulnerable to the deleterious effect of normal aging.

Retrieval context determines whether event boundaries impair or enhance temporal order memory.

Meaningful changes in context create "event boundaries", segmenting continuous experience into distinct episodes in memory. A foundational finding in this literature is that event boundaries impair memory for the temporal order of stimuli spanning a boundary compared to equally spaced stimuli within an event. This seems surprising in light of intuitions about memory in everyday life, where the order of within-event experiences (did I have coffee before the first bite of bagel?) often seems more difficult to recall than the order of events per se (did I have breakfast or do the dishes first?). Here, we aimed to resolve this discrepancy by manipulating whether stimuli carried information about their encoding context during retrieval, as they often do in everyday life (e.g., bagel-breakfast). In Experiments 1 and 2, we show that stimuli inherently associated with a unique encoding context produce a "flipped" order memory effect, whereby temporal memory was superior for cross-boundary than within-event item pairs. In Experiments 3 and 4, we added context information at retrieval to a standard laboratory event memory protocol where stimuli were encoded in the presence of arbitrary context cues (colored frames). We found that whether temporal order memory for cross-boundary stimuli was enhanced or impaired relative to within-event items depended on whether the context was present or absent during the memory test. Taken together, we demonstrate that the effect of event boundaries on temporal memory is malleable, and determined by the availability of context information at retrieval.

The Role of Executive Functions in Item Recognition and Temporal Order Memory Development.

Item recognition and temporal order memory follow different developmental trajectories during middle childhood, with item recognition performance stabilizing and temporal order memory performance continuing to improve. We investigated the potential unique role of individual executive functions on item recognition and temporal order memory during this critical development period. Our results replicate and expand on previous findings, suggesting that executive functions, specifically inhibitory control and working memory, may be more crucial for successful temporal order memory than for item recognition during middle childhood.

Hippocampal Representations of Event Structure and Temporal Context during Episodic Temporal Order Memory.

The hippocampus plays an important role in representing spatial locations and sequences and in transforming representations. How these representational structures and operations support memory for the temporal order of random items is still poorly understood. We addressed this question by leveraging the method of loci, a powerful mnemonic strategy for temporal order memory that particularly recruits hippocampus-dependent computations of spatial locations and associations. Applying representational similarity analysis to functional magnetic resonance imaging activation patterns revealed that hippocampal subfields contained representations of multiple features of sequence structure, including spatial locations, location distance, and sequence boundaries, as well as episodic-like temporal context. Critically, the hippocampal CA1 exhibited spatial transformation of representational patterns, showing lower pattern similarity for items in same locations than closely matched different locations during retrieval, whereas the CA23DG exhibited sequential transformation of representational patterns, showing lower pattern similarity for items in near locations than in far locations during encoding. These transformations enabled the encoding of multiple items in the same location and disambiguation of adjacent items. Our results suggest that the hippocampus can flexibly reconfigure multiplexed event structure representations to support accurate temporal order memory.

The Fragility of Temporal Memory in Alzheimer's Disease.

BACKGROUND: Although episodic memory impairment is one of the hallmarks of Alzheimer's disease (AD), the relative decline in the components of episodic memory (What, Where, and When) and the effects of cognitive training on each of them are still unknown. OBJECTIVE: We aimed to independently assess the impairment in each component of episodic memory in early to moderate AD and address whether it can be enhanced through active, spatiotemporal episodic training. METHODS: A non-verbal scene-based episodic memory task was developed to assess the ability to remember What, Where, and When information. Experiment 1 tested whether this task can differentiate AD subjects (N = 16) from healthy controls (N = 16). In Experiment 2, 13 AD subjects underwent 16 training sessions, followed by a re-administration of the scene-based memory task. Experiment 3 tested 42 healthy older adults and 51 younger adults on the same task to investigate the effects of normal aging. RESULTS: Of the three components, When memory had the highest predictive power in distinguishing AD from normal aging. Following training of AD subjects, only Where memory improved. Only What memory revealed a significant decline in healthy subjects from 65-85 years of age. CONCLUSION: These findings shed new light on the importance of the temporal component of episodic memory as a behavioral marker of AD. The selective improvement of spatial but not temporal memory through training further demonstrates the fragility of temporal memory even in early AD. Neuroscientific research is needed to distinguish whether the Where component was enhanced by improvements in hippocampal spatial representation or by other compensatory mechanisms.

