| dc.description.abstracteng | Within the field of sleep research, it is well established that all organisms, which possess a nervous system, need to sleep. This underlines the severity of sleep functions. In humans, sleep is essential for memory function, immune system function and energy conservation. However, none of these functions explain why sleep induces a change in consciousness.
To answer these and other remaining questions about sleep, C. elegans is the optimal model organism. It offers the opportunity to study sleep in a very simple environment. Adult hermaphrodites have only 302 neurons. The connectivity of all neurons is known. Furthermore, its complete genome is sequenced. Finally, its transparency and its easy genetic tractability allow for the application of almost all known imaging methods and tools to manipulate its behavior.
In my thesis, I focused on the quiescence behavior taking place throughout the development of C. elegans, which I will be referring to as sleep or lethargus. Lethargus takes places at the end of each of the four larval stages. Despite its simplicity, sleep in C. elegans displays an astonishing amount of similarities to mammalian systems. In mammals, wake-active and sleep-active brain regions mutually inhibit each other in a so-called flip-flop switch. In C. elegans, the single interneuron RIS was proven to be sleep-active. Similarly to mammalian systems, high RIS activity dampens the activity of the whole nervous system in the worm.
What is not known about RIS are the neuronal networks controlling it. To shed light on that question former colleagues and I screened through all RIS presynaptic neurons using the optogenetic tools ReaChR and ArchT. Their optogenetic depolarization and hyperpolarization revealed that RIS presynaptic neurons differ in their effect on RIS. Amongst all RIS presynaptic neurons, PVC neurons were identified as activators of RIS in lethargus and RIM as modulators of RIS activity in lethargus. Both PVC and RIM neurons belong to the class of command locomotion interneurons. The regulation of RIS by command locomotion interneurons allows a direct link of sleep to locomotion, arousal and homeostasis.
A side project of my thesis, aimed for the identification of potential suppressors of the aptf-1 mutant phenotype. Aptf-1 mutants fail to immobilize in lethargus. After EMS mutagenesis, two suppressor candidates were successfully isolated according to their ability to immobilize in lethargus. The identification of candidate genes is still under research.
Taken together, the presented work reveals a complex regulation of RIS in lethargus by its directly presynaptic neurons. The fact that even such a simple organism has a highly complex neuronal network for sleep regulation, strengthens the choice of C. elegans as the best model organism for sleep research. With the vast amount of available tools, not only it allows for the identification of RIS-regulating neurons, like PVC and RIM neurons, but it also opens the door for a closer understanding of regulatory pathways upstream of PVC and RIM neurons respectively as a future perspective. The introduced circuit model for sleep regulation, provides in-depth insights into RIS regulation and explains how lethargus in | de |