The role of experience in prioritizing hippocampal replay.

During sleep, recent memories are replayed by the hippocampus, leading to their consolidation, with a higher priority given to salient experiences. To examine the role of replay in the selective strengthening of memories, we recorded large ensembles of hippocampal place cells while male rats ran repeated spatial trajectories on two linear tracks, differing in either their familiarity or number of laps run. We observed that during sleep, the rate of replay events for a given track increased proportionally with the number of spatial trajectories run by the animal. In contrast, the rate of sleep replay events decreased if the animal was more familiar with the track. Furthermore, we find that the cumulative number of awake replay events occurring during behavior, influenced by both the novelty and duration of an experience, predicts which memories are prioritized for sleep replay, providing a more parsimonious neural correlate for the selective strengthening of memories.

Courtship behaviour reveals temporal regularity is a critical social cue in mouse communication.

While animals navigating the real world face a barrage of sensory input, their brains evolved to perceptually compress multidimensional information by selectively extracting the features relevant for survival. Notably, communication signals supporting social interactions in several mammalian species consist of acoustically complex sequences of vocalisations. However, little is known about what information listeners extract from such time-varying sensory streams. Here, we utilise female mice's natural behavioural response to male courtship songs to identify the relevant acoustic dimensions used in their social decisions. We found that females were highly sensitive to disruptions of song temporal regularity and preferentially approached playbacks of intact over rhythmically irregular versions of male songs. In contrast, female behaviour was invariant to manipulations affecting the songs' sequential organisation or the spectro-temporal structure of individual syllables. The results reveal temporal regularity as a key acoustic cue extracted by mammalian listeners from complex vocal sequences during goal-directed social behaviour.

Memory capacity and prioritization in female mice.

Our brain's capacity for memory storage may be vast but is still finite. Given that we cannot remember the entirety of our experiences, how does our brain select what to remember and what to forget? Much like the triage of a hospital's emergency room, where urgent cases are prioritized and less critical patients receive delayed or even no care, the brain is believed to go through a similar process of memory triage. Recent salient memories are prioritized for consolidation, which helps create stable, long-term representations in the brain; less salient memories receive a lower priority, and are eventually forgotten if not sufficiently consolidated (Stickgold and Walker in Nat Neurosci 16(2):139-145, 2013). While rodents are a primary model for studying memory consolidation, common behavioral tests typically rely on a limited number of items or contexts, well within the memory capacity of the subject. A memory test allowing us to exceed an animal's memory capacity is key to investigating how memories are selectively strengthened or forgotten. Here we report a new serial novel object recognition task designed to measure memory capacity and prioritization, which we test and validate using female mice.

Behaviourally modulated hippocampal theta oscillations in the ferret persist during both locomotion and immobility.

Theta oscillations are a hallmark of hippocampal activity across mammals and play a critical role in many hippocampal models of memory and spatial navigation. To reconcile the cross-species differences observed in the presence and properties of theta, we recorded hippocampal local field potentials in rats and ferrets during auditory and visual localisation tasks designed to vary locomotion and sensory attention. Here, we show that theta oscillations occur during locomotion in both ferrets and rats, however during periods of immobility, theta oscillations persist in the ferret, contrasting starkly with the switch to large irregular activity (LIA) in the rat. Theta during immobility in the ferret is identified as analogous to Type 2 theta that has been observed in rodents due to its sensitivity to atropine, and is modulated by behavioural state with the strongest theta observed during reward epochs. These results demonstrate that even under similar behavioural conditions, differences exist between species in the relationship between theta and behavioural state.

Experience-driven rate modulation is reinstated during hippocampal replay.

Replay, the sequential reactivation within a neuronal ensemble, is a central hippocampal mechanism postulated to drive memory processing. While both rate and place representations are used by hippocampal place cells to encode behavioral episodes, replay has been largely defined by only the latter - based on the fidelity of sequential activity across neighboring place fields. Here, we show that dorsal CA1 place cells in rats can modulate their firing rate between replay events of two different contexts. This experience-dependent phenomenon mirrors the same pattern of rate modulation observed during behavior and can be used independently from place information within replay sequences to discriminate between contexts. Our results reveal the existence of two complementary neural representations available for memory processes.