Delayed voluntary physical exercise restores "when" and "where" object recognition memory after traumatic brain injury.

Physical exercise has been associated with improved cognition and may even reduce memory deficits after brain injuries. The aims of this work were to: 1) assess whether voluntary physical exercise can reduce the deficits associated with traumatic brain injury (TBI) in two different components of episodic-like memory based on object recognition, temporal order memory ("when"), and object location memory ("where"); and 2) determine whether changes in levels of brain-derived neurotrophic factor (BDNF) in the hippocampus and prefrontal cortex, as well as alterations in hippocampal cytokines, insulin-like growth factor-1 (IGF-1) and vascular endothelial growth factor (VEGF), may influence the effects exercise has on either or both tasks. The rats were distributed into a sham group, a TBI group that remained sedentary (TBI-sed), and a TBI group that had access to a running wheel for a 25-day period from post-injury day 11 (TBI-exe). The rats were sacrificed after the "where" memory task, at post-injury day 37. Physical exercise restored the "when" and "where" memories, which had been impaired by the TBI, and increased the concentration of BDNF in the hippocampus, but not the prefrontal cortex. Neither TBI nor exercise were found to significantly affect hippocampal cytokines, IGF-1 or VEGF at this time post-injury. BDNF levels showed significant positive correlations with exercise, and with "when" (but not "where") memory. These results indicate that post-injury physical exercise restores "when" and "where" object recognition memory tasks after TBI, and that increased BDNF seems to be involved in this effect, particularly with regard to "when" memory.

Fallacious reversal of event-order during recall reveals memory reconstruction in rhesus monkeys.

Whether nonhuman primate species can construct, still less reconstruct, order of past events remains controversial. Here we show that rhesus macaques are capable of reconstructing the temporal order of memory traces of dynamic videos. We made use of 2000 unseen naturalistic videos of wildlife content for encoding, and then probed monkeys' recollection of temporal-order of events with a temporal-order judgement (TOJ) test. This encoding-TOJ procedure was repeated at three different time points (day 1, day 2, and day 32+). We specifically tested for differential TOJ memory performance for videos that were displayed in a reverse sequence versus videos that were displayed in a normal sequence at these different time points. We observed that during TOJ monkeys committed more errors for video content that were shown in reverse but only upon re-exposures (i.e., day 2 and day 32+). Moreover, this memory distortion effect is significantly accentuated by social relevance of the video content. We interpret that the monkeys reversed the out-of-order events in accordance to their knowledge priors; such fallaciously re-ordered memory traces then led to higher rate of errors. Demonstrating in macaque monkeys a form of errors in temporal-order memory for reverse videos carries implications for studying memory retrospection in the primates.

Longitudinal Development of Memory for Temporal Order in Early to Middle Childhood.

Existing studies examining the development of temporal order memory show that although young children perform above chance on some tasks assessing temporal order memory, there are significant age-related differences across childhood. Yet, the trajectory of children's ability to retrieve temporal order remains unclear as existing conclusions are drawn from cross-sectional studies. The present study utilized an accelerated longitudinal design in order to characterize the developmental trajectory of temporal order memory in a sample of 200 healthy 4- to 8-year-old children. Specifically, two tasks commonly used in the literature were tested longitudinally: a primacy judgment task and an ordering task. Results revealed that, even after controlling for differences in IQ, linearly increasing trajectories characterized age-related change in performance for both tasks; however, change appeared greater for the temporal ordering task. Further, performance on the two tasks was positively related, suggesting shared underlying mechanisms. These findings provide a more thorough understanding of temporal order memory in early to middle childhood by characterizing the developmental trajectories of two commonly used tasks and have important implications for our understanding of children's developing memory more broadly.

Y-Shaped Maze to Test Spontaneous Object Recognition and Temporal Order Memory After Traumatic Brain Injury.

Traumatic brain injury (TBI) is one of the most frequent causes of brain damage. Cognitive deficits have been reported in the literature after mild-to-severe TBI affecting memory, language, executive functions, attention, and information processing speed. In this chapter, we describe a method to characterize cognitive impairment in rats following TBI of various intensities. The focus will be on spontaneous object recognition and temporal order memory in rats. These tests are performed in a Y-shaped maze. We have previously identified using this method persistent spontaneous object recognition and temporal order memory deficits following mild-to-moderate TBI in the animals up to 35-day postinjury.

Deficits in temporal order memory induced by interferon-alpha (IFN-α) treatment are rescued by aerobic exercise.

