Crucial role for CA2 inputs in the sequential organization of CA1 time cells supporting memory

There is considerable evidence for hippocampal time cells that briefly activate in succession to represent the temporal structure of memories. Previous studies have shown that time cells can be disrupted while leaving place cells intact, indicating that spatial and temporal information can be coded in parallel. However, the circuits in which spatial and temporal information are coded have not been clearly identified. Here we investigated temporal and spatial coding by dorsal hippocampal CA1 (dCA1) neurons in mice trained on a classic spatial working-memory task. On each trial, the mice approached the same choice point on a maze but were trained to alternate between traversing one of two distinct spatial routes (spatial coding phase). In between trials, there was a 10-s mnemonic delay during which the mouse continuously ran in a fixed location (temporal coding phase). Using cell-type–specific optogenetic methods, we found that inhibiting dorsal CA2 (dCA2) inputs into dCA1 degraded time cell coding during the mnemonic delay and impaired the mouse’s subsequent memory-guided choice. Conversely, inhibiting dCA2 inputs during the spatial coding phase had a negligible effect on place cell activity in dCA1 and no effect on behavior. Collectively, our work demonstrates that spatial and temporal coding in dCA1 is largely segregated with respect to the dCA2–dCA1 circuit and suggests that CA2 plays a critical role in representing the flow of time in memory within the hippocampal network.

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Human hippocampal neurons track moments in a sequence of events

10.1101/2020.12.17.423193 ◽

2020 ◽

Author(s):

Leila Reddy ◽

Benedikt Zoefel ◽

Jessy K. Possel ◽

Judith C. Peters ◽

Doris Dijksterhuis ◽

...

Keyword(s):

Episodic Memory ◽

Hippocampal Neurons ◽

Critical Role ◽

Memory Task ◽

Temporal Information ◽

Firing Activity ◽

Population Activity ◽

Sequence Of Events ◽

Human Hippocampus ◽

Representation Of Time

AbstractAn indispensable feature of episodic memory is our ability to temporally piece together different elements of an experience into a coherent memory. Hippocampal “time cells” – neurons that represent temporal information – may play a critical role in this process. While these cells have been repeatedly found in rodents, it is still unclear to what extent similar temporal selectivity exists in the human hippocampus. Here we show that temporal context modulates the firing activity of human hippocampal neurons during structured temporal experiences. We recorded neuronal activity in the human brain while patients learned predictable sequences of pictures. We report that human time cells fire at successive moments in this task. Furthermore, time cells also signaled inherently changing temporal contexts during empty 10-second gap periods between trials, while participants waited for the task to resume. Finally, population activity allowed for decoding temporal epoch identity, both during sequence learning and during the gap periods. These findings suggest that human hippocampal neurons could play an essential role in temporally organizing distinct moments of an experience in episodic memory.Significance StatementEpisodic memory refers to our ability to remember the “what, where, and when” of a past experience. Representing time is an important component of this form of memory. Here, we show that neurons in the human hippocampus represent temporal information. This temporal signature was observed both when participants were actively engaged in a memory task, as well as during 10s-long gaps when they were asked to wait before performing the task. Furthermore, the activity of the population of hippocampal cells allowed for decoding one temporal epoch from another. These results suggest a robust representation of time in the human hippocampus.

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Time cells in the human hippocampus and entorhinal cortex support episodic memory

10.1101/2020.02.03.932749 ◽

2020 ◽

Cited By ~ 3

Author(s):

Gray Umbach ◽

Pranish Kantak ◽

Joshua Jacobs ◽

Michael Kahana ◽

Brad E. Pfeiffer ◽

...

Keyword(s):

Episodic Memory ◽

Entorhinal Cortex ◽

Cell Activity ◽

Memory Task ◽

Temporal Information ◽

Temporal Organization ◽

Human Epilepsy ◽

Human Hippocampus ◽

Phase Precession ◽

Episodic Memories

AbstractThe organization of temporal information is critical for the encoding and retrieval of episodic memories. In the rodent hippocampus and entorhinal cortex, recent evidence suggests that temporal information is encoded by a population of “time cells.” We identify time cells in humans using intracranial microelectrode recordings obtained from 27 human epilepsy patients who performed an episodic memory task. We show that time cell activity predicts the temporal organization of episodic memories. A significant portion of these cells exhibits phase precession, a key phenomenon not previously seen in human recordings. These findings establish a cellular mechanism for the representation of temporal information in the human brain needed to form episodic memories.

