Pattern dynamics and stochasticity of the brain rhythms.

Our current understanding of brain rhythms is based on quantifying their instantaneous or time-averaged characteristics. What remains unexplored is the actual structure of the waves-their shapes and patterns over finite timescales. Here, we study brain wave patterning in different physiological contexts using two independent approaches: The first is based on quantifying stochasticity relative to the underlying mean behavior, and the second assesses "orderliness" of the waves' features. The corresponding measures capture the waves' characteristics and abnormal behaviors, such as atypical periodicity or excessive clustering, and demonstrate coupling between the patterns' dynamics and the animal's location, speed, and acceleration. Specifically, we studied patterns of θ, γ, and ripple waves recorded in mice hippocampi and observed speed-modulated changes of the wave's cadence, an antiphase relationship between orderliness and acceleration, as well as spatial selectiveness of patterns. Taken together, our results offer a complementary-mesoscale-perspective on brain wave structure, dynamics, and functionality.

Temporal coding and rate remapping: Representation of nonspatial information in the hippocampus.

Hippocampal place cells represent nonspatial information through a process called rate remapping, which involves a change in the firing rate of a place cell without changes in its spatial specificity. However, many hippocampal phenomena occur on very short time scales over which long-term average firing rates are not an appropriate description of activity. To understand how rate remapping relates to fine-scale temporal firing phenomena, we asked how rate remapping affected burst firing and trial-to-trial spike count variability. In addition, we looked at how rate remapping relates to the theta-frequency oscillations of the hippocampus, which are thought to temporally organize firing on time scales faster than 100 ms. We found that theta phase coding was preserved through changes in firing rate due to rate remapping. Interestingly, rate remapping in CA1 in response to task demands preferentially occurred during the first half of the theta cycle. The other half of the theta cycle contained preferential expression of phase precession, a phenomenon associated with place cell sequences, in agreement with previous results. This difference of place cell coding during different halves of the theta cycle supports recent theoretical suggestions that different processes occur during the two halves of the theta cycle. The differentiation between the halves of the theta cycle was not clear in recordings from CA3 during rate remapping induced by task-irrelevant sensory changes. These findings provide new insight into the way that temporal coding is utilized in the hippocampus and how rate remapping is expressed through that temporal code.

Progressive functional impairments of hippocampal neurons in a tauopathy mouse model.

The age-dependent progression of tau pathology is a major characteristic of tauopathies, including Alzheimer's disease (AD), and plays an important role in the behavioral phenotypes of AD, including memory deficits. Despite extensive molecular and cellular studies on tau pathology, it remains to be determined how it alters the neural circuit functions underlying learning and memory in vivo. In rTg4510 mice, a Tau-P301L tauopathy model, hippocampal place fields that support spatial memories are abnormal at old age (7-9 months) when tau tangles and neurodegeneration are extensive. However, it is unclear how the abnormality in the hippocampal circuit function arises and progresses with the age-dependent progression of tau pathology. Here we show that in young (2-4 months of age) rTg4510 mice, place fields of hippocampal CA1 cells are largely normal, with only subtle differences from those of age-matched wild-type control mice. Second, high-frequency ripple oscillations of local field potentials in the hippocampal CA1 area are significantly reduced in young rTg4510 mice, and even further deteriorated in old rTg4510 mice. The ripple reduction is associated with less bursty firing and altered synchrony of CA1 cells. Together, the data indicate that deficits in ripples and neuronal synchronization occur before overt deficits in place fields in these mice. The results reveal a tau-pathology-induced progression of hippocampal functional changes in vivo.

Initiation of sleep-dependent cortical-hippocampal correlations at wakefulness-sleep transition.

Sleep is involved in memory consolidation. Current theories propose that sleep-dependent memory consolidation requires active communication between the hippocampus and neocortex. Indeed, it is known that neuronal activities in the hippocampus and various neocortical areas are correlated during slow-wave sleep. However, transitioning from wakefulness to slow-wave sleep is a gradual process. How the hippocampal-cortical correlation is established during the wakefulness-sleep transition is unknown. By examining local field potentials and multiunit activities in the rat hippocampus and visual cortex, we show that the wakefulness-sleep transition is characterized by sharp-wave ripple events in the hippocampus and high-voltage spike-wave events in the cortex, both of which are accompanied by highly synchronized multiunit activities in the corresponding area. Hippocampal ripple events occur earlier than the cortical high-voltage spike-wave events, and hippocampal ripple incidence is attenuated by the onset of cortical high-voltage spike waves. This attenuation leads to a temporary weak correlation in the hippocampal-cortical multiunit activities, which eventually evolves to a strong correlation as the brain enters slow-wave sleep. The results suggest that the hippocampal-cortical correlation is established through a concerted, two-step state change that first synchronizes the neuronal firing within each brain area and then couples the synchronized activities between the two regions.

