Temporal Order Memory Task Research Articles

Maternal fluoxetine impairs synaptic transmission and plasticity in the medial prefrontal cortex and alters the structure and function of dorsal raphe nucleus neurons in offspring mice

Selective serotonin (5-HT) reuptake inhibitors (SSRIs) are commonly prescribed to women during pregnancy and breastfeeding despite posing a risk of adverse cognitive outcomes and affective disorders for the child. The consequences of SSRI-induced excess of 5-HT during development for the brain neuromodulatory 5-HT system remain largely unexplored. In this study, an SSRI - fluoxetine (FLX) - was administered to C57BL/6 J mouse dams during pregnancy and lactation to assess its effects on the offspring. We found that maternal FLX decreased field potentials, impaired long-term potentiation, facilitated long-term depression and tended to increase the density of 5-HTergic fibers in the medial prefrontal cortex (mPFC) of female but not male adolescent offspring. These effects were accompanied by deteriorated performance in the temporal order memory task and reduced sucrose preference with no change in marble burying behavior in FLX-exposed female offspring. We also found that maternal FLX reduced the axodendritic tree complexity of 5-HT dorsal raphe nucleus (DRN) neurons in female but not male offspring, with no changes in the excitability of DRN neurons of either sex. While no effects of maternal FLX on inhibitory postsynaptic currents (sIPSCs) in DRN neurons were found, we observed a significant influence of FLX exposure on kinetics of spontaneous excitatory postsynaptic currents (sEPSCs) in DRN neurons. Finally, we report that no changes in field potentials and synaptic plasticity were evident in the mPFC of the offspring after maternal exposure during pregnancy and lactation to a new antidepressant, vortioxetine. These findings show that in contrast to the mPFC, long-term consequences of maternal FLX exposure on the structure and function of DRN 5-HT neurons are mild and suggest a sex-dependent, distinct sensitivity of cortical and brainstem neurons to FLX exposure in early life. Vortioxetine appears to exert fewer side effects with regards to the mPFC when compared with FLX.

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 accountsposit 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.

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.

The fornix supports episodic memory during childhood.

Episodic memory relies on the coordination of widespread brain regions that reconstruct spatiotemporal details of an episode. These topologically dispersed brain regions can rapidly communicate through structural pathways. Research in animal and human lesion studies implicate the fornix-the major output pathway of the hippocampus-in supporting various aspects of episodic memory. Because episodic memory undergoes marked changes in early childhood, we tested the link between the fornix and episodic memory in an age window of robust memory development (ages 4-8years). Children were tested on the stories subtest from the Children's Memory Scale, a temporal order memory task, and a source memory task. Fornix streamlines were reconstructed using probabilistic tractography to estimate fornix microstructure. In addition, we measured fornix macrostructure and computed free water. To assess selectivity of our findings, we also reconstructed the uncinate fasciculus. Findings show that children's memory increases from ages 4 to 8 and that fornix micro- and macrostructure increases between ages 4 and 8. Children's memory performance across nearly every memory task correlated with individual differences in fornix, but not uncinate fasciculus, white matter. These findings suggest that the fornix plays an important role in supporting the development of episodic memory, and potentially semantic memory, in early childhood.

Limitations of the rat medial forebrain lesion model to study prefrontal cortex mediated cognitive tasks in Parkinson’s disease

Parkinson’s Disease (PD) is a progressive movement disorder characterized by the loss of dopaminergic neurons in the midbrain. Besides motor impairment, PD patients exhibit non-motor symptoms that negatively impact their quality of life and often manifest prior to motor deficits. One such symptom is mild cognitive impairment (PD-MCI), which is comprised of deficits in executive function such as working memory, attention, cognitive flexibility, and spatial memory. The 6-hydroxydopamine (6-OHDA) induced unilateral medial forebrain bundle (MFB) lesion animal model successfully recapitulates PD motor impairment but is also used to assess non-motor deficits. The present study utilizes a unilateral 6-OHDA induced MFB lesion rodent model to investigate prefrontal cortex (PFC)-mediated cognitive processes that are impaired in PD patients. In a test of attentional set shifting, PD rodents demonstrated deficits in simple discrimination, but not in rule reversal or extradimensional shifts. PD rodents also exhibited deficits in a temporal order memory task but had no deficits in novel/spatial object recognition or object-in-place tasks. These results reveal limitations of the 6-OHDA induced unilateral MFB lesion model to completely recapitulate PD-MCI symptoms suggesting a need for better lesion models to study PD-MCI.

