Development of neuronal tracers to study leptin modulation of dopamine circuits


Principal Investigator: Ralph J DiLeone
Abstract: Novel strategies and tools are needed to better define neural circuitry in the brain. While genomic analysis and genetic tests of function are becoming more routine and efficient, defining gene function in the context of neural circuitry remains a technical challenge. The goal of the current exploratory proposal is to establish a set of flexible, viral-based, tracing tools that will help to both outline specific circuitry and test the effects of genes on axonal and synaptic plasticity. Preliminary data demonstrates the use of viruses to deliver proteins that effectively label synapses, as well as multisynaptic circuits. The tracing tools will be used to explore neural plasticity in dopamine circuits in response to the metabolic hormone leptin. The mesolimbic and mesocortical dopamine system project from the ventral tegmental area (VTA) to the nucleus accumbens and prefrontal cortex. The VTA dopamine neurons are important modulators of motivated behavior and play a particularly important role in the development of drug addiction as well as food intake. Leptin is made in fat cells and communicates to the brain to control food intake and metabolism. Loss of leptin leads to dramatic increases in food intake and body weight. While most current research has focused on leptin receptor function within the hypothalamus, it is now clear that leptin signals directly to dopamine neurons of the midbrain to reduce feeding behavior and alter responses to drugs of abuse. Proposed experiments will use novel leptin-responsive tracers to identify mesolimbic and mesocortical neural circuits modulated by leptin. Leptin has been shown to influence both development of axonal projections, as well as synaptic organization, and is here hypothesized to regulate dopamine neuronal projections and synapses. Combining RNAi gene knockdown with these tracers offers an unprecendented way to visualize synaptic neural circuit plasticity in response to genetic manipulation of individual neurons. Moreover, the strategy and reagents being developed should have broad application to the study of a variety of neural circuits in a range of model organisms. PUBLIC HEALTH RELEVANCE: Defining the neural pathways and circuits of the brain is critical for understanding neurological and psychiatric disease. The proposed experiments will characterize how brain reward circuits respond to changes in levels of a hormone that is produced in fat cells. Studying how these circuits respond to changes in body fat levels is relevant to the problems of drug addiction as well as obesity.
Funding Period: ----------------2009 - ---------------2011-
more information: NIH RePORT