Probing of hypothalamic circuits in arousal using optogenetics. While the functions of sleep are still a matter of debate and may include memory consolidation and plasticity, the neural substrates of sleep and wakefulness are the subject of intense study. Successive sleep and wakefulness cycles rely on an appropriate balance between sleep-promoting nuclei of the brain, including inhibitory cells of the ventro-lateral preotpic area and anterior hypothalamus and, arousal-promoting nuclei from the brainstem and the posterior hypothalamus. Hence, the hypothalamus contains cells types able to regulate the occurrence and maintenance of sleep and wake events. Indeed, two distinct neuron populations restricted to the hypothalamus have been recently identified as critical modulator of the sleep-wake cycle: the Melanin-ConcentratingHormone (MCH)- and Hypocretins/Orexins (Hcrt^Ox)- expressing neurons. Although the Hcrt system is involved in boundaries state control, the precise physiological function of the MCH system on the sleep-wake cycle and the mechanisms of action involved remains unclear. Here we propose :o use in vitro and in vivo optogenetics to establish causal link between activation of the MCH system and sleep-wake cycle architecture. My hypothesis is that the sleep-promoting role of the MCH system balances the wake-promoting properties of the Hcrt system, providing a hypothalamic switch that modulates vigilance states according to physiological demands/hemostats including sleep pressure and negative energy balance. To test this hypothesis, our short-term objectives are divided into three specific aims:
Specific Aim1 : Define a window of efficacy for optical stimulation of ChR2-expressing MCH neurons in vitro and in vivo.
Specific Aim2 : Manipulate the activity of MCH neurons in vitro to study the dynamic of the MCH-Hcrt hypothalamic circuit.
Specific Aim3 : Determine the role of the MCHsystem on the sleep-wake cycle upon specific physiological demands including sleep deprivation and fasting. x>ng-term perspectives of this project envision the study of plasticity of these hypothalamic circuits and its implication n complex behaviors including sleep and goal-oriented behaviors that leads to neuropsychiatric diseases.
| Zhang, Feng; Gradinaru, Viviana; Adamantidis, Antoine R et al. (2010) Optogenetic interrogation of neural circuits: technology for probing mammalian brain structures. Nat Protoc 5:439-56 |
| Tsai, Hsing-Chen; Zhang, Feng; Adamantidis, Antoine et al. (2009) Phasic firing in dopaminergic neurons is sufficient for behavioral conditioning. Science 324:1080-4 |
| Carter, Matthew E; Adamantidis, Antoine; Ohtsu, Hiroshi et al. (2009) Sleep homeostasis modulates hypocretin-mediated sleep-to-wake transitions. J Neurosci 29:10939-49 |
| Adamantidis, Antoine; de Lecea, Luis (2009) A role for Melanin-Concentrating Hormone in learning and memory. Peptides 30:2066-70 |
