Medial entorhinal cortex lesions produce delay-dependent disruptions in memory for elapsed time

Vo, Annette; Tabrizi, Nina S.; Hunt, Thomas C.; Cayanan, Kayla; Chitale, Saee; Anderson, Lucy G.; Tenney, Sarah; White, André O.; Sabariego, Marta; Hales, Jena B.

doi:10.1016/j.nlm.2021.107507

Cited by 11 publications

(10 citation statements)

References 47 publications

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“…These results point to a specific necessity of MEC in flexible, context-dependent timing behavior. Overall, our findings are in line with prior work demonstrating inactivation or lesions to MEC can disrupt timing behavior 18,44,45 .…”

Section: Discussionsupporting

confidence: 92%

Medial entorhinal cortex plays a specialized role in learning of flexible, context-dependent interval timing behavior

Heys

Bigus

Lee

et al. 2023

Preprint

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In order to survive and adapt in a dynamic environment, animals must perceive and remember the temporal structure of events and actions across a wide range of timescales, including so-called interval timing on the scale of seconds to minutes1,2. Episodic memory (i.e. the ability to remember specific, personal events that occur in spatial and temporal context) requires accurate temporal processing and is known to require neural circuits in the medial temporal lobe (MTL), including medial entorhinal cortex (MEC)3–5. Recently, it has been discovered that neurons in MEC termed time cells, fire regularly at brief moments as animals engage in interval timing behavior, and as a population, display sequential neural activity that tiles the entire timed epoch6. It has been hypothesized that MEC time cell activity could provide temporal information necessary for episodic memories, yet it remains unknown whether the neural dynamics of MEC time cells display a critical feature necessary for encoding experience. That is, whether MEC time cells display context-dependent activity. To address this question, we developed a novel behavioral paradigm that requires learning complex temporal contingencies. Applying this novel interval timing task in mice, in concert with methods for manipulating neural activity and methods for large-scale cellular resolution neurophysiological recording, we have uncovered a specific role for MEC in flexible, context-dependent learning of interval timing behavior. Further, we find evidence for a common circuit mechanism that could drive both sequential activity of time cells and spatially selective neurons in MEC.

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Section: Discussionsupporting

confidence: 92%

Medial entorhinal cortex plays a specialized role in learning of flexible, context-dependent interval timing behavior

Heys

Bigus

Lee

et al. 2023

Preprint

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show abstract

“…We find that mice are completely unable to learn this task with MEC inactivation. This is in line with prior work demonstrating inactivation or lesions to MEC can disrupt timing behavior (Heys et al 2020; Dias, Ferreira, and Remondes 2021; Vo et al 2021). Notably, the large effect we have observed in the novel tDNMS task (Cohen’s d = 1.13 for the % change in performance from session 1-7&8 for control and MEC inactivation mice), perhaps indicates that more flexible and/or complex timing behavior relies heavily on MEC compared to simple tasks where effects are small or nonexistent (further discussion below).…”

Section: Discussionsupporting

confidence: 92%

“…If so, as for space, we would expect MTL regions to 1) be necessary for interval timing behavior, 2) contain cells selective to time, and 3) use distinct patterns of timeselective cells to form "timelines" of unique experiences, akin to maps. Prior work suggests that MEC fits the first two criteria: MEC is both 1) necessary for interval timing behavior [17][18][19] and 2) contains time cells that fire regularly at discrete moments as rodents report temporal durations on the scale of seconds 20 . As a population, different MEC time cells fire regularly at different moments in a timed interval, like the second hand of a clock, thereby forming a sequence of neural activity, tiling the entire timing epoch.…”

Section: Main Textmentioning

confidence: 99%

“…Prior studies provide experimental support that MEC is involved in timing, and suggest timing is supported by sequential time cell activity. However, studies have reported modest, sometimes inconsistent effects of MEC inhibition on timing behavior (Heys and Dombeck 2018; Heys et al 2020; Dias, Ferreira, and Remondes 2021; Vo et al 2021). We suggest the lack of a clear understanding of MEC in timing behavior stems from the use of timing tasks that do not fit the flexible learning constraints of the MTL memory system, and may instead be learned or solved though other circuits.…”

Section: Introductionmentioning

confidence: 99%

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Medial entorhinal cortex plays a specialized role in learning of flexible, context-dependent interval timing behavior

