Abstracts (Talks)




A motor theory of sleep-wake control

Sleep is a fundamental biological process, and its disruption has profound impacts on human health. Using a variety of techniques including optogenetics, electrophysiology, imaging, and gene expression profiling, we identify key neurons in the sleep control circuits and map their synaptic connections. Sleep appears to be controlled by a highly distributed network spanning the forebrain, midbrain, and hindbrain, where REM and non-REM sleep neurons are part of the central somatic and autonomic motor circuits. The intimate association between the sleep and autonomic/somatic motor control circuits suggests that a primary function of sleep is to promote biological processes incompatible with movement.



Local and global regulation of sleep

Sleep can be defined on at least two distinct levels: the behaviour of the whole organism and the spatiotemporal patterns of neuronal activity in the brain. Upon falling asleep, cortical networks alternate between periods of generalized population firing (ON) and periods of relative silence (OFF). This pattern of neuronal activity gives rise to electroencephalogram (EEG) oscillations at a frequency of approximately 1-4 Hz, which are termed slow waves. Contrary to the widely-held notion, waking and sleep are not global, mutually exclusive states, and research over the last decade revealed that spontaneous brain activity during sleep can be locally modulated. For example, during NREM sleep, population periods of spiking activity can be often seen in one region of the cortex while another region is in an OFF-state. Also, during REM sleep the occurrence of NREM-like local activity is common, suggesting that in some cortical regions sleep has properties of a unitary state. Similarly, analysis of sleep spindles across cortical areas and layers reveals a complex dynamics, both with respect to their spatio-temporal synchronisation and the relationship with other cortical oscillations. Finally, sleep deprivation is associated with increased low-frequency EEG activity during waking in both animals and humans, and recordings in rodents suggested that this EEG pattern reflects the occurrence of local neuronal OFF periods. This notion suggests that sleep and wakefulness are not mutually exclusive states, and sleep is regulated not only at the global level of the whole brain, but also at the level of local cortical networks.



Dissection of sleep circuits and functions in the brain

Brain activity during sleep is characterized by circuit-specific oscillations, including slow waves, spindles and theta, that are nested in thalamocortical or hippocampus networks. A major challenge is to determine the neural mechanisms underlying these oscillations and their functional implications. In this lecture, I will summarize our most recent studies investigating the role of the thalamus and the hippocampus in the temporal and spatial organization of low frequency oscillations including slow waves and theta rhythms, respectively, as well as their functional implication in sleep structure and functions.



Neural mechanisms for emotional memory consolidation during sleep

The hippocampus and the amygdala are two structures required for emotional memory. The hippocampus encodes the spatial or contextual part of the memory. This information is believed to be later consolidated through reactivations of the wakefulness activity during Non-REM sleep hippocampal fast oscillations called “ripples”. On the other hand, the amygdala processes the emotional valence of an event, and both the hippocampus and the amygdala are required to associate an emotion to the memory of an event or place. However, it is yet mostly unknown how the two structures interact during sleep to sustain such an association. Using large scale neuronal recordings in freely moving rats, we have shown that the hippocampus and amygdala jointly reactivate during Non-REM sleep ripples following a spatial aversive training. Hippocampal ripples during sleep thus emerge as a crucial time windows for intra-hippocampus and cross-structure reactivations sustaining the consolidation of spatial and emotional memories. The role of REM-sleep, theta oscillations and the associated neural dynamics in the amygdala for aversive memory consolidation and regulation remains to be further explored.



Accounting for sleep loss in early modern England

Sleep, rest of things, O pleasing Deity,

Peace of the soul, which cares dost crucify,

Weary bodies refresh and mollify.

In his famous work of 1621, The Anatomy of Melancholy, English clergyman Robert Burton (1577-1640) drew on the words of the Roman poet Ovid, to express this commonplace view of sleep. This treasured state of nocturnal repose was widely credited with the power to refresh tired bodies, to keep Christian souls in good order, and to soothe the mind's troubles. The Anatomy of Melancholy is perhaps the strongest piece of textual evidence from early modern England to show that people understood a consistent link between sleep quality, and physical and mental health. This paper reveals how a handful of men and women in sixteenth and seventeenth-century England explained and experienced sleep loss, the broader medical, cultural and Christian frameworks that shaped their perceptions; and the techniques they used to prevent and treat sleep loss to preserve the health of body and mind.



