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Cellular mechanisms of cortical awakening and alertness – AWAKE CX

Submission summary

More than one third of the population suffers from sleep-wake disorders. Difficulties to maintain wakefulness (narcolepsy, hypersomnia, sommolence) are the most invalidating disorders and are responsible for many accidents every year. One of the largest obstacles facing medical research into these disorders is the lack of knowledge of the cellular mechanisms of wakefulness and its pathologies. The cerebral cortex, as the centre of cognitive functions, is the ultimate target for the networks of neurons controlling behavioral states. In addition to the well known changes in cortical activities (oscillations) across states of vigilance, recent studies have revealed that the transition from one state to another is also accompanied by modifications of the intrinsic properties of cortical neurons and a selective modulation of thalamo-cortical and cortico-cortical synaptic inputs. Thus, behavioral state transition involves a highly complex functional reorganization of the cortical network that is believed to be responsible for the disruption of sensory information processing and the loss of consciousness during deep sleep. This new conceptual approach of behavioral states differs from the initial idea that cortical rhythms only define states of vigilance. There is general agreement that the functional reorganization of the cortical network is under the control of neurotransmitters (e.g. histamine, orexins, acetylcholine, noradrenaline and serotonin) released in a state-dependent manner from neurons projecting diffusely to the cortex. Recent studies in our laboratory have demonstrated the synergistic and complementary role of histaminergic (HA) and orexinergic (Orx) neurons located in the posterior hypothalamus, in maintaining cortical and behavioral wakefulness. However, their specific physiological mode of action in the cortex is not yet understood, mainly due to the difficulty of making in vivo intracellular recordings. Indeed, the role of ascending neuromodulators in setting cortical states has essentially been investigated at the cellular level in reduced preparations, i.e. in vitro. They usually have various post-synaptic effects depending on neuronal types and layers, and pre-synaptic effects depending on the origin of synaptic inputs. It is thus difficult to extrapolate their role to the intact cortical network. Moreover, converging evidence indicate major differences in fundamental properties of the cortical network in vivo as compared to in vitro conditions. Therefore, a complete understanding of the role of ascending neuromodulatory systems can only be achieved by studying their action at the cellular level in vivo and under physiological conditions. Our study will focus on the role and mechanisms of action of HA and Orx in setting cortical states at multiple levels: Our first objective will be to define the anatomical organization of HA and Orx innervations within the neocortex of the mouse. Using immunocytochemistry, confocal microscopy and 3D reconstruction, we will determine and compare the distribution of HA, Orx and other ascending neuromodulatory system fibers and terminals. Our second objective will be to determine the physiological action of HA and Orx on the cortical network in vivo. By combining local pharmacological applications, intracellular recordings or amperometric microbiosensors for glutamate in anesthetized mice, we will investigate the effects of HA and Orx on (1) the spontaneous cortical activity, (2) intrinsic properties of cortical neurons, (3) synaptic transmission from cortico-cortical and thalamo-cortical inputs, (4) establishment of synaptic plasticity, (5) processing of sensory information (such as whisker stimulation) and (6) regulation of ambient glutamate concentration. Finally, we will explore the pathological aspects of wakefulness using unique genetic models of somnolence and narcolepsy. We will first attempt to identify a cellular phenotype of these sleep-wake disorders. We will use intracellular recordings in non-anesthetized head-fixed mice to compare the properties of the cortical network and cortical response to sensory stimulation, in wild type mice and their transgenic littermates. We will also develop new behavioral paradigms, in head-fixed mice, that would be compatible with intracellular recordings, in order to investigate functional deficits in transgenic mice when confronted to a behavioral challenge involving attention, sensory perception or learning. This project will allow for the first time a fine characterization of the effects and cellular mechanisms of action of HA and Orx at the cortical level and under physiopathological conditions. One of the original features of this project is to combine a unique in vivo intracellular approach with local pharmacology to provide experimental responses to current major questions with regards to brain activation, alertness and sleep-wake disorders.

Project coordinator

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

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Beginning and duration of the scientific project: - 0 Months

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