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Principal Investigator: Manuel Rosero
Organization: FRED HUTCHINSON CANCER CENTER
Fiscal Year: 2024
Award: $44,503
Funding agency: National Institute of Neurological Disorders and Stroke
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.
Terms: <Animals><Application Context><Assay><Behavior><Bioassay><Biological Assay><Brain><Brain Nervous System><C elegans><C. elegans><C.elegans><CNG channel (rod)><Caenorhabditis elegans><Candidate Disease Gene><Candidate Gene><Cell Communication and Signaling><Cell Signaling><Collection><Color><Coupling><Cyclic GMP><Deoxyguanylate Cyclase><Encephalon><Environment><Enzyme Gene><Enzymes><Esthesia><Experimental Designs><Failure><Genes><Genetic><Goals><Guanosine Cyclic Monophosphate><Guanyl Cyclase><Guanylate Cyclase><Health><Human><Illusions><Image><Individual><Inosinate Cyclase><Intermediary Metabolism><Intracellular Communication and Signaling><Invertebrata><Invertebrates><Locomotion><Mental disorders><Mental health disorders><Metabolic Control><Metabolic Processes><Metabolism><Modern Man><Molecular><Nematoda><Nematodes><Nerve Cells><Nerve Unit><Nervous System><Nervous System Diseases><Nervous System Disorder><Neural Cell><Neurocyte><Neurologic Body System><Neurologic Disorders><Neurologic Organ System><Neurological Disorders><Neurons><Optical Illusions><Pathway interactions><Perception><Phosphodiesterases><Psychiatric Disease><Psychiatric Disorder><QOL><Quality of life><Regulation><Role><Sensation><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Signaling Molecule><Taxes><Translating><Work><biological signal transduction><cGMP><cationic channel protein (rod)><contextual factors><cyclic-nucleotide gated channel><cyclic-nucleotide gated ion channels><design><designing><experience><experiment><experimental research><experimental study><experiments><guanylyl cyclase><imaging><improved><in vivo><interdisciplinary approach><mental illness><movie><multidisciplinary approach><neural circuit><neural circuitry><neurocircuitry><neurological disease><neuronal><neuronal circuit><neuronal circuitry><novel><pathway><phosphoric diester hydrolase><physical property><psychiatric illness><psychological disorder><response><roundworm><social><social role><synaptic circuit><synaptic circuitry>