Impairments in experience-dependent scaling and stability of hippocampal place fields limit spatial learning in a mouse model of Alzheimer's disease.

Impaired spatial memory characterizes many mouse models for Alzheimer's disease, but we understand little about how this trait arises. Here, we use a transgenic model of amyloidosis to examine the relationship between behavioral performance in tests of spatial navigation and the function of hippocampal place cells. We find that amyloid precursor protein (APP) mice require considerably more training than controls to reach the same level of performance in a water maze task, and recall the trained location less well 24 h later. At a single cell level, place fields from control mice become more stable and spatially restricted with repeated exposure to a new environment, while those in APP mice improve less over time, ultimately producing a spatial code of lower resolution, accuracy, and reliability than controls. The limited refinement of place fields in APP mice likely contributes to their delayed water maze acquisition, and provides evidence for circuit dysfunction underlying cognitive impairment.

Observational activation of anterior cingulate cortical neurons coordinates hippocampal replay in social learning.

Social learning enables a subject to make decisions by observing the actions of another. How neural circuits acquire relevant information during observation to guide subsequent behavior is unknown. Utilizing an observational spatial working memory task, we show that neurons in the rat anterior cingulate cortex (ACC) associated with spatial trajectories during self-running in a maze are activated when observing another rat running the same maze. The observation-induced ACC activities are reduced in error trials and are correlated with activities of hippocampal place cells representing the same trajectories. The ACC activities during observation also predict subsequent hippocampal place cell activities during sharp-wave ripples and spatial contents of hippocampal replay prior to self-running. The results support that ACC neurons involved in decisions during self-running are reactivated during observation and coordinate hippocampal replay to guide subsequent spatial navigation.

Memory rescue and learning in synaptic impaired neuronal circuits.

Neuronal impairment is a characteristic of Alzheimer's disease (AD), but its effect on neural activity dynamics underlying memory deficits is unclear. Here, we studied the effects of synaptic impairment on neural activities associated with memory recall, memory rescue, and learning a new memory, in an integrate-and-fire neuronal network. Our results showed that reducing connectivity decreases the neuronal synchronization of memory neurons and impairs memory recall performance. Although, slow-gamma stimulation rescued memory recall and slow-gamma oscillations, the rescue caused a side effect of activating mixed memories. During the learning of a new memory, reducing connectivity caused impairment in storing the new memory, but did not affect previously stored memories. We also explored the effects of other types of impairments including neuronal loss and excitation-inhibition imbalance and the rescue by general increase of excitability. Our results reveal potential computational mechanisms underlying the memory deficits caused by impairment in AD.

Tetrode recording of rat CA1 place cells in an observational spatial working memory task.

Social observation facilitates spatial learning by activation of hippocampal place cell patterns. Here, we describe an observational spatial working memory task to investigate the neural circuits underlying observational learning. This approach trains observer rats to learn to run a T-maze by observing a demonstrator's spatial trajectory while recording their hippocampal CA1 place cell activities in a course of several hours. The protocol provides a tool to study neural activities at population level in a social setting. For complete details on the use and execution of this protocol, please refer to Mou et al. (2021).

Observational learning promotes hippocampal remote awake replay toward future reward locations.

The neural circuit mechanisms underlying observational learning, learning through observing the behavior of others, are poorly understood. Hippocampal place cells are important for spatial learning, and awake replay of place cell patterns is involved in spatial decisions. Here we show that, in observer rats learning to run a maze by watching a demonstrator's spatial trajectories from a separate nearby observation box, place cell patterns during self-running in the maze are replayed remotely in the box. The contents of the remote awake replay preferentially target the maze's reward sites from both forward and reverse replay directions and reflect the observer's future correct trajectories in the maze. In contrast, under control conditions without a demonstrator, the remote replay is significantly reduced, and the preferences for reward sites and future trajectories disappear. Our results suggest that social observation directs the contents of remote awake replay to guide spatial decisions in observational learning.

Place cells dynamically refine grid cell activities to reduce error accumulation during path integration in a continuous attractor model.

