2014 — 2018 |
Leutgeb, Jill K |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
A Neuronal Code For Extended Time in the Hippocampal-Entorhinal Circuitry @ University of California San Diego
PROJECT SUMMARY/ABSTRACT The hippocampal formation is critical for the formation and retrieval of autobiographical memories, which consist of information about what happened when and where. It is known how objects, context and space (what, where) are represented in the hippocampus and it has recently been described that time (when events occur) on a scale of seconds to minutes is represented by the sequential activation of hippocampal cells. On a longer time scale, a time-varying neural code has previously been shown by theoretical models to be suitable for estimating the recency of a remembered event. In recently published results and results presented as preliminary data, we identify a novel, time-varying hippocampal neural code that can represent how long ago an event occurred on a time scale of hours and days. Our data first identified that the neuronal firing patterns of CA1 cells are characterized by a monotonic accumulation of rate differences as a function of time between experiences. However, we demonstrate that stored information does not simply deteriorate in the CA1 area, but that the code for time can co-exist with reliable coding for other aspects of an event, such as the spatial location or the context. We also found that CA3 contains an exquisitely precise code for context and space that does not vary over time. New preliminary data show an effect in CA2 that is opposite of CA3. CA2 cells represent elapsed time but no information about context. Based on these findings, we hypothesize that the neuronal code for extended time is combined with spatial and contextual information in the CA1 cell population to guide behavior in which the recency of a previous event is remembered. Using a combination of behavioral testing and single-unit recordings in awake behaving rodents, this hypothesis is tested in three aims that: (1) determine whether the neuronal code for extended time intervals is generated in the hippocampal CA2 neural network, (2) determine whether the input from the hippocampal CA3 subregion is necessary for maintaining the stable memory coding component in the CA1 neural network over hours and days, and (3) determine whether a time-varying neural code in hippocampal CA1 and CA2 subregions is correlated with remembering how long ago. The first two aims address how different subregions contribute to the time-varying and stable components of the neural code. In addition to defining the function of CA2 for temporal coding and the function of CA3 in enabling stable memory representations, we will also ask whether the entorhinal cortex can represent time on an extended scale and is thus a brain region in which temporal coding over a large range of scales can be found. In the third aim, we will use a behavioral task in which it has been shown that rats remember how long ago over extended time periods. We will measure the similarity of activity patterns in place cell populations between two time points and determine whether the change in neuronal firing patterns corresponds to the rat's estimate of elapsed time. Taken together, these studies will be important for understanding the neural network mechanisms for long-term memory stability and temporal event coding in the brain structures that support episodic memory. Understanding the key mechanisms for memory processing will guide efforts to repair circuit dysfunction in psychiatric, neurological, and neurodegenerative diseases.
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0.958 |
2019 — 2021 |
Leutgeb, Jill K Miller, Cory T [⬀] Wixted, John T (co-PI) [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Neural Basis of Memory in Primate Medial Temporal Lobe @ University of California, San Diego
Project Summary The medial temporal lobe (MTL) plays a critical role in the rapid formation of episodic memories in human and nonhuman primates, while research performed in freely-moving rodents has likewise identified these same structure as being pivotal for spatial navigation. Each of these lines of work reflect powerful research traditions that have significantly contributed to our understanding of medial temporal lobe function, but questions remain about how to reconcile their considerable data sets. One compelling hypothesis is that the same neural mechanisms that support the role of MTL in spatial navigation also support the formation of episodic memories. We propose an innovative set of experiments designed to directly test this hypothesis Our approach involves recording neural activity from the same neurons in the medial temporal lobe of marmoset monkeys in two contexts. One involves head-restrained subjects performing a recognition memory task typical of human experiments while in the other freely-moving subjects navigate spatial environments commonly used in studies of rodents. Our innovative approach will allow us to test ? for the first time - whether the same neurons in primate medial temporal lobe support behaviors performed in tasks representative of these two research traditions. Aim 1 seeks to characterize recognition memory in marmosets using a task that ? like spatial navigation ? relies on incidental memory formation. Experiments in Aim 2 examine the role of the hippocampal CA fields and entorhinal cortex in spatial navigation, including the putative existence of place cells and grid cells, respectively. Aim 3 directly tests the principal question of this proposal by recording from the identical neurons while subjects perform the recognition memory task in Aim 1 and navigate spatial environments similar to studies in Aim 2.
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0.958 |
2020 — 2021 |
Leutgeb, Jill K |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Hippocampal Network Mechanisms For Memory-Guided Behavior @ University of California, San Diego
PROJECT DESCRIPTION While the significance of brain oscillations as an indication of synchronized neuronal activity has been widely acknowledged, our understanding of how coordinated neuronal firing patterns support behavior and memory processing is only beginning to emerge. In particular, oscillations in complex memory tasks are highly dynamic with frequent transitions between predominant frequency ranges. Different brain states that are associated with behavior are characterized by a wide range of oscillatory frequencies that likely reflect distinct underlying network mechanisms to support different phases of memory. Yet, memory-guided behavior requires the uninterrupted retention and updating of task-relevant information across numerous transitions between brain states. One of the remaining key outstanding questions is thus how information is not only retained but also organized to become task-relevant throughout these transitions. To study this question, we will focus on the hippocampal dentate-CA3 network where we have recently shown that the dentate gyrus is critical for the generation of prospective coding of future correct choices by CA3 cells during sharp-wave ripples (SWRs) in a dentate-dependent working memory task. SWRs are high-frequency oscillations that are accompanied by brief increases in firing rates during which behaviorally relevant events are replayed. While our previous work determined that the prospective coding occurred during SWRs at reward locations, we propose to next determine whether the dentate inputs to CA3 are also critical for prospective coding during theta oscillations along the path to future reward locations. Given that our previous and preliminary data support the possibility that the dentate is necessary for prospective coding in CA3 during SWRs and theta states, we propose to next identify how prospective coding is coordinated across the transition between these brain states in order to support the planning of future decisions and trajectories. We predict that the neuronal representations of all available choices are played out during SWRs, while a selection of the next choice occurs during the subsequent theta state. Finally, we will establish a causal relationship between predictive neuronal firing sequences generated during high-frequency oscillations and predictive sequences in theta states by disrupting CA3 SWRs and examining subsequent behavioral choices and subsequent spike sequences in theta cycles. Taken together, these studies will allow us to describe network mechanisms in the hippocampus that dynamically interleave across brain states to support hippocampus-dependent memory. Our work will potentially also have significant implications for therapeutic intervention in diseases with gender-dependent memory comorbidities, as we will investigate potential sex differences for dentate-CA3 network computations critical for memory formation. This fills a gap in our understanding as no studies on functional network differences have been reported for this circuit despite clear evidence for sex differences in dentate-CA3 anatomy, plasticity, and response to aging, stress and diseases such as depression and epilepsy.
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0.958 |