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1.
J Neurosci ; 42(18): 3797-3810, 2022 05 04.
Article in English | MEDLINE | ID: mdl-35351831

ABSTRACT

Humans have the ability to store and retrieve memories with various degrees of specificity, and recent advances in reinforcement learning have identified benefits to learning when past experience is represented at different levels of temporal abstraction. How this flexibility might be implemented in the brain remains unclear. We analyzed the temporal organization of male rat hippocampal population spiking to identify potential substrates for temporally flexible representations. We examined activity both during locomotion and during memory-associated population events known as sharp-wave ripples (SWRs). We found that spiking during SWRs is rhythmically organized with higher event-to-event variability than spiking during locomotion-associated population events. Decoding analyses using clusterless methods further indicate that a similar spatial experience can be replayed in multiple SWRs, each time with a different rhythmic structure whose periodicity is sampled from a log-normal distribution. This variability increases with experience despite the decline in SWR rates that occurs as environments become more familiar. We hypothesize that the variability in temporal organization of hippocampal spiking provides a mechanism for storing experiences with various degrees of specificity.SIGNIFICANCE STATEMENT One of the most remarkable properties of memory is its flexibility: the brain can retrieve stored representations at varying levels of detail where, for example, we can begin with a memory of an entire extended event and then zoom in on a particular episode. The neural mechanisms that support this flexibility are not understood. Here we show that hippocampal sharp-wave ripples, which mark the times of memory replay and are important for memory storage, have a highly variable temporal structure that is well suited to support the storage of memories at different levels of detail.


Subject(s)
Hippocampus , Learning , Animals , Male , Rats
2.
Cell ; 180(3): 552-567.e25, 2020 02 06.
Article in English | MEDLINE | ID: mdl-32004462

ABSTRACT

Cognitive faculties such as imagination, planning, and decision-making entail the ability to represent hypothetical experience. Crucially, animal behavior in natural settings implies that the brain can represent hypothetical future experience not only quickly but also constantly over time, as external events continually unfold. To determine how this is possible, we recorded neural activity in the hippocampus of rats navigating a maze with multiple spatial paths. We found neural activity encoding two possible future scenarios (two upcoming maze paths) in constant alternation at 8 Hz: one scenario per ∼125-ms cycle. Further, we found that the underlying dynamics of cycling (both inter- and intra-cycle dynamics) generalized across qualitatively different representational correlates (location and direction). Notably, cycling occurred across moving behaviors, including during running. These findings identify a general dynamic process capable of quickly and continually representing hypothetical experience, including that of multiple possible futures.


Subject(s)
Behavior, Animal/physiology , Cognition/physiology , Decision Making/physiology , Hippocampus/physiology , Action Potentials/physiology , Animals , Locomotion/physiology , Male , Maze Learning/physiology , Nerve Net/physiology , Neurons/physiology , Rats , Rats, Long-Evans , Theta Rhythm/physiology
3.
Neuron ; 101(1): 21-31.e5, 2019 01 02.
Article in English | MEDLINE | ID: mdl-30502044

ABSTRACT

The brain is a massive neuronal network, organized into anatomically distributed sub-circuits, with functionally relevant activity occurring at timescales ranging from milliseconds to years. Current methods to monitor neural activity, however, lack the necessary conjunction of anatomical spatial coverage, temporal resolution, and long-term stability to measure this distributed activity. Here we introduce a large-scale, multi-site, extracellular recording platform that integrates polymer electrodes with a modular stacking headstage design supporting up to 1,024 recording channels in freely behaving rats. This system can support months-long recordings from hundreds of well-isolated units across multiple brain regions. Moreover, these recordings are stable enough to track large numbers of single units for over a week. This platform enables large-scale electrophysiological interrogation of the fast dynamics and long-timescale evolution of anatomically distributed circuits, and thereby provides a new tool for understanding brain activity.