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Time cells in the human hippocampus and entorhinal cortex support episodic memory

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2013250117 ◽

2020 ◽

Vol 117 (45) ◽

pp. 28463-28474 ◽

Cited By ~ 1

Author(s):

Gray Umbach ◽

Pranish Kantak ◽

Joshua Jacobs ◽

Michael Kahana ◽

Brad E. Pfeiffer ◽

...

Keyword(s):

Episodic Memory ◽

Entorhinal Cortex ◽

Cell Activity ◽

Memory Task ◽

Cellular Mechanism ◽

Temporal Information ◽

Temporal Organization ◽

Human Epilepsy ◽

Human Hippocampus ◽

Episodic Memories

The organization of temporal information is critical for the encoding and retrieval of episodic memories. In the rodent hippocampus and entorhinal cortex, evidence accumulated over the last decade suggests that populations of “time cells” in the hippocampus encode temporal information. We identify time cells in humans using intracranial microelectrode recordings obtained from 27 human epilepsy patients who performed an episodic memory task. We show that time cell activity predicts the temporal organization of retrieved memory items. We also uncover evidence of ramping cell activity in humans, which represents a complementary type of temporal information. These findings establish a cellular mechanism for the representation of temporal information in the human brain needed to form episodic memories.

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LncRNA SNHG12 Improves Cerebral Ischemic-reperfusion Injury by Activating SIRT1/FOXO3a Pathway through I nhibition of Autophagy and Oxidative Stress

Current Neurovascular Research ◽

10.2174/1567202617666200727142019 ◽

2020 ◽

Vol 17 (4) ◽

pp. 394-401

Author(s):

Yuanhua Wu ◽

Yuan Huang ◽

Jing Cai ◽

Donglan Zhang ◽

Shixi Liu ◽

...

Keyword(s):

Oxidative Stress ◽

Molecular Mechanisms ◽

Ischemia Reperfusion ◽

Critical Role ◽

Cell Activity ◽

Ht22 Cells ◽

Cerebral Ischemic ◽

Cerebral Ischemic Reperfusion ◽

And Oxidative Stress

Background: Ischemia/reperfusion (I/R) injury involves complex biological processes and molecular mechanisms such as autophagy. Oxidative stress plays a critical role in the pathogenesis of I/R injury. LncRNAs are the regulatory factor of cerebral I/R injury. Methods: This study constructs cerebral I/R model to investigate role of autophagy and oxidative stress in cerebral I/R injury and the underline regulatory mechanism of SIRT1/ FOXO3a pathway. In this study, lncRNA SNHG12 and FOXO3a expression was up-regulated and SIRT1 expression was down-regulated in HT22 cells of I/R model. Results: Overexpression of lncRNA SNHG12 significantly increased the cell viability and inhibited cerebral ischemicreperfusion injury induced by I/Rthrough inhibition of autophagy. In addition, the transfected p-SIRT1 significantly suppressed the release of LDH and SOD compared with cells co-transfected with SIRT1 and FOXO3a group and cells induced by I/R and transfected with p-SNHG12 group and overexpression of cells co-transfected with SIRT1 and FOXO3 further decreased the I/R induced release of ROS and MDA. Conclusion: In conclusion, lncRNA SNHG12 increased cell activity and inhibited oxidative stress through inhibition of SIRT1/FOXO3a signaling-mediated autophagy in HT22 cells of I/R model. This study might provide new potential therapeutic targets for further investigating the mechanisms in cerebral I/R injury and provide.

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Multilab Direct Replication of Flavell, Beach, and Chinsky (1966): Spontaneous Verbal Rehearsal in a Memory Task as a Function of Age

Advances in Methods and Practices in Psychological Science ◽

10.1177/25152459211018187 ◽

2021 ◽

Vol 4 (2) ◽

pp. 251524592110181

Author(s):

Emily M. Elliott ◽

Candice C. Morey ◽

Angela M. AuBuchon ◽

Nelson Cowan ◽

Chris Jarrold ◽

...

