Animals must weigh competing needs and states to generate adaptive behavioral responses to the environment. Sensorimotor circuits are thus tasked with integrating diverse external and internal cues relevant to these needs to generate context-appropriate behaviors. However, the mechanisms that underlie this integration are largely unknown. Here, we show that a wide range of states and stimuli converge upon a single Caenorhabditis elegans olfactory neuron to modulate food-seeking behavior. Using an unbiased ribotagging approach, we find that the expression of olfactory receptor genes in the AWA olfactory neuron is influenced by a wide array of states and stimuli, including feeding state, physiological stress, and recent sensory cues. We identify odorants that activate these state-dependent olfactory receptors and show that altered expression of these receptors influences food-seeking and foraging. Further, we dissect the molecular and neural circuit pathways through which external sensory information and internal nutritional state are integrated by AWA. This reveals a modular organization in which sensory and state-related signals arising from different cell types in the body converge on AWA and independently control chemoreceptor expression. The synthesis of these signals by AWA allows animals to generate sensorimotor responses that reflect the animal’s overall state. Our findings suggest a general model in which sensory- and state-dependent transcriptional changes at the sensory periphery modulate animals’ sensorimotor responses to meet their ongoing needs and states.

Animals must weigh competing needs and states to generate adaptive behavioral responses to the environment. Sensorimotor circuits are thus tasked with integrating diverse external and internal cues relevant to these needs to generate context-appropriate behaviors. However, the mechanisms that underlie this integration are largely unknown. Here, we show that a wide range of states and stimuli converge upon a single C. elegans olfactory neuron to modulate food-seeking behavior. Using an unbiased ribotagging approach, we find that the expression of olfactory receptor genes in the AWA olfactory neuron is influenced by a wide array of states and stimuli, including feeding state, physiological stress, and recent sensory cues. We identify odorants that activate these state-dependent olfactory receptors and show that altered expression of these receptors influences food-seeking and foraging. Further, we dissect the molecular and neural circuit pathways through which these diverse cues are integrated by AWA. This reveals a modular organization in which state-related signals arising from different cell types in the body converge on AWA and independently control chemoreceptor expression. The synthesis of these signals by AWA allows animals to generate sensorimotor responses that reflect the animal’s overall state. Our findings suggest a general model in which state-dependent transcriptional changes at the sensory periphery modulate animals’ sensorimotor responses to meet their ongoing needs and states.

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all-atom molecular dynamics simulations we provide extensive insight into microsecond dynamics of a villin solution at different concentrations, as a simple model of cellular environment. Since inaccuracies of current force fields are known to result in exaggerated protein aggregation we increase protein-water interactions to better reproduce available experimental results. The simulations show that protein rotational diffusion slows down more significantly than translational diffusion with increasing concentration, while protein internal dynamics remain largely unaltered. These findings correlate with observed formation of sub-microsecond persisting protein clusters which size distribution shifts toward larger clusters with increasing protein concentration. We show that diffusion coefficients estimated for simulation-derived cluster structures weighted by the cluster size distribution mostly reproduce the observed overall diffusion. It indicates the clusters formation as a primary determinant of diffusion slow-down upon crowding. Finally, we shed light on protein diffusion in a heterogeneous protein solution, near a lipid membrane and in the presence of metabolites. The most abundant NFkB family member, p65 (also called RelA), exerts its transcriptional regulatory function as a homo-or hetero-dimer with p50. The two dimers have different but overlapping DNA binding specificities, considered to be the key to fine control of gene regulation. Past crystallographic studies on NFkB-DNA complexes showed high structural homology among different NFkB dimers and left a puzzle: how do NFkB dimers bind to DNA with different affinities? In this study, we discovered drastically different conformational dynamics between two free NFkB dimers: p65p50 and p65 homodimer. Hydrogen-deuterium exchange mass spectrometry (HDXMS) revealed different exchange levels in the p65 DNA-binding domains (DBDs) of the homodimer as compared to the heterodimer, suggesting a sub-global conformational difference between p65 bound to p50 and p65 bound to another p65. Furthermore, molecular dynamics (MD) simulations elucidated the conformational ensembles that give rise to different HDX patterns. We found that when not bound to DNA, the two DBDs of the NFkB dimer can twist around the linker between the dimerization domain and the DBD with a large amplitude (30 Å ). Through MD simulations, we observed very distinct conformational relaxation processes from DNA-bound to free states for p65p50 and p65 homodimer. While the two DBDs in p65p50 move apart from each other, those in p65 homodimer come together and form new contacts. The new protein interface captured by MD in the p65 homodimer explains the different HDX behaviors between NFkB dimers. Moreover, we suggest that the differences in DNA-binding affinities are a consequence of distinct conformational dynamics displayed by the free NFkB dimers. By combining HDX-MS and MD simulations, we here provide an example of understanding how signaling proteins function from the standpoint of conformational dynam...