How do our brains store memories? We now know that this is a complex and dynamic process, involving multiple regions of the brain. A brain region, called the hippocampus, plays an important role in memory formation. While we sleep, the hippocampus works to consolidate information, and eventually creates stable, long-term memories that are then stored in other parts of the brain. But how does the hippocampus do this? Neuroscientists believe that it can replay the patterns of brain activity that represent particular memories. By repeatedly doing this while we sleep, the hippocampus can then direct the transfer of this information to the rest of the brain for storage. The behaviour of nerve cells in the brain underpins these patterns of brain activity. When a nerve cell is active, it fires tiny electrical impulses that can be detected experimentally. The brain thus represents information in two ways: which nerve cells are active and when (sequential patterns); and how active the nerve cells are (how fast they fire electrical impulses or firing rate). For example, when an animal moves from one location to another, special place cells in the hippocampus become active in a distinct sequence. Depending on the context, they will also fire faster or slower. We know that the hippocampus can replay sequential patterns of nerve cell activity during memory consolidation, but whether it can also replay the firing rates associated with a particular experience is still unknown. Tirole, Huelin Gorriz et al. set out to determine if the hippocampus could also preserve the information encoded by firing rate during replay. In the experiments, rats explored two different environments that they had not seen before. The activity of the rats' place cells was recorded before and after they explored, and also later while they were sleeping. Analysis of the recordings revealed that during replay, the rats' hippocampi could indeed reproduce both the sequential patterns of activity and the firing rate of the place cells. It also confirmed that each environment was associated with unique firing rates ­ in other words, the firing rates were memory-specific. These results contribute to our understanding of how the hippocampus represents and processes information about our experiences. More broadly, they also shed new light on how the brain lays down memories, by revealing a key part of the mechanism that it uses to consolidate that information.

Predictive maps in rats and humans for spatial navigation.

Much of our understanding of navigation comes from the study of individual species, often with specific tasks tailored to those species. Here, we provide a novel experimental and analytic framework integrating across humans, rats, and simulated reinforcement learning (RL) agents to interrogate the dynamics of behavior during spatial navigation. We developed a novel open-field navigation task ("Tartarus maze") requiring dynamic adaptation (shortcuts and detours) to frequently changing obstructions on the path to a hidden goal. Humans and rats were remarkably similar in their trajectories. Both species showed the greatest similarity to RL agents utilizing a "successor representation," which creates a predictive map. Humans also displayed trajectory features similar to model-based RL agents, which implemented an optimal tree-search planning procedure. Our results help refine models seeking to explain mammalian navigation in dynamic environments and highlight the utility of modeling the behavior of different species to uncover the shared mechanisms that support behavior.

Interpreting wide-band neural activity using convolutional neural networks.

Rapid progress in technologies such as calcium imaging and electrophysiology has seen a dramatic increase in the size and extent of neural recordings. Even so, interpretation of this data requires considerable knowledge about the nature of the representation and often depends on manual operations. Decoding provides a means to infer the information content of such recordings but typically requires highly processed data and prior knowledge of the encoding scheme. Here, we developed a deep-learning framework able to decode sensory and behavioral variables directly from wide-band neural data. The network requires little user input and generalizes across stimuli, behaviors, brain regions, and recording techniques. Once trained, it can be analyzed to determine elements of the neural code that are informative about a given variable. We validated this approach using electrophysiological and calcium-imaging data from rodent auditory cortex and hippocampus as well as human electrocorticography (ECoG) data. We show successful decoding of finger movement, auditory stimuli, and spatial behaviors - including a novel representation of head direction - from raw neural activity.

Post-stimulatory activity in primate auditory cortex evoked by sensory stimulation during passive listening.