Navigation is one of the most fundamental skills of animals. During spatial navigation, grid cells in the medial entorhinal cortex process speed and direction of the animal to map the environment. Hippocampal place cells, in turn, encode place using sensory signals and reduce the accumulated error of grid cells for path integration. Although both cell types are part of the path integration system, the dynamic relationship between place and grid cells and the error reduction mechanism is yet to be understood. We implemented a realistic model of grid cells based on a continuous attractor model. The grid cell model was coupled to a place cell model to address their dynamic relationship during a simulated animal's exploration of a square arena. The grid cell model processed the animal's velocity and place field information from place cells. Place cells incorporated salient visual features and proximity information with input from grid cells to define their place fields. Grid cells had similar spatial phases but a diversity of spacings and orientations. To determine the role of place cells in error reduction for path integration, the animal's position estimates were decoded from grid cell activities with and without the place field input. We found that the accumulated error was reduced as place fields emerged during the exploration. Place fields closer to the animal's current location contributed more to the error reduction than remote place fields. Place cells' fields encoding space could function as spatial anchoring signals for precise path integration by grid cells.

Rapid Spectral Dynamics in Hippocampal Oscillons.

Neurons in the brain are submerged into oscillating extracellular potential produced by synchronized synaptic currents. The dynamics of these oscillations is one of the principal characteristics of neurophysiological activity, broadly studied in basic neuroscience and used in applications. However, our interpretation of the brain waves' structure and hence our understanding of their functions depend on the mathematical and computational approaches used for data analysis. The oscillatory nature of the wave dynamics favors Fourier methods, which have dominated the field for several decades and currently constitute the only systematic approach to brain rhythms. In the following study, we outline an alternative framework for analyzing waves of local field potentials (LFPs) and discuss a set of new structures that it uncovers: a discrete set of frequency-modulated oscillatory processes-the brain wave oscillons and their transient spectral dynamics.

Rational designing of oscillatory rhythmicity for memory rescue in plasticity-impaired learning networks.

In the brain, oscillatory strength embedded in network rhythmicity is important for processing experiences, and this process is disrupted in certain psychiatric disorders. The use of rhythmic network stimuli can change these oscillations and has shown promise in terms of improving cognitive function, although the underlying mechanisms are poorly understood. Here, we combine a two-layer learning model, with experiments involving genetically modified mice, that provides precise control of experience-driven oscillations by manipulating long-term potentiation of excitatory synapses onto inhibitory interneurons (LTPE→I). We find that, in the absence of LTPE→I, impaired network dynamics and memory are rescued by activating inhibitory neurons to augment the power in theta and gamma frequencies, which prevents network overexcitation with less inhibitory rebound. In contrast, increasing either theta or gamma power alone was less effective. Thus, inducing network changes at dual frequencies is involved in memory encoding, indicating a potentially feasible strategy for optimizing network-stimulating therapies.

Coordinated memory replay in the visual cortex and hippocampus during sleep.

Sleep replay of awake experience in the cortex and hippocampus has been proposed to be involved in memory consolidation. However, whether temporally structured replay occurs in the cortex and whether the replay events in the two areas are related are unknown. Here we studied multicell spiking patterns in both the visual cortex and hippocampus during slow-wave sleep in rats. We found that spiking patterns not only in the cortex but also in the hippocampus were organized into frames, defined as periods of stepwise increase in neuronal population activity. The multicell firing sequences evoked by awake experience were replayed during these frames in both regions. Furthermore, replay events in the sensory cortex and hippocampus were coordinated to reflect the same experience. These results imply simultaneous reactivation of coherent memory traces in the cortex and hippocampus during sleep that may contribute to or reflect the result of the memory consolidation process.

LSD degrades hippocampal spatial representations and suppresses hippocampal-visual cortical interactions.

Lysergic acid diethylamide (LSD) produces hallucinations, which are perceptions uncoupled from the external environment. How LSD alters neuronal activities in vivo that underlie abnormal perceptions is unknown. Here, we show that when rats run along a familiar track, hippocampal place cells under LSD reduce their firing rates, their directionality, and their interaction with visual cortical neurons. However, both hippocampal and visual cortical neurons temporarily increase firing rates during head-twitching, a behavioral signature of a hallucination-like state in rodents. When rats are immobile on the track, LSD enhances cortical firing synchrony in a state similar to the wakefulness-to-sleep transition, during which the hippocampal-cortical interaction remains dampened while hippocampal awake reactivation is maintained. Our results suggest that LSD suppresses hippocampal-cortical interactions during active behavior and during immobility, leading to internal hippocampal representations that are degraded and isolated from external sensory input. These effects may contribute to LSD-produced abnormal perceptions.

Firing rate dynamics in the hippocampus induced by trajectory learning.