Subject(s)
Brain/physiology , Electrodes, Implanted/standards , Electrophysiological Phenomena/physiology , Nerve Net/physiology , Polymers/standards , Animals , Electrodes, Implanted/trends , Male , Rats , Rats, Long-Evans
4.
Elife ; 62017 08 03.
Article in English | MEDLINE | ID: mdl-28826483

ABSTRACT

While ongoing experience proceeds continuously, memories of past experience are often recalled as episodes with defined beginnings and ends. The neural mechanisms that lead to the formation of discrete episodes from the stream of neural activity patterns representing ongoing experience are unknown. To investigate these mechanisms, we recorded neural activity in the rat hippocampus and prefrontal cortex, structures critical for memory processes. We show that during spatial navigation, hippocampal CA1 place cells maintain a continuous spatial representation across different states of motion (movement and immobility). In contrast, during sharp-wave ripples (SWRs), when representations of experience are transiently reactivated from memory, movement- and immobility-associated activity patterns are most often reactivated separately. Concurrently, distinct hippocampal reactivations of movement- or immobility-associated representations are accompanied by distinct modulation patterns in prefrontal cortex. These findings demonstrate a continuous representation of ongoing experience can be separated into independently reactivated memory representations.


Subject(s)
CA1 Region, Hippocampal/physiology , Movement/physiology , Prefrontal Cortex/physiology , Spatial Memory/physiology , Temporal Lobe/physiology , Animals , Brain Waves , CA1 Region, Hippocampal/cytology , Interneurons/cytology , Interneurons/physiology , Male , Mental Recall/physiology , Prefrontal Cortex/cytology , Pyramidal Cells/cytology , Pyramidal Cells/physiology , Rats , Rats, Long-Evans , Rest/physiology , Temporal Lobe/cytology
5.
J Neurophysiol ; 116(5): 2221-2235, 2016 11 01.
Article in English | MEDLINE | ID: mdl-27535369

ABSTRACT

Sharp-wave ripple (SWR) events in the hippocampus replay millisecond-timescale patterns of place cell activity related to the past experience of an animal. Interrupting SWR events leads to learning and memory impairments, but how the specific patterns of place cell spiking seen during SWRs contribute to learning and memory remains unclear. A deeper understanding of this issue will require the ability to manipulate SWR events based on their content. Accurate real-time decoding of SWR replay events requires new algorithms that are able to estimate replay content and the associated uncertainty, along with software and hardware that can execute these algorithms for biological interventions on a millisecond timescale. Here we develop an efficient estimation algorithm to categorize the content of replay from multiunit spiking activity. Specifically, we apply real-time decoding methods to each SWR event and then compute the posterior probability of the replay feature. We illustrate this approach by classifying SWR events from data recorded in the hippocampus of a rat performing a spatial memory task into four categories: whether they represent outbound or inbound trajectories and whether the activity is replayed forward or backward in time. We show that our algorithm can classify the majority of SWR events in a recording epoch within 20 ms of the replay onset with high certainty, which makes the algorithm suitable for a real-time implementation with short latencies to incorporate into content-based feedback experiments.


Subject(s)
Action Potentials/physiology , Computer Systems , Hippocampus/physiology , Linear Models , Algorithms , Animals , Male , Rats , Rats, Long-Evans , Time Factors
6.
Neuron ; 90(4): 740-51, 2016 05 18.
Article in English | MEDLINE | ID: mdl-27161522

ABSTRACT

Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer's disease (AD), but the mechanism by which it causes cognitive decline is unclear. In knockin (KI) mice, human apoE4 causes age-dependent learning and memory impairments and degeneration of GABAergic interneurons in the hippocampal dentate gyrus. Here we report two functional apoE4-KI phenotypes involving sharp-wave ripples (SWRs), hippocampal network events critical for memory processes. Aged apoE4-KI mice had fewer SWRs than apoE3-KI mice and significantly reduced slow gamma activity during SWRs. Elimination of apoE4 in GABAergic interneurons, which prevents learning and memory impairments, rescued SWR-associated slow gamma activity but not SWR abundance in aged mice. SWR abundance was reduced similarly in young and aged apoE4-KI mice; however, the full SWR-associated slow gamma deficit emerged only in aged apoE4-KI mice. These results suggest that progressive decline of interneuron-enabled slow gamma activity during SWRs critically contributes to apoE4-mediated learning and memory impairments. VIDEO ABSTRACT.