Under certain circumstances, cortical neurons are capable of elevating their firing for long durations in the absence of a stimulus. Such activity has typically been observed and interpreted in the context of performance of a behavioural task. Here we investigated whether post-stimulatory activity is observed in auditory cortex and the medial geniculate body of the thalamus in the absence of any explicit behavioural task. We recorded spiking activity from single units in the auditory cortex (fields A1, R and RT) and auditory thalamus of awake, passively-listening marmosets. We observed post-stimulatory activity that lasted for hundreds of milliseconds following the termination of the acoustic stimulus. Post-stimulatory activity was observed following both adapting, sustained and suppressed response profiles during the stimulus. These response types were observed across all cortical fields tested, but were largely absent from the auditory thalamus. As well as being of shorter duration, thalamic post-stimulatory activity emerged following a longer latency than in cortex, indicating that post-stimulatory activity may be generated within auditory cortex during passive listening. Given that these responses were observed in the absence of an explicit behavioural task, post-stimulatory activity in sensory cortex may play a functional role in processes such as echoic memory and temporal integration that occur during passive listening.

The role of adaptation in generating monotonic rate codes in auditory cortex.

In primary auditory cortex, slowly repeated acoustic events are represented temporally by the stimulus-locked activity of single neurons. Single-unit studies in awake marmosets (Callithrix jacchus) have shown that a sub-population of these neurons also monotonically increase or decrease their average discharge rate during stimulus presentation for higher repetition rates. Building on a computational single-neuron model that generates stimulus-locked responses with stimulus evoked excitation followed by strong inhibition, we find that stimulus-evoked short-term depression is sufficient to produce synchronized monotonic positive and negative responses to slowly repeated stimuli. By exploring model robustness and comparing it to other models for adaptation to such stimuli, we conclude that short-term depression best explains our observations in single-unit recordings in awake marmosets. Together, our results show how a simple biophysical mechanism in single neurons can generate complementary neural codes for acoustic stimuli.

How Targeted Memory Reactivation Promotes the Selective Strengthening of Memories in Sleep.

Over the last ten years, scientists have developed a method called targeted memory reactivation (TMR) for selectively strengthening memories during sleep. Prior to this, memory manipulation during sleep was at most a plot device in science fiction movies, but a large corpus of studies now demonstrates that TMR is both reliable and effective. TMR studies hypothesize that this method taps into normal consolidation mechanisms that require the repeated replay of memories during sleep. This idea has recently been supported by several new studies demonstrating that TMR upregulates the reactivation of cued memories, and that such upregulation predicts subsequent memory performance. This new body of work provides a unique window onto many properties of memory reactivation and helps to close the gap between our understanding of replay in rodents, where it has been visualised at the neural level for many years, and humans, where such studies are only just starting to become possible. We will discuss this new literature and highlight the vast potential of these new methods for future research.

A review of neurobiological factors underlying the selective enhancement of memory at encoding, consolidation, and retrieval.

How is the strength of a memory determined? This review discusses three main factors that contribute to memory enhancement - 1) emotion, 2) targeted memory reactivation, and 3) neural reinstatement. Whilst the mechanisms through which memories become enhanced vary, this review demonstrates that activation of the basolateral amygdala and hippocampal formation are crucial for facilitating encoding, consolidation, and retrieval. Here we suggest methodological factors to consider in future studies, and discuss several unanswered questions that should be pursued in order to clarify selective memory enhancement.

Neuronal Mechanisms and Transformations Encoding Time-Varying Signals.

Sensation in natural environments requires the analysis of time-varying signals. While previous work has uncovered how a signal's temporal rate is represented by neurons in sensory cortex, in this issue of Neuron, new evidence from Gao et al. (2016) provides insights on the underlying mechanisms.

Tracking the Time-Dependent Role of the Hippocampus in Memory Recall Using DREADDs.

