Hippocampal place cells assemblies are believed to support the cognitive map, and their reactivations during sleep are thought to be involved in spatial memory consolidation. By triggering intracranial rewarding stimulations by place cell spikes during sleep, we induced an explicit memory trace, leading to a goal-directed behavior toward the place field. This demonstrates that place cells' activity during sleep still conveys relevant spatial information and that this activity is functionally significant for navigation.

Brain–body interactions are thought to be essential in emotions but their physiological basis remains poorly understood. In mice, regular 4 Hz breathing appears during freezing after cue-fear conditioning. Here we show that the olfactory bulb (OB) transmits this rhythm to the dorsomedial prefrontal cortex (dmPFC) where it organizes neural activity. Reduction of the respiratory-related 4 Hz oscillation, via bulbectomy or optogenetic perturbation of the OB, reduces freezing. Behavioural modelling shows that this is due to a specific reduction in freezing maintenance without impacting its initiation, thus dissociating these two phenomena. dmPFC LFP and firing patterns support the region’s specific function in freezing maintenance. In particular, population analysis reveals that network activity tracks 4 Hz power dynamics during freezing and reaches a stable state at 4 Hz peak that lasts until freezing termination. These results provide a potential mechanism and a functional role for bodily feedback in emotions and therefore shed light on the historical James–Cannon debate.

Real-time tracking of vigilance states related to both sleep or anaesthesia has been a goal for over a century. However, sleep scoring cannot currently be performed with brain signals alone, despite the deep neuromodulatory transformations that accompany sleep state changes. Therefore, at heart, the operational distinction between sleep and wake is that of immobility and movement, despite numerous situations in which this one-to-one mapping fails. Here we demonstrate, using local field potential (LFP) recordings in freely moving mice, that gamma (50–70 Hz) power in the olfactory bulb (OB) allows for clear classification of sleep and wake, thus providing a brain-based criterion to distinguish these two vigilance states without relying on motor activity. Coupled with hippocampal theta activity, it allows the elaboration of a sleep scoring algorithm that relies on brain activity alone. This method reaches over 90% homology with classical methods based on muscular activity (electromyography [EMG]) and video tracking. Moreover, contrary to EMG, OB gamma power allows correct discrimination between sleep and immobility in ambiguous situations such as fear-related freezing. We use the instantaneous power of hippocampal theta oscillation and OB gamma oscillation to construct a 2D phase space that is highly robust throughout time, across individual mice and mouse strains, and under classical drug treatment. Dynamic analysis of trajectories within this space yields a novel characterisation of sleep/wake transitions: whereas waking up is a fast and direct transition that can be modelled by a ballistic trajectory, falling asleep is best described as a stochastic and gradual state change. Finally, we demonstrate that OB oscillations also allow us to track other vigilance states. Non-REM (NREM) and rapid eye movement (REM) sleep can be distinguished with high accuracy based on beta (10–15 Hz) power. More importantly, we show that depth of anaesthesia can be tracked in real time using OB gamma power. Indeed, the gamma power predicts and anticipates the motor response to stimulation both in the steady state under constant anaesthetic and dynamically during the recovery period. Altogether, this methodology opens the avenue for multi-timescale characterisation of brain states and provides an unprecedented window onto levels of vigilance.

Rodents are the main animal model to study sleep. Yet, in spite of a large consensus on the distinction between rapid-eye-movements sleep (REM) and non-REM sleep (NREM) in both humans and rodent, there is still no equivalent in mice of the NREM subdivision classically described in humans.Here we propose a classification of sleep stages in mice, inspired by human sleep scoring.By using chronic recordings in medial prefrontal cortex (mPFC) and hippocampus we can classify three NREM stages with a stage N1 devoid of any low oscillatory activity and N3 with a high density of delta waves. These stages displayed the same evolution observed in human during the whole sleep or within sleep cycles. Importantly, as in human, N1 in mice is the first stage observed at sleep onset and is increased after sleep fragmentation in Orexin-/mice, a mouse model of narcolepsy.We also show that these substages are associated to massive modification of neuronal activity. Moreover, considering these stages allows to predict mPFC neurons evolution of firing rates across sleep period. Notably, neurons preferentially active within N3 decreased their activity over sleep while the opposite is seen for those preferentially active in N1 and N2.Overall this new approach shows the feasibility of NREM sleep sub-classification in rodents, and, in regard to the similarity between sleep in both species, will pave the way for further studies in sleep pathologies given the perturbation of specific sleep substages in human pathologies such as insomnia, somnambulism, night terrors, or fibromyalgia.

