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IBEC Seminar: Luis de Lecea
Thursday, November 19, 2015 @ 12:00 pm–1:00 pm
Optogenetic control of arousal
Luis de Lecea, Department of Psychiatry and Behavioral Sciences, Stanford University School of MedicineChanges in arousal states are at the core of most neuropsychiatric disorders. Several groups of monoaminergic neurons have long been known to facilitate arousal state transitions. Here we will review the role of hypocretin/orexin neurons in the dynamics of sleep-to-wake transitions. I will also show data demonstrating that dopaminergic neurons of the ventral tegmental area (VTA) directly and causally control the generation and maintenance of electrocortical and behavioral arousal. Combining chemogenetic and optogenetic tools with polysomnographic recordings in mice, we show that activity in VTA-dopaminergic neurons is necessary for arousal, and that their chemogenetic inhibition suppresses wakefulness to promote both non-rapid eye movement (NREM) and REM sleep. Moreover, chemogenetic inhibition of VTA-dopaminergic neurons suppresses wakefulness even in the face of highly salient stimuli related to reproduction, feeding and predation. Nevertheless, prior to inducing sleep, chemogenetic inhibition of VTA-dopaminergic neurons promotes goal-directed and sleep-related nest building behavior. Optogenetic stimulation, in contrast, initiates and maintains long-term wakefulness and suppresses sleep and sleep-related nesting behavior. We further show that the nucleus accumbens (NAc) circuit, and not the medial prefrontal cortex (mPFC), mediates most of VTA-dopaminergic effects on arousal. After collecting data from multiple brain structures involved in arousal states, we propose a computational model that assigns probabilities to optogenetically-induced arousal state transitions in individual brain structures. We identify feedback, redundancy, and gating hierarchy as three fundamental aspects of this model. Incorporation of conductance-based models of neuronal ensembles into this model and existing models of cortical excitability will provide more comprehensive insight into arousal state dynamics as well as arousal-related disorders.