The hippocampus is critical for the storage of new autobiographical experiences as memories. Following an initial encoding stage in the hippocampus, memories undergo a process of systems-level consolidation, which leads to greater stability through time and an increased reliance on neocortical areas for retrieval. The extent to which the retrieval of these consolidated memories still requires the hippocampus is unclear, as both spared and severely degraded remote memory recall have been reported following post-training hippocampal lesions. One difficulty in definitively addressing the role of the hippocampus in remote memory retrieval is the precision with which the entire volume of the hippocampal region can be inactivated. To address this issue, we used Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), a chemical-genetic tool capable of highly specific neuronal manipulation over large volumes of brain tissue. We find that remote (>7 weeks after acquisition), but not recent (1-2 days after acquisition) contextual fear memories can be recalled after injection of the DREADD agonist (CNO) in animals expressing the inhibitory DREADD in the entire hippocampus. Our data demonstrate a time-dependent role of the hippocampus in memory retrieval, supporting the standard model of systems consolidation.

Does the Hippocampus Map Out the Future?

Decades of research have established two central roles of the hippocampus--memory consolidation and spatial navigation. Recently, a third function of the hippocampus has been proposed: simulating future events. However, claims that the neural patterns underlying simulation occur without prior experience have come under fire in light of newly published data.

Flies Sleep on It, or Fuhgeddaboudit!

Many studies in diverse organisms, including humans, have demonstrated a fundamental role for sleep in the formation of memories. A new study by Berry et al. indicates that, in fruit flies, sleep accomplishes this in part by preventing an active process of forgetting.

The role of inhibition in a computational model of an auditory cortical neuron during the encoding of temporal information.

In auditory cortex, temporal information within a sound is represented by two complementary neural codes: a temporal representation based on stimulus-locked firing and a rate representation, where discharge rate co-varies with the timing between acoustic events but lacks a stimulus-synchronized response. Using a computational neuronal model, we find that stimulus-locked responses are generated when sound-evoked excitation is combined with strong, delayed inhibition. In contrast to this, a non-synchronized rate representation is generated when the net excitation evoked by the sound is weak, which occurs when excitation is coincident and balanced with inhibition. Using single-unit recordings from awake marmosets (Callithrix jacchus), we validate several model predictions, including differences in the temporal fidelity, discharge rates and temporal dynamics of stimulus-evoked responses between neurons with rate and temporal representations. Together these data suggest that feedforward inhibition provides a parsimonious explanation of the neural coding dichotomy observed in auditory cortex.

Global timing: a conceptual framework to investigate the neural basis of rhythm perception in humans and non-human species.

Timing cues are an essential feature of music. To understand how the brain gives rise to our experience of music we must appreciate how acoustical temporal patterns are integrated over the range of several seconds in order to extract global timing. In music perception, global timing comprises three distinct but often interacting percepts: temporal grouping, beat, and tempo. What directions may we take to further elucidate where and how the global timing of music is processed in the brain? The present perspective addresses this question and describes our current understanding of the neural basis of global timing perception.

Enhance, delete, incept: manipulating hippocampus-dependent memories.

Here we provide a brief overview of recent research on memory manipulation. We focus primarily on memories for which the hippocampus is thought to be required due to its central importance in the study of memory. The repertoire of methods employed is expanding and includes optogenetics, transcranial stimulation, deep brain stimulation, cued reactivation during sleep and the use of pharmacological agents. In addition, the possible mechanisms underlying these memory changes have been investigated using techniques such as single unit recording and functional magnetic resonance imaging (fMRI). This article is part of a Special Issue entitled 'Memory enhancement'.

Dual-pitch processing mechanisms in primate auditory cortex.

Pitch, our perception of how high or low a sound is on a musical scale, is a fundamental perceptual attribute of sounds and is important for both music and speech. After more than a century of research, the exact mechanisms used by the auditory system to extract pitch are still being debated. Theoretically, pitch can be computed using either spectral or temporal acoustic features of a sound. We have investigated how cues derived from the temporal envelope and spectrum of an acoustic signal are used for pitch extraction in the common marmoset (Callithrix jacchus), a vocal primate species, by measuring pitch discrimination behaviorally and examining pitch-selective neuronal responses in auditory cortex. We find that pitch is extracted by marmosets using temporal envelope cues for lower pitch sounds composed of higher-order harmonics, whereas spectral cues are used for higher pitch sounds with lower-order harmonics. Our data support dual-pitch processing mechanisms, originally proposed by psychophysicists based on human studies, whereby pitch is extracted using a combination of temporal envelope and spectral cues.