Variability is a prominent feature of behavior and is an active element of certain behavioral strategies. To understand how neuronal circuits control variability, we examined the propagation of sensory information in a chemotaxis circuit of C. elegans where discrete sensory inputs can drive a probabilistic behavioral response. Olfactory neurons respond to odor stimuli with rapid and reliable changes in activity, but downstream AIB interneurons respond with a probabilistic delay. The interneuron response to odor depends on the collective activity of multiple neurons-AIB, RIM, and AVA-when the odor stimulus arrives. Certain activity states of the network correlate with reliable responses to odor stimuli. Artificially generating these activity states by modifying neuronal activity increases the reliability of odor responses in interneurons and the reliability of the behavioral response to odor. The integration of sensory information with network states may represent a general mechanism for generating variability in behavior.

Translating a graded morphogen distribution into tight response borders is central to all developmental processes. Yet, the molecular mechanisms generating such behavior are poorly understood. During patterning of the Drosophila embryonic ventral ectoderm, a graded mitogenactivated protein kinase (MAPK) activation is converted into an all-or-none degradation switch of the Yan transcriptional repressor. Replacing the cardinal phosphorylated amino acid of Yan by a phosphomimetic residue allowed its degradation in a MAPK-independent manner, consistent with Yan phosphorylation being the critical event in generating the switch. Several alternative threshold mechanisms that could, in principle, be realized by this phosphorylation, including first order, cooperativity, positive feedback and zero-order ultrasensitivity, were analyzed. We found that they can be distinguished by their kinetics and steady-state responses to Yan overexpression. In agreement with the predictions for zero-order kinetics, an increase in Yan levels did not shift the degradation border, but significantly elevated the time required to reach steady state. We propose that a reversible loop of Yan phosphorylation implements a zero-order ultrasensitivity-like threshold mechanism, with the capacity to form sharp thresholds that are independent of the level of Yan.

Cells use transporters of different affinities to regulate nutrient influx. When nutrients are depleted, low-affinity transporters are replaced by high affinity ones. High-affinity transporters are helpful when concentrations of nutrients are low, but the advantage of reducing their abundance when nutrients are abundant is less intuitive. When we eliminated such reduced production of the S. cerevisiae high affinity transporters for phosphate and zinc, the elapsed time from the initiation of the starvation program until the lack of nutrients actually limited growth was shortened, and recovery from starvation was delayed. The later phenotype was rescued by constitutive activation of the starvation program. Dual-transporter systems appear to prolong preparation for starvation and to facilitate subsequent recovery, which may optimize sensing of nutrient depletion by integrating internal and external information about nutrient availability.

Cells must adjust their gene expression in order to compete in a constantly changing environment. Two alternative strategies could in principle ensure optimal coordination of gene expression with physiological requirements. First, characters of the internal physiological state, such as growth rate, metabolite levels, or energy availability, could be feedback to tune gene expression. Second, internal needs could be inferred from the external environment, using evolutionary-tuned signaling pathways. Coordination of ribosomal biogenesis with the requirement for protein synthesis is of particular importance, since cells devote a large fraction of their biosynthetic capacity for ribosomal biogenesis. To define the relative contribution of internal vs. external sensing to the regulation of ribosomal biogenesis gene expression in yeast, we subjected S. cerevisiae cells to conditions which decoupled the actual vs. environmentally-expected growth rate. Gene expression followed the environmental signal according to the expected, but not the actual, growth rate. Simultaneous monitoring of gene expression and growth rate in continuous cultures further confirmed that ribosome biogenesis genes responded rapidly to changes in the environments but were oblivious to longer-term changes in growth rate. Our results suggest that the capacity to anticipate and prepare for environmentally-mediated changes in cell growth presented a major selection force during yeast evolution.

Depletion of essential nutrients triggers regulatory programs that prolong cell growth and survival. Starvation-induced processes increase nutrient transport, mobilize nutrient storage, and recycle nutrients between cellular components. This leads to an effective increase in intracellular nutrients, which may act as a negative feedback that downregulates the starvation program. To examine how cells overcome this potential instability, we followed the transcription response of budding yeast transferred to medium lacking phosphate. Genes were induced in two temporal waves. The first wave was stably maintained and persisted even upon phosphate replenishment, indicating a positive feedback loop. This commitment was abolished after 2 hr with the induction of the second expression wave, coinciding with the reduction in cell growth rate. We show that the overall temporal stability of the expression response depends on the sequential pattern of gene induction. Our results emphasize the key role of gene expression dynamics in optimizing cellular adaptation.