Keyword(s):

Cognitive Development ◽

Young Children ◽

Memory Performance ◽

Critical Role ◽

Memory Task ◽

Older Children ◽

Continuous Increase ◽

Verbal Rehearsal ◽

Picture Memory ◽

Spontaneous Production

Work by Flavell, Beach, and Chinsky indicated a change in the spontaneous production of overt verbalization behaviors when comparing young children (age 5) with older children (age 10). Despite the critical role that this evidence of a change in verbalization behaviors plays in modern theories of cognitive development and working memory, there has been only one other published near replication of this work. In this Registered Replication Report, we relied on researchers from 17 labs who contributed their results to a larger and more comprehensive sample of children. We assessed memory performance and the presence or absence of verbalization behaviors of young children at different ages and determined that the original pattern of findings was largely upheld: Older children were more likely to verbalize, and their memory spans improved. We confirmed that 5- and 6-year-old children who verbalized recalled more than children who did not verbalize. However, unlike Flavell et al., substantial proportions of our 5- and 6-year-old samples overtly verbalized at least sometimes during the picture memory task. In addition, continuous increase in overt verbalization from 7 to 10 years old was not consistently evident in our samples. These robust findings should be weighed when considering theories of cognitive development, particularly theories concerning when verbal rehearsal emerges and relations between speech and memory.

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Brain hemodynamic response in Examiner–Examinee dyads during spatial short-term memory task: an fNIRS study

Experimental Brain Research ◽

10.1007/s00221-021-06073-0 ◽

2021 ◽

Author(s):

Francesco Panico ◽

Stefania De Marco ◽

Laura Sagliano ◽

Francesca D’Olimpio ◽

Dario Grossi ◽

...

Keyword(s):

Working Memory ◽

Cognitive Processes ◽

Short Term Memory ◽

Spatial Working Memory ◽

Brain Activity ◽

Memory Task ◽

Neural Correlates ◽

Short Term ◽

Term Memory ◽

The Real

AbstractThe Corsi Block-Tapping test (CBT) is a measure of spatial working memory (WM) in clinical practice, requiring an examinee to reproduce sequences of cubes tapped by an examiner. CBT implies complementary behaviors in the examiners and the examinees, as they have to attend a precise turn taking. Previous studies demonstrated that the Prefrontal Cortex (PFC) is activated during CBT, but scarce evidence is available on the neural correlates of CBT in the real setting. We assessed PFC activity in dyads of examiner–examinee participants while completing the real version of CBT, during conditions of increasing and exceeding workload. This procedure allowed to investigate whether brain activity in the dyads is coordinated. Results in the examinees showed that PFC activity was higher when the workload approached or reached participants’ spatial WM span, and lower during workload conditions that were largely below or above their span. Interestingly, findings in the examiners paralleled the ones in the examinees, as examiners’ brain activity increased and decreased in a similar way as the examinees’ one. In the examiners, higher left-hemisphere activity was observed suggesting the likely activation of non-spatial WM processes. Data support a bell-shaped relationship between cognitive load and brain activity, and provide original insights on the cognitive processes activated in the examiner during CBT.

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Neuropsychological impairment in patients with major depressive disorder: the effects of feedback on task performance

Psychological Medicine ◽

10.1017/s0033291702007018 ◽

2003 ◽

Vol 33 (3) ◽

pp. 455-467 ◽

Cited By ~ 177

Author(s):

F. C. MURPHY ◽

A. MICHAEL ◽

T. W. ROBBINS ◽

B. J. SAHAKIAN

Keyword(s):

Working Memory ◽

Negative Feedback ◽

Performance Feedback ◽

Visual Discrimination ◽

Negative Reinforcement ◽

Spatial Working Memory ◽

Memory Task ◽

Depressive Illness ◽

Reversal Task ◽

Depressed Patients

Background. Recent evidence suggests that an abnormal response to performance feedback may contribute to the wide-ranging neuropsychological deficits typically associated with depressive illness. The present research sought to determine whether the inability of depressed patients to utilize performance feedback advantageously is equally true for accurate and misleading feedback.Method. Patients with major depression and matched controls completed: (1) a visual discrimination and reversal task that featured intermittent and misleading negative feedback; and (2) feedback and no-feedback versions of a computerised test of spatial working memory. In the feedback version, negative feedback was accurate, highly informative, and could be used as a mnemonic aid.Results. On the Probability Reversal task, depressed patients were impaired in their ability to maintain response set in the face of misleading negative feedback as shown by their increased tendency to switch responding to the ‘incorrect’ stimulus following negative reinforcement, relative to that of controls. Patients' ability to acquire and reverse the necessary visual discrimination was unimpaired. On the Spatial Working Memory task, depressed patients made significantly more between-search errors than controls on the most difficult trials, but their ability to use negative feedback to facilitate performance remained intact.Conclusions. The present results suggest that feedback can have different effects in different contexts. Misleading, negative feedback appears to disrupt the performance of depressed patients, whereas negative but accurate feedback does not. These findings are considered in the context of recent studies on reinforcement systems and their associated neurobiological substrates.

