Two neural circuits that we propose to study control appetitive Pavlovian learning and sleep. Abnormalities in these neural circuits are linked to drug addiction and sleep disorders, two major human health problems with severe negative consequences to human productivity. We focus on a class of neurons that originate from one of the five known progenitor domains in the ventral neural tube. These neurons are called the V2a neurons and are generated throughout the hindbrain and spinal cord. Following genetic ablation of V2a neurons, mice show significant deficit in appetitive Pavlovian learning and sleep. Which V2a neurons are recruited to neural circuits that regulate appetitive Pavlovian learning and sleep? Do V2a neurons project to and connect with known elements of the neural circuitry underlying appetitive Pavlovian learning and sleep? Finding answers to these questions is significant at three levels. (1) It would lead to important new insights for understanding the evolution and adaptability of the nervous system and how microcircuits are assembled. (2) It would for the first time demonstrate that inputs from pontine nuclei are needed for appetitive Pavlovian learning and that V2a neurons and their connections to the mesolimbic system might play a critical role in drug addiction. (3) It will provide neural basis of sleep induced muscle atonia and sleep disorders caused by its malfunction. To answer the aforementioned questions we have devised a genetic strategy to target pontine V2a neurons that originate from rhombomere 1 (r1-V2a neurons). We propose to use a mouse genetics approach to test three hypotheses. (1) The r1-V2a lineage generates neurons that populate functionally diverse pontine tegmental nuclei. (2) The r1-V2a neurons regulate appetitive Pavlovian learning via direct projections to the RMTg. (3) The r1-V2a neurons regulate sleep architecture via direct projections to interneurons in the ventral spinal cord. Successful completion of these studies will demonstrate that embryonic V2a neurons originating from r1 are recruited to distinct neural circuits that regulate appetitive Pavlovian learning and sleep.

R01NS078181

2012-09-01

2018-05-31