Visuospatial Temporal Order Memory Deficits in Older Adults with HIV Infection

To compare temporal order memory in older adults with and without human immunodeficiency virus (HIV) infection. The frontal and temporal lobes play a key role in temporal order memory for items in a sequence. HIV-associated episodic memory deficits correlate with damage to neocortical interneurons in the fronto-striato-thalamo-cortical pathway and with atypical activation of the medial temporal lobes. Therefore, temporal order memory may be sensitive to neuropathological changes in individuals with HIV. In this study, 50 HIV-seropositive individuals aged ≥ 50 years and 50 seronegative controls performed a computerized visuospatial temporal order memory task. During the sample phase of each trial, participants were shown circles presented 1 at a time in a random sequence at the end of each of the 8 arms of a radial maze. During the choice phase, they were shown the maze with a circle at the ends of 2 of the arms and asked which circle had appeared earlier than the other in the original sequence. Performance in both groups improved as a function of greater temporal separation between circle presentations. However, the HIV group had significantly worse memory impairment across all temporal separations, and the impairment was independently associated with clinical deficits in executive function and delayed retrospective memory. Our results extend prior findings that HIV is associated with deficits in strategic aspects of memory encoding and retrieval. The neural mechanisms warrant further research, as do potential impacts on everyday function, eg, adherence to antiretroviral drug regimens.

The dopamine D1 receptor agonist SKF 38393 improves temporal order memory performance in maternally deprived rats

Previously, we showed that maternal deprivation (MD) (3h/day, postnatal-day 1–14) impaired the performance at adulthood in the object temporal order memory task (TMT) that principally implicates the medial prefrontal cortex (mPFC). Dopamine (DA) transmission in the PFC may play a critical role in the achievement of the TMT. Here, to investigate whether MD could results in dysfunction of the DA system in the mPFC, we assessed in this region the tissue contents and extracellular levels of DA and its metabolites, as the density of D1 receptor. Besides we examined whether an agonist of the DA receptor D1, the SKF38393, could have a beneficial effect on the performance of deprived (D) rats in the TMT. We observed that MD induced a significant reduction of the extracellular level of DOPAC in the mPFC and in the density of the D1 receptor in the anterior cingulate cortex, a sub-region of mPFC. On the other hand, we observed that an acute systemic injection of a D1 receptor agonist, SKF38393, was effective to correct the memory deficiency of D rats in the TMT, when administered before the retrieval phase. We showed that a stress suffered by rats during the perinatal period led to dysfunction of the adult DA system, possibly triggering greater vulnerability to cognitive and mood disorders. Interestingly, an acute administration of a D1 receptor agonist in adulthood was sufficient to improve the deficit in the temporal memory. A better understanding of this phenomenon would permit the development of treatments adapted to patients with a history of early traumatic experiences.

The histamine H1 receptor and recollection-based discrimination in a temporal order memory task in the mouse

The histaminergic system in the central nervous system is involved in a variety of physiological, pathological and behavioral processes. There is now substantial evidence for an important role of histaminergic neurotransmission in learning and memory related processes. The histamine H1 receptor (H1R) is the most abundant histamine receptor in the mammalian brain. We have recently demonstrated that the genetic inactivation of the H1R in mice impairs episodic-like memory, defined as the ability to remember previous experiences with respect to their content and their temporal and spatial context. The ability to encode and retrieve the temporal order of unique events, that is its temporal context, is a core feature of episodic memory. Here we asked whether episodic-like memory deficits of H1R-KO mice are possibly due to changes in the processing, encoding or maintenance of temporal or sequence information which is critical for episodic-like memory formation. H1R-KO mice were tested in the temporal object memory (TOM) task with different inter-trial intervals (ITIs). H1R-KO mice showed impaired TOM when being tested under both, short and longer ITIs. Another aim of the study was to determine whether temporal order discrimination is based on either familiarity or recollection-based memory processes. The performance of wild type (WT) animals in the TOM task suggests that they used recollection-like discrimination strategies.