Subject(s)
Apolipoprotein E4/metabolism , Cognition Disorders/metabolism , Hippocampus/metabolism , Interneurons/metabolism , Memory Disorders/metabolism , Aging , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Animals , Apolipoprotein E4/genetics , Cognition Disorders/genetics , Disease Models, Animal , Gene Knock-In Techniques/methods , Maze Learning/physiology , Memory Disorders/genetics , Mice, Transgenic
7.
Nature ; 531(7593): 185-90, 2016 Mar 10.
Article in English | MEDLINE | ID: mdl-26934224

ABSTRACT

How does an animal know where it is when it stops moving? Hippocampal place cells fire at discrete locations as subjects traverse space, thereby providing an explicit neural code for current location during locomotion. In contrast, during awake immobility, the hippocampus is thought to be dominated by neural firing representing past and possible future experience. The question of whether and how the hippocampus constructs a representation of current location in the absence of locomotion has been unresolved. Here we report that a distinct population of hippocampal neurons, located in the CA2 subregion, signals current location during immobility, and does so in association with a previously unidentified hippocampus-wide network pattern. In addition, signalling of location persists into brief periods of desynchronization prevalent in slow-wave sleep. The hippocampus thus generates a distinct representation of current location during immobility, pointing to mnemonic processing specific to experience occurring in the absence of locomotion.


Subject(s)
Hippocampus/cytology , Hippocampus/physiology , Neurons/physiology , Orientation/physiology , Sleep/physiology , Space Perception/physiology , Action Potentials , Animals , Hippocampus/anatomy & histology , Male , Models, Neurological , Movement , Rats , Rats, Long-Evans , Spatial Memory/physiology
8.
PLoS One ; 8(9): e73114, 2013.
Article in English | MEDLINE | ID: mdl-24023818

ABSTRACT

Hippocampal information processing is often described as two-state, with a place cell state during movement and a reactivation state during stillness. Relatively little is known about how the network transitions between these different patterns of activity during exploration. Here we show that hippocampal network changes quickly and continuously as animals explore and become familiar with initially novel places. We measured the relationship between moment-by-moment changes in behavior and information flow through hippocampal output area CA1 in rats. We examined local field potential (LFP) patterns, evoked potentials and ensemble spiking and found evidence suggestive of a smooth transition from strong CA3 drive of CA1 activity at low speeds to entorhinal cortical drive of CA1 activity at higher speeds. These changes occurred with changes in behavior on a timescale of less than a second, suggesting a continuous modulation of information processing in the hippocampal circuit as a function of behavioral state.


Subject(s)
CA1 Region, Hippocampal/physiology , CA3 Region, Hippocampal/physiology , Exploratory Behavior/physiology , Nerve Net/physiology , Animals , Behavior, Animal/physiology , Brain Waves/physiology , CA1 Region, Hippocampal/cytology , CA3 Region, Hippocampal/cytology , Evoked Potentials/physiology , Learning/physiology , Male , Nerve Net/cytology , Neurons/cytology , Rats , Time Factors
9.
Neuron ; 77(6): 1163-73, 2013 Mar 20.
Article in English | MEDLINE | ID: mdl-23522050

ABSTRACT

The hippocampus frequently replays memories of past experiences during sharp-wave ripple (SWR) events. These events can represent spatial trajectories extending from the animal's current location to distant locations, suggesting a role in the evaluation of upcoming choices. While SWRs have been linked to learning and memory, the specific role of awake replay remains unclear. Here we show that there is greater coordinated neural activity during SWRs preceding correct, as compared to incorrect, trials in a spatial alternation task. As a result, the proportion of cell pairs coactive during SWRs was predictive of subsequent correct or incorrect responses on a trial-by-trial basis. This effect was seen specifically during early learning, when the hippocampus is essential for task performance. SWR activity preceding correct trials represented multiple trajectories that included both correct and incorrect options. These results suggest that reactivation during awake SWRs contributes to the evaluation of possible choices during memory-guided decision making.