The hippocampus is essential for spatial navigation, which may involve sequential learning. However, how the hippocampus encodes new sequences in familiar environments is unknown. To study the impact of novel spatial sequences on the activity of hippocampal neurons, we monitored hippocampal ensembles while rats learned to switch from two familiar trajectories to a new one in a familiar environment. Here, we show that this novel spatial experience induces two types of changes in firing rates, but not locations of hippocampal place cells. First, place-cell firing rates on the two familiar trajectories start to change before the actual behavioral switch to the new trajectory. Second, repeated exposure on the new trajectory is associated with an increased dependence of place-cell firing rates on immediate past locations. The result suggests that sequence encoding in the hippocampus may involve integration of information about the recent past into current state.

Comparing Mouse and Rat Hippocampal Place Cell Activities and Firing Sequences in the Same Environments.

Hippocampal place cells are key to spatial representation and spatial memory processing. They fire at specific locations in a space (place fields) and fire in precise patterns during theta sequences and during ripple-associated replay events. These phenomena have been extensively studied in rats, but to a less extent in mice. The availability of versatile genetic manipulations gives mice an advantage for place cell studies. However, it is unknown how place fields and place cell sequences in the same environment differ between mice and rats. Here, we provide a quantitative comparison in place field properties, as well as theta sequences and replays, between rats and mice as they ran on the same novel track and as they rested afterwards. We found that place cells in mice display less spatial specificity with more but smaller place fields. Theta oscillations, theta phase precession and aspects of theta sequences in mice are similar as those in rats. The ripple-associated replay, however, is relatively rare during stopping on the novel track in mice. The replay is present during resting after the track running, but is weaker in mice than the replay in rats. Our results suggest that place cells in mice and rats are qualitatively similar, but with substantial quantitative differences.

Impaired spatial memory codes in a mouse model of Rett syndrome.

The Mecp2+/- mouse model recapitulates many phenotypes of patients with Rett syndrome (RTT), including learning and memory deficits. It is unknown, however, how the disease state alters memory circuit functions in vivo in RTT mice. Here we recorded from hippocampal place cells, which are thought to encode spatial memories, in freely moving RTT mice and littermate controls. We found that place cells in RTT mice are impaired in their experience-dependent increase of spatial information. This impairment is accompanied by an enhanced baseline firing synchrony of place cells within ripple oscillations during rest, which consequently occludes the increase in synchrony after a novel experience. Behaviorally, contextual memory is normal at short but not long time scale in RTT mice. Our results suggest that hypersynchrony interferes with memory consolidation and leads to impaired spatial memory codes in RTT mice, providing a possible circuit mechanism for memory deficits in Rett Syndrome.

Real-Time Readout of Large-Scale Unsorted Neural Ensemble Place Codes.

Uncovering spatial representations from large-scale ensemble spike activity in specific brain circuits provides valuable feedback in closed-loop experiments. We develop a graphics processing unit (GPU)-powered population-decoding system for ultrafast reconstruction of spatial positions from rodents' unsorted spatiotemporal spiking patterns, during run behavior or sleep. In comparison with an optimized quad-core central processing unit (CPU) implementation, our approach achieves an ∼20- to 50-fold increase in speed in eight tested rat hippocampal, cortical, and thalamic ensemble recordings, with real-time decoding speed (approximately fraction of a millisecond per spike) and scalability up to thousands of channels. By accommodating parallel shuffling in real time (computation time <15 ms), our approach enables assessment of the statistical significance of online-decoded "memory replay" candidates during quiet wakefulness or sleep. This open-source software toolkit supports the decoding of spatial correlates or content-triggered experimental manipulation in closed-loop neuroscience experiments.

Social Observation Task in a Linear Maze for Rats.

Animals often learn through observing their conspecifics. However, the mechanisms of them obtaining useful knowledge during observation are beginning to be understood. This protocol describes a novel social observation task to test the 'local enhancement theory', which proposes that presence of social subjects in an environment facilitates one's understanding of the environments. By combining behavior test and in vivo electrophysiological recording, we found that social observation can facilitate the observer's spatial representation of an unexplored environment. The task protocol was published in Mou and Ji, 2016.

Hippocampal awake replay in fear memory retrieval.

Hippocampal place cells are key to episodic memories. How these cells participate in memory retrieval remains unclear. After rats acquired a fear memory by receiving mild footshocks in a shock zone on a track, we analyzed place cells when the animals were placed on the track again and displayed an apparent memory retrieval behavior: avoidance of the shock zone. We found that place cells representing the shock zone were reactivated, despite the fact that the animals did not enter the shock zone. This reactivation occurred in ripple-associated awake replay of place cell sequences encoding the paths from the animal's current positions to the shock zone but not in place cell sequences within individual cycles of theta oscillation. The result reveals a specific place-cell pattern underlying inhibitory avoidance behavior and provides strong evidence for the involvement of awake replay in fear memory retrieval.