Maternal deprivation induces deficits in temporal memory and cognitive flexibility and exaggerates synaptic plasticity in the rat medial prefrontal cortex

Early life adverse events can lead to structural and functional impairments in the prefrontal cortex (PFC). Here, we investigated whether maternal deprivation (MD) alters PFC-dependent executive functions, neurons and astrocytes number and synaptic plasticity in adult male Long-Evans rats. The deprivation protocol consisted of a daily separation of newborn Long-Evans pups from their mothers and littermates 3h/day postnatal day 1–14. Cognitive performances were assessed in adulthood using the temporal order memory task (TMT) and the attentional set-shifting task (ASST) that principally implicates the PFC and the Morris water maze task (WMT) that does not essentially rely on the PFC. The neurons and astrocytes of the prelimbic (PrL) area of the medial PFC (mPFC) were immunolabelled respectively with anti-NeuN and anti-GFAP antibodies and quantified by stereology. The field potentials evoked by electrical stimulation of ventral hippocampus (ventral HPC) were recorded in vivo in the PrL area. In adulthood, MD produced cognitive deficits in two PFC-dependent tasks, the TMT and ASST, but not in the WMT. In parallel, MD induced in the prelimbic area of the medial PFC an upregulation of long-term potentiation (LTP), without any change in the number of neurons and astrocytes. We provide evidence that MD leads in adults to an alteration of the cognitive abilities dependent on the PFC, and to an exaggerated synaptic plasticity in this region. We suggest that this latter phenomenon may contribute to the impairments in the cognitive tasks.

Temporal order memory deficits prior to clinical diagnosis in Huntington’s disease

The current study examined temporal order memory in preclinical Huntington's disease (pre-HD). Participants were separated into less than 5 years (pre-HD near) and more than 5 years (pre-HD far) from estimated age of clinical diagnosis. Participants completed a temporal order memory task on a computerized radial eight-arm maze. On the study phase of each trial, participants viewed a random sequence of circles appearing one at a time at the end of each arm. On the choice phase, participants viewed two circles at the end of the study phase arms and chose the circle occurring earliest in the sequence. The task involved manipulations of the temporal lag, defined as the number of arms occurring in the sample phase sequence between the two choice phase arms. Research suggests that there is more interference for temporally proximal stimuli relative to temporally distal stimuli. There were no significant differences between the pre-HD far group and controls on the temporal order memory task. The pre-HD near group demonstrated significant impairments relative to the other groups on closer temporal lags, but were normal on the furthest temporal lag. Therefore, temporal order memory declines with increased temporal interference in pre-HD close to estimated diagnosis of HD.

Poster 7: Memory for Temporal Sequences for the Early Detection of Cognitive Changes in Preclinical Huntington's Disease

Previous research implicates the prefrontal cortex in memory for temporal order. Since frontal-striatal circuits are disrupted early in Huntington's disease (HD), temporal order memory may be particularly sensitive to neuropathological changes in preclinical HD. Eighteen presymptomatic gene carriers, 18 age- and sex-matched normal controls, and 18 non-gene–carriers were administered a visuospatial temporal order memory task on a computerized radial eight-arm maze. Presymptomatic gene carriers were assigned to two groups consisting of presymptomatic gene carriers less than five years away from estimated age of onset (HD Close group, n = 10) and presymptomatic gene carriers more than five years away from estimated age of onset (HD Far group, n = 8). On the study phase, the participant was shown a random sequence of circles presented one at a time at the end of each of the eight arms. On the choice phase, the participant was presented with a circle at the end of two of the study phase arms and was asked to choose the circle that occurred earlier in the sequence. Parametric manipulations of the temporal metric were carried out by systematically changing the temporal separation lag between the two circles in the choice phase. As expected, all groups showed superior performance on distal temporal separation lags compared to proximal temporal separation lags. However, the HD Close group demonstrated impairments relative to the HD Far group, non-gene–carriers, and normal controls on more proximal temporal separation lags ( p

Recognition Memory for Objects, Place, and Temporal Order: A Disconnection Analysis of the Role of the Medial Prefrontal Cortex and Perirhinal Cortex

Recognition memory requires judgments of the previous occurrence of stimuli made on the basis of the relative familiarity of individual objects, or by integrating information concerning objects and location, or by using recency information. The present study examined the role of the medial prefrontal cortex (mPFC) and perirhinal cortex (PRH) in these distinct recognition memory processes using a series of behavioral tests: a novel object preference task, an object-in-place task, and a temporal order memory task. Also, a disconnection procedure was used to test whether these regions form components of an integrated system for recognition memory. Male DA rats received bilateral lesions in the PRH or mPFC or unilateral lesions placed in both cortices in either the same (PRH-mPFC IPSI) or contralateral (PRH-mPFC CONTRA) hemispheres. A fifth group underwent sham surgery (SHAM). In the object-in-place and temporal order memory tasks, the PRH, mPFC, and PRH-mPFC CONTRA groups were significantly impaired. However, performance in the novel object preference task was only impaired in the PRH group. No group was impaired in the object location task. These results demonstrate that the mPFC and PRH are crucial for object-in-place associational and recency discriminations, whereas the PRH but not the mPFC is important for the discrimination of novel and familiar individual objects. Importantly, these results provide direct support for the hypothesis that to make discriminations based on associational or recency information, both cortical regions operate within an integrated neural network for recognition memory.