How sleep and wake shape astrocyte physiology

Astrocytes outnumber neurons and have recently been assigned a fundamental role in most, if not all, brain functions, including neurovascular coupling and metabolite clearing, as well as control of neuronal excitability and synaptic plasticity. All these processes are affected by the sleep/wake cycle but the link between astrocytes and sleep has been studied only marginally, and mostly in one direction. Several impactful studies have shown how astrocytes can modulate sleep need by affecting neuronal activity during wake. Our studies focus on the other side of the story, that is, how sleep and wake can affect astrocytes. Using two very different but equally innovative approaches, gene expression analysis using TRAP methodology (a method “in between” transcriptomics and proteomics) and tridimensional electron microscopy, we found that several functions of astrocytes are profoundly modulated by sleep and wake. An intriguing and unexpected finding that offers great scientific insights and therapeutic potential.



Sleep-dependent memory consolidation: oscillations and ensembles

Our laboratory is addressing how sleep contributes to memory consolidation and associated synaptic plasticity in the mouse brain. We hypothesize that some forms of brain plasticity occur preferentially during sleep due to its unique patterns of network activity. Here, I'll discuss our use of pharmacogenetic and optogenetic tools to silence or rhythmically activate subsets of neurons involved in generating sleep-associated network oscillations. We are studying how these manipulations affect both neural and behavioral plasticity. In thalamocortical circuits following novel sensory experiences, we find increases in the coherence of network oscillations during sleep that predict subsequent plasticity. Disruption of these oscillations leads to a loss of plasticity and a failure in long-term memory formation. A correlate of memory formation is the long-term stabilization of spike-timing relationships within neuronal ensembles, which can last for several hours following learning. Manipulations which disrupt network oscillations and memory also disrupt this stabilization process, while augmentation of oscillations enhance stabilization and preserve memory. We hypothesize that sleep-associated network oscillations promote stable reactivation of neuronal ensembles, which in turn drives synaptic plasticity and long-term memory storage across brain circuits.



Experience and sleep-dependent dendritic spine plasticity in the cortex

Recent studies have suggested that sleep is important for experience-dependent formation and maintenance of new synapses. In many parts of the nervous system, experience-dependent refinement of neural circuits predominantly involves the elimination of existing synaptic connections. The role of sleep in such experience-dependent synapse elimination, however, remains unknown. Using transcranial two-photon microscopy, we investigated the role of sleep in experience-dependent dendritic spine elimination of layer 5 pyramidal neurons in the mouse primary visual cortex (V1) and frontal association cortex (FrA). We found that monocular deprivation (MD) or auditory-cued fear conditioning (FC) caused rapid dendritic spine elimination in the developing V1 or FrA, respectively. Notably, MD- or FC-induced spine elimination was significantly reduced after either total sleep deprivation or REM sleep deprivation. Total sleep or REM sleep deprivation also prevented MD- and FC-induced reduction of layer 5 pyramidal neuronal activity in response to visual or conditioned auditory stimuli. Furthermore, we observed a substantial increase in dendritic calcium spikes in both V1 and FrA during REM sleep as compared to other brain states. Blockade of dendritic calcium spikes specifically during REM sleep prevented MD- and FC-induced dendritic spine elimination in the V1 and FrA. Taken together, these findings reveal an important role of REM sleep in experience-dependent elimination of synaptic connections and reduction of neuronal activity in the cortex.



Sleeping on the wing 

Wakefulness enables animals to interact adaptively with the environment. Paradoxically, in insects to humans, the efficacy of wakefulness depends on daily sleep, a mysterious, usually quiescent state of reduced environmental awareness. However, several birds fly non-stop for days, weeks or months without landing, questioning whether and how they sleep. It has been commonly assumed that such birds sleep with one cerebral hemisphere at a time (i.e. unihemispherically) and with only the corresponding eye closed, as observed in swimming dolphins. However, the discovery that birds on land can perform adaptively despite sleeping very little raised the possibility that birds forgo sleep during long flights. In this seminar, I will review our recent work demonstrating for the first time that at least some birds can sleep on the wing, but they do so in both expected and unexpected ways. Finally, I will discuss the implications of this research for understanding the adverse effects of sleep loss typically experienced by other animals.


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