Recent evidence underlines the crucial role of neuronal cytoskeleton in the pathophysiology of psychiatric diseases. In this line, the deletion of STOP/MAP6 (Stable Tubule Only Polypeptide), a microtubule-stabilizing protein, triggers various neurotransmission and behavioral defects, suggesting that STOP knockout (KO) mice could be a relevant experimental model for schizoaffective symptoms. To establish the predictive validity of such a mouse line, in which the brain serotonergic tone is dramatically imbalanced, the effects of a chronic fluoxetine treatment on the mood status of STOP KO mice were characterized. Moreover, we determined the impact, on mood, of a chronic treatment by epothilone D, a taxol-like microtubule-stabilizing compound that has previously been shown to improve the synaptic plasticity deficits of STOP KO mice. We demonstrated that chronic fluoxetine was either antidepressive and anxiolytic, or prodepressive and anxiogenic, depending on the paradigm used to test treated mutant mice. Furthermore, control-treated STOP KO mice exhibited paradoxical behaviors, compared with their clear-cut basal mood status. Paradoxical fluoxetine effects and control-treated STOP KO behaviors could be because of their hyper-reactivity to acute and chronic stress. Interestingly, both epothilone D and fluoxetine chronic treatments improved the short-term memory of STOP KO mice. Such treatments did not affect the serotonin and norepinephrine transporter densities in cerebral areas of mice. Altogether, these data demonstrated that STOP KO mice could represent a useful model to study the relationship between cytoskeleton, mood, and stress, and to test innovative mood treatments, such as microtubule-stabilizing compounds. Keywords: antidepressant, anxiety/depression, corticosterone, microtubule-stabilizing compound, serotonin/ norepinephrine transporters, stress. J. Neurochem. (2012) 123, 982-996. Schizophrenia and mood disorders are common, chronic, and debilitating psychiatric illnesses, which have a high prevalence, regardless of countries and cultures, and have a considerable socioeconomic cost (Eaton et al. 2008). For example, unipolar major depression, bipolar disorder, and schizophrenia are ranked first, sixth, and ninth, respectively, in the World Health Organization estimates for diseaserelated lifetime disabilities, and 2% of humans are affected by schizophrenia or bipolar disorder (Lopez et al. 2006;Mathers and Loncar 2006 (Gardiner et al. 2011). Recently, it was found that microtubule deregulation and alterations were related to modifications of integrated brain functions both in animal models and in psychiatric diseases. The first evidence for such a role of cytoskeleton disorganization in psychiatric-like characteristics arises from the deletion in mice of the microtubule-stabilizing protein STOP (Stable Tubule Only Polypeptide, Andrieux et al. 2002). Indeed, STOP knockout (KO) mice exhibit abnormalities of glutamatergic, dopaminergic, acetylcholinergic/nicotinic, serotonergic, and noradrenergic...

Does the body play an active role in emotions? Since the original James/Cannon controversy this debate has mainly been fueled by introspective accounts of human experience. Here, we use the animal model to demonstrate a physiological mechanism for bodily feedback and its causal role in the stabilization of emotional states. We report that during fear-related freezing mice breathe at 4Hz and show, using probabilistic modelling, that optogenetic perturbation of this feedback specifically reduces freezing maintenance without impacting its initiation. This rhythm is transmitted by the olfactory bulb to the prefrontal cortex where it organizes neural firing and optogenetic probing of the circuit demonstrates frequency-specific tuning that maximizes prefrontal cortex responsivity at 4Hz, the breathing frequency during freezing. These results point to a brain-body-brain loop in which the initiation of emotional behavior engenders somatic changes which then feedback to the cortex to directly participate in sustaining emotional states.We thank L. Roux and A. Sirota. for discussions, and A. Peyrache for discussion and critical readings of an earlier version of the manuscript.

Cortical slow waves and delta waves are hallmarks of NREM sleep and key elements in physiological processes such as memory consolidation and sleep homeostasis. However, no clear distinction has been made between the two types of electrophysiological events. We introduce a new distinction between slow waves, large amplitude waves on filtered LFP cortical signals, and delta waves, characterized by an inversion between deep and superficial layers and the co-occurrence with a cortical down state. Detection of slow waves, as large amplitude waves during NREM sleep, reveals that a large portion of them does not share the properties of delta waves and does not co-occur with cortical down states. Therefore, we distinguish type-1 slow waves, that are associated to a down state, from type-2 slow waves. We show that 1) only type-1 slow waves undergo strong homeostatic regulations and 2) type- 2 slow waves create confusion about the temporal link with hippocampal sharp-wave ripples. Thus, we confirm that delta waves detected with our new method can be used as a proxy for down state. Altogether, this confirms the importance of a robust and accurate definition of delta waves to understand the fine neurophysiological mechanisms at stake during NREM sleep.

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