In vivo mechanisms for integration of contextual information

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ABSTRACT A fundamental feature of human brain is its ability to use contextual information from past experience to modulate behavior. Failure to use context to modulate behavior has a great impact in human health. For instance, individuals with neurological and mental disorders often have difficulties understanding their physical surroundings and social settings, lowering their quality of life, and damaging their ability to interact with others. While the importance of context-dependent modulation of behavior is clear, little is known about the molecular and circuit principles that facilitate this key brain function. In this proposal I aim to uncover signaling mechanisms that tune the activity of neural circuits to support context-dependent behavior. To this end, I will take advantage of the genetic power and the circuit simplicity of the nematode C. elegans. My working hypothesis is that cGMP signals facilitate context-dependent behavior by fine tuning the activity of neuronal circuits that regulate behavior. To understand how individual components of a cGMP signaling pathway contribute to context-dependent behavior in living animals, I have designed experiments with two specific aims. Aim 1 will examine a working hypothesis that cyclic nucleotide-gated (CNG) channels regulate context- dependent behavior. In support of this hypothesis, I found that two genes of CNG channel subunits (tax-2 and cng-3) are required for context-dependent behavior. To understand the role of CNG channels, I will identify the neuron(s) in which tax-2 and cng-3 function, and I will determine their impact on neuronal activity in living circuits for locomotor behavior. Results from this Aim will determine how CNG channels influence context integration in living circuits. Aim 2 will Determine the role of cGMP metabolism in context-dependent modulation of behavior. cGMP is a short-lived molecular messenger. Its synthesis and degradation are under the control of metabolic enzymes. My working hypothesis is that specific enzymes underlying cGMP metabolism have an important role in context-dependent modulation of living neural circuits. Consistent with this idea, I identified three genes (gcy-12, gcy-18, and pde-4), encoding enzymes of cGMP metabolism, as key players in context-dependent behavior. To elucidate how these cGMP enzymes modulate context-dependent behavior, I will determine the neurons where gcy-12, gcy-18, and pde-4 function and demonstrate their role in coupling the sensation of contextual information to behavior modulation. Together, studies in this proposal will elucidate the molecular and circuit mechanisms behind the cGMP modulation of context-dependent behavior.