Mathilde C. C. Guillaumin

Flexible behaviour requires predictions that extend beyond direct experience, yet the neural mechanisms that support this process remain unclear. A candidate mechanism occurs during hippocampal sharp-wave ripples (SWRs), in which generative replay combines representations for discrete past events into novel activity patterns. However, it remains unknown whether comparable computations occur in neocortex. Using simultaneous electrophysiology and calcium imaging across hippocampus and neocortex, we record neural activity in freely moving mice during an inference task and in subsequent sleep. We show that neuronal sequences in primary visual cortex (V1) encode relationships that were never directly experienced, providing evidence for generative replay outside the hippocampus. Generative replay in V1 is predicted by preceding hippocampal activity, suggesting that hippocampal activity provides a teaching signal to reorganise neocortical representations during sleep. These findings identify a hippocampal-neocortical mechanism for generative replay which may support the construction of a hierarchical generative model to enable flexible behaviour.

Electrophysiological recordings from freely behaving animals are a widespread and powerful mode of investigation in sleep research. These recordings generate large amounts of data that require sleep stage annotation (polysomnography), in which the data is parcellated according to three vigilance states: awake, rapid eye movement (REM) sleep, and non-REM (NREM) sleep. Manual and current computational annotation methods ignore intermediate states because the classification features become ambiguous, even though intermediate states contain important information regarding vigilance state dynamics. To address this problem, we have developed "Somnotate"—a probabilistic classifier based on a combination of linear discriminant analysis (LDA) with a hidden Markov model (HMM). First we demonstrate that Somnotate sets new standards in polysomnography, exhibiting annotation accuracies that exceed human experts on mouse electrophysiological data, remarkable robustness to errors in the training data, compatibility with different recording configurations, and an ability to maintain high accuracy during experimental interventions. However, the key feature of Somnotate is that it quantifies and reports the certainty of its annotations. We leverage this feature to reveal that many intermediate vigilance states cluster around state transitions, whereas others correspond to failed attempts to transition. This enables us to show for the first time that the success rates of different types of transition are differentially affected by experimental manipulations and can explain previously observed sleep patterns. Somnotate is open-source and has the potential to both facilitate the study of sleep stage transitions and offer new insights into the mechanisms underlying sleep-wake dynamics.

Overeating is driven by both the hedonic component (‘liking’) of food, and the motivation (‘wanting’) to eat it. The nucleus accumbens (NAc) is a key brain center implicated in these processes, but how distinct NAc cell populations encode ‘liking’ and ‘wanting’ to shape overconsumption remains unclear. Here, we probed the roles of NAc D1 and D2 cells in these processes using cell-specific recording and optogenetic manipulation in diverse behavioral paradigms that disentangle reward traits of ‘liking’ and ‘wanting’ related to food choice and overeating in healthy mice. Medial NAc shell D2 cells encoded experience-dependent development of ‘liking’, while D1 cells encoded innate ‘liking’ during the first food taste. Optogenetic control confirmed causal links of D1 and D2 cells to these aspects of ‘liking’. In relation to ‘wanting’, D1 and D2 cells encoded and promoted distinct aspects of food approach: D1 cells interpreted food cues while D2 cells also sustained food-visit-length that facilitates consumption. Finally, at the level of food choice, D1, but not D2, cell activity was sufficient to switch food preference, programming subsequent long-lasting overconsumption. By revealing complementary roles of D1 and D2 cells in consumption, these findings assign neural bases to ‘liking’ and ‘wanting’ in a unifying framework of D1 and D2 cell activity.

Growing evidence suggests that brain activity during sleep, as well as sleep regulation, are tightly linked with synaptic function and network excitability at the local and global levels. We previously reported that a mutation in synaptobrevin 2 ( Vamp2 ) in restless ( rlss ) mice results in a marked increase of wakefulness and suppression of sleep, in particular REM sleep (REMS) as well as increased consolidation of sleep and wakefulness. In the current study, using finer-scale in vivo electrophysiology recordings, we report that spontaneous cortical activity in rlss mice during NREM sleep (NREMS) is characterised by an occurrence of abnormally prolonged periods of complete neuronal silence (OFF-periods), often lasting several seconds, similar to the burst suppression pattern typically seen under deep anaesthesia. Increased incidence of prolonged network OFF-periods was not specific to NREMS, but also present in REMS and wake in rlss mice. Slow-wave activity (SWA) was generally increased in rlss mice, while higher frequencies including theta-frequency activity were decreased, further resulting in diminished differences between vigilance states. The relative increase in SWA after sleep deprivation was attenuated in rlss mice, suggesting either that rlss mice experience persistently elevated sleep pressure, or, alternatively, that the intrusion of sleep-like patterns of activity into awake state diminishes the accumulation of sleep drive. We propose that deficit in global synaptic neurotransmitter release leads to ‘state inertia’, reflected in an abnormal propensity of brain networks to enter and remain in a persistent ‘default state’ resembling coma or deep anaesthesia.

