Timothy D. Wiggin, Ph.D. - US grants

DESCRIPTION (provided by applicant): The vertebrate spinal cord contains a central pattern generator (CPG) capable of producing coordinated locomotion (e.g., walking, swimming, flying), even in isolation from the brain. However, the neuronal populations that generate the locomotor rhythm are unknown. Identifying the neural populations that generate locomotion would remove a major barrier in the study of the modulation, degeneration and regeneration of locomotion. The objective of this application is to characterize one promising population of spinal neurons: the V3 interneurons. The V3 neurons satisfy two important criteria for locomotor rhythm generation: first, they are located in the ventral medial spinal cord and, second, they are glutamatergic. We hypothesize that V3 neurons are core components of the locomotor CPG. In order to test this hypothesis, we propose three aims. First, we will determine the activity and recruitment patterns of V3 neurons during fictive locomotion. Next, we will determine if V3 neurons have locomotion generating membrane properties. Finally, we will determine if the V3 neurons are necessary for normal locomotion. The completion of these three aims will give us a better understanding of the role of the v3 neurons in locomotion and the overall structure of the vertebrate CPG.

PROJECT SUMMARY / ABSTRACT Disorders of sleep and associative learning co-occur in many diseases, including primary sleep disorders, plasticity disorders, and neurodegenerative disorders. These widespread connections between learning and sleep in human neurological disease indicate that there are neuronal circuits shared by sleep and learning in humans. Because these circuits are shared, therapeutic approaches designed for one system may also benefit the other, for example, treatments for sleep disturbance may also ameliorate symptoms of neurodegenerative disorders. Therefore, understanding the neural circuits connecting sleep and learning has the potential for significant scientific and translational impact. However, sleep and learning are both complex behaviors, and tracing a neuron-scale circuit for either is not currently possible in mammals. The fruit fly Drosophila melanogaster has a simpler nervous system than a mammal (about 100,000 neurons), while still displaying robust learning and sleep behaviors. Furthermore, the circuits for associative memory and sleep have been well studied in fruit flies. We propose to study the connections between a pair of neurons known to be necessary for both memory and sleep, the Dorsal Paired Medial neurons (DPMs), and other memory and sleep associated neurons in the fruit fly brain. We hypothesize that DPMs increase in activity after learning, which has two main effects. First, increased DPM activity causes the flies to sleep more. Second, DPMs inhibit dopamine neurons that cause forgetting of recent experiences, thereby improving the formation of new memories. We will test this hypothesis by: 1. Measuring connections between DPMs, dopamine neurons, and an important fly memory system, the Mushroom Body, 2. Blocking the DPMs, and measuring if learning still has an effect on sleep, and 3. Blocking the effect of DPMs on dopamine neurons, and measuring if formation of new memories is affected. Testing this hypotheses will provide important new information. First, we will better understand how an experience is turned into a long term memory in a simple brain, giving us deeper insight into how out own minds work. Second, we will know if the effects that a memory-promoting neuron has on sleep and memory are independent or related to one another. Third, we will gain greater insight into how dopamine neurons that signal value can simultaneously promote learning new memories and forgetting old memories.