Bigus

Lee

Shi

et al. 2023

Preprint

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In order to survive and adapt in a dynamic environment, animals must perceive and remember the temporal structure of events and actions across a wide range of timescales. Prior research to investigate the neurobiological basis underlying so-called interval timing (i.e. timing on the scale of second to minutes) has focused largely on simple timing tasks that require animals to discriminate and/or reproduce stimuli presented at single, fixed durations over thousands of trials. Perhaps not surprisingly, this work has uncovered circuits involved in procedural memory systems, such as the basal ganglia, that play a key role in learning and driving timing behavior. Episodic memory (i.e. the ability to remember specific, personal events that occur in spatial and temporal context) also requires accurate temporal processing and is known to require neural circuits in the medial temporal lobe (MTL), including entorhinal cortex. However, a clear role for medial temporal lobe structures in interval timing has been conspicuously lacking. In order to determine the specific role that MTL structures play in timing behavior, we developed a novel behavioral paradigm that requires learning complex temporal contingencies. Applying this novel interval timing task in mice, in concert with methods for manipulating neural activity and methods for large-scale cellular resolution neurophysiological recording, we have uncovered a specific role for medial entorhinal cortex (MEC) in flexible, context-dependent learning of interval timing behavior. We find neurons in MEC, termed time cells, fire in regular time-locked sequences during timing. Remarkably, over the course of learning, these neural dynamics become context-dependent with specific sub-populations of neurons becoming selectively active within particular trial contexts. We also find that this neural activity is disrupted when animals make errors in their timing behavior and that animals are completely unable to learn this timing behavior without MEC activity. Further, we find that MEC activity is not necessary for very rigid forms of timing behavior and that nearby structures, such as the hippocampus, are not necessary for learning this flexible timing task. Finally, the results identify the particular cognitive strategy employed by the animal to discriminate contexts that contain more complex temporal structure, that often exist in nature. Together these results establish a precise role of MEC in learning flexible timing behavior and demonstrate that learning is driven by context-dependent sequential neural dynamics of MEC time cells.

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“…Importantly, the histological validation of surgical performance on the patient H.M.'s brain revealed a lesion of a large portion of the EC while a significant amount of residual hippocampus remained (Annese et al, 2014). Likewise, lesion or neural inactivation of the HPC and MEC in animals shows impairment of memory of “when”, representing the timing and sequence of events and also the association of temporally segregated events (Ainge et al, 2007; Dias et al, 2021; Fortin et al, 2002, 2004; Heys et al, 2020; Jacobs et al, 2013; Kitamura et al, 2014; McEchron et al, 1998; Robinson et al, 2017; Suh et al, 2011; Vo et al, 2021), and “where”, representing spatial orientation, navigation and context (Hales et al, 2014, 2018, 2021; Honey & Good, 1993; Kitamura et al, 2012; Morris et al, 1982; Nakazawa et al, 2004; Phillips & LeDoux, 1992; Steffenach et al, 2005). Correspondingly, findings of place cells (Ekstrom et al, 2003; O'Keefe & Dostrovsky, 1971) and time cells (Kraus et al, 2013; MacDonald et al, 2011; Marks et al, 2019; Pastalkova et al, 2008; Robinson et al, 2017) in the HPC as well as grid cells (Fyhn et al, 2004; Moser et al, 2008) and recently found time‐coding cells (Heys & Dombeck, 2018; Kraus et al, 2015) in the MEC imply that spatial and temporal information is processed in the MEC‐HPC circuit for memory formation.…”

Section: Introductionmentioning

confidence: 99%

Dissecting cell‐type‐specific pathways in medial entorhinal cortical‐hippocampal network for episodic memory

Osanai

Nair

Kitamura

2023

Journal of Neurochemistry

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Episodic memory, which refers to our ability to encode and recall past events, is essential to our daily lives. Previous research has established that both the entorhinal cortex (EC) and hippocampus (HPC) play a crucial role in the formation and retrieval of episodic memories. However, to understand neural circuit mechanisms behind these processes, it has become necessary to monitor and manipulate the neural activity in a cell‐type‐specific manner with high temporal precision during memory formation, consolidation, and retrieval in the EC‐HPC networks. Recent studies using cell‐type‐specific labeling, monitoring, and manipulation have demonstrated that medial EC (MEC) contains multiple excitatory neurons that have differential molecular markers, physiological properties, and anatomical features. In this review, we will comprehensively examine the complementary roles of superficial layers of neurons (II and III) and the roles of deeper layers (V and VI) in episodic memory formation and recall based on these recent findings.

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Medial entorhinal cortex lesions produce delay-dependent disruptions in memory for elapsed time

Cited by 11 publications

References 47 publications

Medial entorhinal cortex plays a specialized role in learning of flexible, context-dependent interval timing behavior

Medial entorhinal cortex plays a specialized role in learning of flexible, context-dependent interval timing behavior

Medial entorhinal cortex plays a specialized role in learning of flexible, context-dependent interval timing behavior

Dissecting cell‐type‐specific pathways in medial entorhinal cortical‐hippocampal network for episodic memory

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