D 1 receptor modulation of memory retrieval performance is associated with changes in pCREB and pDARPP-32 in rat prefrontal cortex

We have recently shown a significant role of dopamine D 1 receptors in recognition and temporal order memory retrieval for objects in rodents [Hotte M, Naudon L, Jay TM. Modulation of recognition and temporal order memory retrieval by dopamine D(1) receptor in rats. Neurobiol Learn Mem 2005;84:85–92]. The present study investigates the signal transduction pathways underlying dopamine D 1 receptor modulation of retrieval performance in these memory tasks at different delays. We analyzed the level of phosphorylation of both CREB (cAMP response element binding protein) and DARPP-32 (dopamine and cAMP-regulated phosphoprotein, 32 kDa) in (1) the prefrontal cortex of rats that had performed the object recognition task, (2) the prefrontal and perirhinal cortices of rats that had performed the temporal order memory task for objects. For comparison, we explored the phosphorylation state of CREB and DARPP-32 in the prefrontal cortex, nucleus accumbens and hippocampus of rats having performed badly on the delayed spatial win-shift task after D 1 blockade. The improvement in recognition and temporal order memory performance at a 4 h-delay was associated with an increased phosphorylation of both CREB and DARPP-32 in the prefrontal cortex of rats treated with the D 1 agonist SKF 81297. By contrast, the significant impairment of delayed spatial memory retrieval after administration of the selective D 1 antagonist SCH 23390 was associated with decreased phosphorylation of CREB and DARPP-32 in the prefrontal cortex. These results provide insight into molecular mechanisms involved in D 1 receptor-dependent modulation of short- versus long-term memory in prefrontal cortex where DARPP-32 in synergy with CREB may represent a pivotal role.

Medial prefrontal cortex is involved in spatial temporal order memory but not spatial recognition memory in tests relying on spontaneous exploration in rats

The present study describes two novel tasks relying on spontaneous patterns of exploration in a radial-arm maze that can be used to assess spatial recognition memory and spatial temporal order memory (i.e. memory for the order in which places have been visited) in the rat. In the recognition memory task, rats were permitted to freely explore two arms in the maze on a first trial and one ‘familiar’ arm and one novelly located arm on a second trial 105 min later. In the temporal order memory task, rats were permitted to explore two arms in the maze on a first trial, two novel arms on a second trial 60 min later, and one ‘older familiar’ arm and one ‘more recent familiar’ arm on a third trial 45 min later. Using these tasks, we found that rats direct greater exploration at a novel than a familiar arm location, thus showing long-term spatial recognition memory, and at an older familiar arm than a more recent familiar arm, thus showing long-term spatial temporal order memory. Lidocaine inactivation of the mPFC prior to the final trial in each task disrupted performance on the temporal order but not the recognition memory task, thereby demonstrating a role for the mPFC in the retrieval and/or use of temporal order information but not in spatial memory per se. These findings highlight the specific involvement of the rat mPFC in temporal order memory and have important implications for a broader understanding of mPFC function.

Temporal order memory in patients with Korsakoff’s syndrome and medial temporal amnesia

Two groups of patients with global amnesia resulting either from Korsakoff’s syndrome (KS) or from medial temporal lobe (MTL) damage were compared with groups of matched healthy control subjects on a list discrimination paradigm. Item recognition memory was matched across the amnesic and control groups in order to determine whether KS, but not MTL amnesics are disproportionately impaired on list discrimination as predicted by Parkin’s [Functional significance of etiological factors in human amnesia. In: Squire LR, Butters N, editors. Neuropsychology of memory, 2nd ed. New York: The Guilford Press, 1992] hypothesis. However, both patient groups were impaired disproportionately on the temporal order memory task, which is inconsistent with Parkin’s hypothesis. It remains possible that the KS patients are more disproportionately impaired than those with MTL damage because both patient groups performed at floor on the list discrimination task. The results are consistent with theories that postulate a critical role for the hippocampus in the kind of associative memory which underlies memory for temporal order, but not in recognition of single items or arbitrary associations between items of similar kinds.