Subject(s)
Decision Making/physiology , Hippocampus/physiology , Learning/physiology , Psychomotor Performance/physiology , Animals , Forecasting , Male , Random Allocation , Rats , Rats, Long-Evans
10.
Science ; 338(6103): 135-9, 2012 Oct 05.
Article in English | MEDLINE | ID: mdl-23042898

ABSTRACT

Regions within the prefrontal cortex are thought to process beliefs about the world, but little is known about the circuit dynamics underlying the formation and modification of these beliefs. Using a task that permits dissociation between the activity encoding an animal's internal state and that encoding aspects of behavior, we found that transient increases in the volatility of activity in the rat medial prefrontal cortex accompany periods when an animal's belief is modified after an environmental change. Activity across the majority of sampled neurons underwent marked, abrupt, and coordinated changes when prior belief was abandoned in favor of exploration of alternative strategies. These dynamics reflect network switches to a state of instability, which diminishes over the period of exploration as new stable representations are formed.


Subject(s)
Behavior, Animal , Nerve Net/physiology , Prefrontal Cortex/physiology , Uncertainty , Animals , Male , Nerve Net/cytology , Neurons/physiology , Prefrontal Cortex/cytology , Rats , Rats, Long-Evans , Rejection, Psychology , Reward
11.
Neuron ; 75(4): 700-13, 2012 Aug 23.
Article in English | MEDLINE | ID: mdl-22920260

ABSTRACT

The replay of previously stored memories during hippocampal sharp wave ripples (SWRs) is thought to support both memory retrieval and consolidation in distributed hippocampal-neocortical circuits. Replay events consist of precisely timed sequences of spikes from CA3 and CA1 neurons that are coordinated both within and across hemispheres. The mechanism of this coordination is not understood. Here, we show that during SWRs in both awake and quiescent states there are transient increases in slow gamma (20-50 Hz) power and synchrony across dorsal CA3 and CA1 networks of both hemispheres. These gamma oscillations entrain CA3 and CA1 spiking. Moreover, during awake SWRs, higher levels of slow gamma synchrony are predictive of higher quality replay of past experiences. Our results indicate that CA3-CA1 gamma synchronization is a central component of awake memory replay and suggest that transient gamma synchronization serves as a clocking mechanism to enable coordinated memory reactivation across the hippocampal network.


Subject(s)
Action Potentials/physiology , Brain Waves/physiology , Hippocampus/cytology , Hippocampus/physiology , Mental Recall/physiology , Neurons/physiology , Animals , Linear Models , Male , Nerve Net/physiology , Rats , Rats, Long-Evans , Space Perception/physiology , Spectrum Analysis , Time Factors , Wakefulness
12.
J Neurosci ; 30(35): 11586-604, 2010 Sep 01.
Article in English | MEDLINE | ID: mdl-20810880

ABSTRACT

To learn we must identify and remember experiences uniquely but also generalize across experiences to extract common features. Hippocampal place cells can show similar firing patterns across locations, but the functional significance of this repetitive activity and the role of experience and learning in generating it are not understood. We therefore examined rat hippocampal place cell activity in the context of spatial tasks with multiple similar spatial trajectories. We found that, in environments with repeating elements, about half of the recorded place cells showed path-equivalent firing, where individual neurons are active in multiple similar locations. In contrast, place cells from animals performing a similar task in an environment with fewer similar elements were less likely to fire in a path-equivalent manner. Moreover, in the environment with multiple repeating elements, path equivalence developed with experience in the task, and increased path equivalence was associated with increased moment-by-moment correlations between pairs of path-equivalent neurons. As a result, correlated firing among path-equivalent neurons increased with experience. These findings suggest that coordinated hippocampal ensembles can encode generalizations across locations. Thus, path-equivalent ensembles are well suited to encode similarities among repeating elements, providing a framework for associating specific behaviors with multiple locations, while neurons without this repetitive structure maintain a distinct population code.