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A Critical Role for Fas Ligand in the Active Suppression of Systemic Immune Responses by Ultraviolet Radiation

Journal of Experimental Medicine ◽

10.1084/jem.189.8.1285 ◽

1999 ◽

Vol 189 (8) ◽

pp. 1285-1294 ◽

Cited By ~ 57

Author(s):

Laurie L. Hill ◽

Vijay K. Shreedhar ◽

Margaret L. Kripke ◽

Laurie B. Owen-Schaub

Keyword(s):

Dna Damage ◽

Immune Responses ◽

Immune Suppression ◽

Fas Ligand ◽

Critical Role ◽

Cell Activity ◽

Contact Hypersensitivity ◽

Delayed Type Hypersensitivity ◽

Intact Cells

Induction of antigen-specific suppression elicited by environmental insults, such as ultraviolet (UV)-B radiation in sunlight, can inhibit an effective immune response in vivo and may contribute to the outgrowth of UV-induced skin cancer. Although UV-induced DNA damage is known to be an initiating event in the immune suppression of most antigen responses, the underlying mechanism(s) of such suppression remain undefined. In this report, we document that Fas ligand (FasL) is critical for UV-induced systemic immune suppression. Normal mice acutely exposed to UV exhibit a profound suppression of both contact hypersensitivity and delayed type hypersensitivity (DTH) reactions and the development of transferable antigen-specific suppressor cells. FasL-deficient mice exposed to UV lack both transferable suppressor cell activity and primary suppression to all antigens tested, with the exception of the DTH response to allogeneic spleen cells. Interestingly, suppression of this response is also known to occur independently of UV-induced DNA damage. Delivery of alloantigen as protein, rather than intact cells, restored the requirement for FasL in UV-induced immune suppression of this response. These results substantiate that FasL/Fas interactions are essential for systemic UV-induced suppression of immune responses that involve host antigen presentation and suggest an interrelationship between UV-induced DNA damage and FasL in this phenomenon. Collectively, our results suggest a model whereby UV-induced DNA damage disarms the immune system in a manner similar to that observed in immunologically privileged sites.

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Antitumor and antimetastatic activity of interleukin 12 against murine tumors.

Journal of Experimental Medicine ◽

10.1084/jem.178.4.1223 ◽

1993 ◽

Vol 178 (4) ◽

pp. 1223-1230 ◽

Cited By ~ 782

Author(s):

M J Brunda ◽

L Luistro ◽

R R Warrier ◽

R B Wright ◽

B R Hubbard ◽

...

Keyword(s):

T Cells ◽

Nk Cell ◽

Critical Role ◽

Cell Activity ◽

Interleukin 12 ◽

Reticulum Cell ◽

Complete Disappearance ◽

Antitumor Effects ◽

Murine Tumors

It has recently been demonstrated that in vivo administration of murine interleukin 12 (IL-12) to mice results in augmentation of cytotoxic natural killer (NK)/lymphocyte-activated killer cell activity, enhancement of cytolytic T cell generation, and induction of interferon gamma secretion. In this study, the in vivo activity of murine IL-12 against a number of murine tumors has been evaluated. Experimental pulmonary metastases or subcutaneous growth of the B16F10 melanoma were markedly reduced in mice treated intraperitoneally with IL-12, resulting in an increase in survival time. The therapeutic effectiveness of IL-12 was dose dependent and treatment of subcutaneous tumors could be initiated up to 14 d after injection of tumor cells. Likewise, established experimental hepatic metastases and established subcutaneous M5076 reticulum cell sarcoma and Renca renal cell adenocarcinoma tumors were effectively treated by IL-12 at doses which resulted in no gross toxicity. Local peritumoral injection of IL-12 into established subcutaneous Renca tumors resulted in regression and complete disappearance of these tumors. IL-12 was as effective in NK cell-deficient beige mice or in mice depleted of NK cell activity by treatment with antiasialo GM1, suggesting that NK cells are not the primary cell type mediating the antitumor effects of this cytokine. However, the efficacy of IL-12 was greatly reduced in nude mice suggesting the involvement of T cells. Furthermore, depletion of CD8+ but not CD4+ T cells significantly reduced the efficacy of IL-12. These results demonstrate that IL-12 has potent in vivo antitumor and antimetastatic effects against murine tumors and demonstrate as well the critical role of CD8+ T cells in mediating the antitumor effects against subcutaneous tumors.

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