Patients receiving cytokine immunotherapy with IFN-α frequently present with neuropsychiatric consequences and cognitive impairments, including a profound depressive-like symptomatology. While the neurobiological substrates of the dysfunction that leads to adverse events in IFN-α-treated patients remains ill-defined, dysfunctions of the hippocampus and prefrontal cortex (PFC) are strong possibilities. To date, hippocampal deficits have been well-characterised; there does however remain a lack of insight into the nature of prefrontal participation. Here, we used a PFC-supported temporal order memory paradigm to examine if IFN-α treatment induced deficits in performance; additionally, we used an object recognition task to assess the integrity of the perirhinal cortex (PRH). Finally, the utility of exercise as an ameliorative strategy to recover temporal order deficits in rats was also explored. We found that IFN-α-treatment impaired temporal order memory discriminations, whereas recognition memory remained intact, reflecting a possible dissociation between recognition and temporal order memory processing. Further characterisation of temporal order memory impairments using a longitudinal design revealed that deficits persisted for 10 weeks following cessation of IFN-α-treatment. Finally, a 6 week forced exercise regime reversed IFN-α-induced deficits in temporal order memory. These data provide further insight into the circuitry involved in cognitive impairments arising from IFN-α-treatment. Here we suggest that PFC (or the hippocampo-prefrontal pathway) may be compromised whilst the function of the PRH is preserved. Deficits may persist after cessation of IFN-α-treatment which suggests that extended patient monitoring is required. Aerobic exercise may be restorative and could prove beneficial for patients treated with IFN-α.

Fellow travellers: Working memory and mental time travel in rodents.

The impairment of mental time travel is a severe cognitive symptom in patients with brain lesions and a number of neuropsychiatric disorders. Whether animals are also able to mentally travel in time both forward and backward is still a matter of debate. In this regard, we have proposed a continuum of mental time travel abilities across different animal species, with humans being the species with the ability to perform most sophisticated forms of mental time travel. In this review and perspective article, we delineate a novel approach to understand the evolution, characteristics and function of human and animal mental time travel. Furthermore, we propose a novel approach to measure mental time travel in rodents in a comprehensive manner using a test battery composed of well-validated and easy applicable tests.

Age-related differences on a new test of temporal order memory for everyday events.

We developed a new test to examine incidental temporal order memory for a self-generated sequence of tasks one might complete in everyday life. Young and older adults were given 10 cards, each listing a task one might accomplish in a typical day. Participants were asked to self-generate a "to do" list by placing the 10 cards in a sequence representing the order in which they would accomplish the tasks, but were not informed of a subsequent memory test. We assessed immediate free recall, delayed free recall, and delayed cued recall for the order of the tasks in the sequence. Older adults were significantly impaired relative to young adults on immediate free recall, delayed free recall, and delayed cued recall. Correlation analyses with standardized neuropsychological tests provide preliminary evidence for construct validity for our test, which is portable and can be rapidly administered in clinical or laboratory settings.

Contributions of primate prefrontal cortex and medial temporal lobe to temporal-order memory.

Neuropsychological and neurophysiological studies have emphasized the role of the prefrontal cortex (PFC) in maintaining information about the temporal order of events or items for upcoming actions. However, the medial temporal lobe (MTL) has also been considered critical to bind individual events or items to their temporal context in episodic memory. Here we characterize the contributions of these brain areas by comparing single-unit activity in the dorsal and ventral regions of macaque lateral PFC (d-PFC and v-PFC) with activity in MTL areas including the hippocampus (HPC), entorhinal cortex, and perirhinal cortex (PRC) as well as in area TE during the encoding phase of a temporal-order memory task. The v-PFC cells signaled specific items at particular time periods of the task. By contrast, MTL cortical cells signaled specific items across multiple time periods and discriminated the items between time periods by modulating their firing rates. Analysis of the temporal dynamics of these signals showed that the conjunctive signal of item and temporal-order information in PRC developed earlier than that seen in v-PFC. During the delay interval between the two cue stimuli, while v-PFC provided prominent stimulus-selective delay activity, MTL areas did not. Both regions of PFC and HPC exhibited an incremental timing signal that appeared to represent the continuous passage of time during the encoding phase. However, the incremental timing signal in HPC was more prominent than that observed in PFC. These results suggest that PFC and MTL contribute to the encoding of the integration of item and timing information in distinct ways.