Subject(s)
Action Potentials/physiology , Hippocampus/physiology , Recognition, Psychology/physiology , Space Perception/physiology , Spatial Behavior/physiology , Animals , Male , Maze Learning/physiology , Rats , Rats, Long-Evans
13.
Neural Comput ; 22(10): 2522-36, 2010 Oct.
Article in English | MEDLINE | ID: mdl-20608872

ABSTRACT

Large data sets arising from neurophysiological experiments are frequently observed with repeating temporal patterns. Our ability to decode these patterns is dependent on the development of methods to assess whether the patterns are significant or occurring by chance. Given a hypothesized sequence within these data, we derive probability formulas to allow assessment of the likelihood of recurrence occurring by chance. We illustrate our approach using data from hippocampal neurons from awake, behaving rats.


Subject(s)
Action Potentials/physiology , Models, Statistical , Nerve Net/physiology , Neurons/physiology , Pattern Recognition, Automated/statistics & numerical data , Algorithms , Animals , Computer Simulation/standards , Hippocampus/physiology , Humans , Magnetic Resonance Imaging/methods , Neural Networks, Computer , Orientation/physiology , Rats , Signal Processing, Computer-Assisted , Space Perception/physiology
14.
Nat Neurosci ; 12(7): 913-8, 2009 Jul.
Article in English | MEDLINE | ID: mdl-19525943

ABSTRACT

Hippocampal replay is thought to be essential for the consolidation of event memories in hippocampal-neocortical networks. Replay is present during both sleep and waking behavior, but although sleep replay involves the reactivation of stored representations in the absence of specific sensory inputs, awake replay is thought to depend on sensory input from the current environment. Here, we show that stored representations are reactivated during both waking and sleep replay. We found frequent awake replay of sequences of rat hippocampal place cells from a previous experience. This spatially remote replay was as common as local replay of the current environment and was more robust when the rat had recently been in motion than during extended periods of quiescence. Our results indicate that the hippocampus consistently replays past experiences during brief pauses in waking behavior, suggesting a role for waking replay in memory consolidation and retrieval.


Subject(s)
Hippocampus/physiology , Memory/physiology , Neurons/physiology , Space Perception/physiology , Wakefulness/physiology , Action Potentials , Animals , Electrodes, Implanted , Environment , Male , Maze Learning/physiology , Microelectrodes , Motor Activity/physiology , Rats , Rats, Long-Evans , Sleep/physiology
15.
J Neurosci ; 28(52): 14271-81, 2008 Dec 24.
Article in English | MEDLINE | ID: mdl-19109508

ABSTRACT

During development, activity-dependent processes increase the specificity of neural responses to stimuli, but the role that this type of process plays in adult plasticity is unclear. We examined the dynamics of hippocampal activity as animals learned about new environments to understand how neural selectivity changes with experience. Hippocampal principal neurons fire when the animal is located in a particular subregion of its environment, and in any given environment the hippocampal representation is sparse: less than half of the neurons in areas CA1 and CA3 are active whereas the rest are essentially silent. Here we show that different dynamics govern the evolution of this sparsity in CA1 and upstream area CA3. CA1, but not CA3, produces twice as many spikes in novel compared with familiar environments. This high rate firing continues during sharp wave ripple events in a subsequent rest period. The overall CA1 population rate declines and the number of active cells decreases as the environment becomes familiar and task performance improves, but the decline in rate is not uniform across neurons. Instead, the activity of cells with initial peak spatial rates above approximately 12 Hz is enhanced, whereas the activity of cells with lower initial peak rates is suppressed. The result of these changes is that the active CA1 population comes to consist of a relatively small group of cells with strong spatial tuning. This process is not evident in CA3, indicating that a region-specific and long timescale process operates in CA1 to create a sparse, spatially informative population of neurons.


Subject(s)
Hippocampus/cytology , Nerve Net/physiology , Nonlinear Dynamics , Pyramidal Cells/physiology , Spatial Behavior/physiology , Animals , Brain Mapping , Environment , Hippocampus/physiology , Male , Maze Learning/physiology , Neural Pathways/physiology , Rats , Rats, Long-Evans , Time Factors
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