The last decades have shown that maintaining a healthy and balanced diet can support brain integrity and functionality, while an inadequate diet can compromise it. However, still little is known about the effects and utility of so-called healthy snacks or drinks and their immediate short-term effects on cognition and physical performance. Here, we prepared dietary modulators comprising the essential macronutrients at different ratios and a controlled balanced dietary modulator. We assessed, in healthy adult mice, the short-term effects of these modulators when consumed shortly prior to tests with different cognitive and physical demands. A high-fat dietary modulator sustained increased motivation compared to a carbohydrate-rich dietary modulator (p = 0.041) which had a diminishing effect on motivation (p = 0.018). In contrast, a high-carbohydrate modulator had an initial beneficial effect on cognitive flexibility (p = 0.031). No apparent effects of any of the dietary modulators were observed on physical exercise. There is increasing public demand for acute cognitive and motor function enhancers that can improve mental and intellectual performance in daily life, such as in the workplace, studies, or sports activities. Our findings suggest such enhancers should be tailored to the cognitive demand of the task undertaken, as different dietary modulators will have distinct effects when consumed shortly prior to the task.

Evidence from human and animal studies has shown that maternal overnutrition and/or obesity are linked with neurobehavioral changes in the offspring. This fetal programming is characterized by adaptive responses to changes in the nutritional state during early life. In the past decade, an association has been made between overconsumption of highly-palatable food by the mother during fetal development and abnormal behaviors resembling addiction in the offspring. Maternal overnutrition can lead to alterations in the offspring’s brain reward circuitry leading to hyperresponsiveness of this circuit following exposure to calorie-dense foods later in life. Given the accumulating evidence indicating that the central nervous system plays a pivotal role in regulating food intake, energy balance, and the motivation to seek food, a dysfunction in the reward circuitry may contribute to the addiction-like behaviors observed in the offspring. However, the underlying mechanisms leading to these alterations in the reward circuitry during fetal development and their relevance to the increased risk for the offspring to later develop addictive-like behaviors is still unclear. Here, we review the most relevant scientific reports about the impact of food overconsumption during fetal development and its effect on addictive-like behaviors of the offspring in the context of eating disorders and obesity.

During non-rapid eye movement sleep (NREM), synchronised neuronal activity is reflected in a specific neural oscillation observed in neocortical electrophysiological signals: a low frequency component characterised by depth-positive/surface-negative potentials known as slow waves, corresponding to alternating periods of high (ON period) and low (OFF period) spiking activity. Often overlooked in favour of slow waves, there is an interest in understanding how neuronal silencing during OFF periods leads to the generation of slow waves and whether this relationship changes between cortical layers. The foremost issue in detecting population OFF periods is the absence of a formal, widely adopted definition. Here, we grouped segments of high frequency neural activity containing spikes, recorded from the neocortex, on the basis of amplitude and asked whether the population of low amplitude (LA) segments displayed the expected characteristics of OFF periods. We corroborate previous studies showing that LA segments in neural activity signals are a uniquely identifiable structure with distinct characteristics from the surrounding signal that identify them as OFF periods including NREM sleep predominance and association with a local field potential (LFP) slow wave. In addition, we attribute new characteristics to these segments not previously associated with OFF periods: vigilance-state-dependent duration and duration-dependent homeostatic response. This could suggest that ON/OFF periods are currently underdefined, and their appearance is less binary than previously considered, instead representing a continuum.

Summary: The slow oscillation is a central neuronal dynamic during sleep, and is generated by alternating periods of high and low neuronal activity (ON‐ and OFF‐states). Mounting evidence causally links the slow oscillation to sleep's functions, and it has recently become possible to manipulate the slow oscillation non‐invasively and phase‐specifically. These developments represent promising clinical avenues, but they also highlight the importance of improving our understanding of how ON/OFF‐states affect incoming stimuli and what role they play in neuronal plasticity. Most studies using closed‐loop stimulation rely on the electroencephalogram and local field potential signals, which reflect neuronal ON‐ and OFF‐states only indirectly. Here we develop an online detection algorithm based on spiking activity recorded from laminar arrays in mouse motor cortex. We find that online detection of ON‐ and OFF‐states reflects specific phases of spontaneous local field potential slow oscillation. Our neuronal‐spiking‐based closed‐loop procedure offers a novel opportunity for testing the functional role of slow oscillation in sleep‐related restorative processes and neural plasticity.

Significance: Our current understanding of how sleep is regulated is based upon the model of sleep homeostasis, which defines a variable called Process S as a measure of sleep need, and a so-called “flip-flop” model of state switching, which builds on a notion of a mutually antagonistic relationship between subcortical sleep-promoting and wake-promoting circuits. The neurobiological substrates of the interaction between the sleep switch and Process S are unknown. Our study identifies a previously unrecognized role of hypothalamic circuitry in tuning within-state brain activity or levels of arousal, which in turn determine the homeostatic drive for sleep.