Persistent neural activity that outlasts an initial stimulus is thought to provide a mechanism for the transient storage of memory. In this issue of Neuron, Fransén et al. identify important principles for a cell-autonomous mechanism of graded persistent firing using an elegant combination of experimental and computational approaches.

Mean-Field theory is extended to recurrent networks of spiking neurons endowed with short-term depression (STD) of synaptic transmission. The extension involves the use of the distribution of interspike intervals of an integrate-and-fire neuron receiving a Gaussian current, with a given mean and variance, in input. This, in turn, is used to obtain an accurate estimate of the resulting postsynaptic current in presence of STD. The stationary states of the network are obtained requiring self-consistency for the currents-those driving the emission processes and those generated by the emitted spikes. The model network stores in the distribution of two-state efficacies of excitatory-to-excitatory synapses, a randomly composed set of external stimuli. The resulting synaptic structure allows the network to exhibit selective persistent activity for each stimulus in the set. Theory predicts the onset of selective persistent, or working memory (WM) activity upon varying the constitutive parameters (e.g. potentiated/depressed long-term efficacy ratio, parameters associated with STD), and provides the average emission rates in the various steady states. Theoretical estimates are in remarkably good agreement with data "recorded" in computer simulations of the microscopic model.

Nine human neurodegenerative diseases are due to expansion of a CAG repeat- encoding glutamine within the open reading frame of the respective genes. Polyglutamine (polyQ) expansion confers dominant toxicity, resulting in neuronal degeneration. MicroRNAs (miRNAs) have been shown to modulate programmed cell death during development. To address whether miRNA pathways play a role in neurodegeneration, we tested whether genes critical for miRNA processing modulated toxicity induced by the spinocerebellar ataxia type 3 (SCA3) protein. These studies revealed a striking enhancement of polyQ toxicity upon reduction of miRNA processing in Drosophila and human cells. In parallel genetic screens, we identified the miRNA bantam (ban) as a potent modulator of both polyQ and tau toxicity in flies. Our studies suggest that ban functions downstream of toxicity of the SCA3 protein, to prevent degeneration. These findings indicate that miRNA pathways dramatically modulate polyQ- and tau-induced neurodegeneration, providing the foundation for new insight into therapeutics.

Visual, auditory, somatosensory, and olfactory stimuli generate temporally precise patterns of action potentials (spikes). It is unclear, however, how the precision of spike generation relates to the pattern and variability of synaptic input elicited by physiological stimuli. We determined how synaptic conductances evoked by light stimuli that activate the rod bipolar pathway control spike generation in three identified types of mouse retinal ganglion cells (RGCs). The relative amplitude, timing, and impact of excitatory and inhibitory input differed dramatically between On and Off RGCs. Spikes evoked by repeated somatic injection of identical light-evoked synaptic conductances were more temporally precise than those evoked by light. However, the precision of spikes evoked by conductances that varied from trial to trial was similar to that of light-evoked spikes. Thus, the rod bipolar pathway modulates different RGCs via unique combinations of synaptic input, and RGC temporal variability reflects variability in the input this circuit provides.

Metal ion homeostasis is critical to the survival of all cells. Regulation of nickel concentrations in Escherichia coli is mediated by the NikR repressor via nickel-induced transcriptional repression of the nickel ABC-type transporter, NikABCDE. Here, we report two crystal structures of nickel-activated E. coli NikR, the isolated repressor at 2.1 A resolution and in a complex with its operator DNA sequence from the nik promoter at 3.1 A resolution. Along with the previously published structure of apo-NikR, these structures allow us to evaluate functional proposals for how metal ions activate NikR, delineate the drastic conformational changes required for operator recognition, and describe the formation of a second metal-binding site in the presence of DNA. They also provide a rare set of structural views of a ligand-responsive transcription factor in the unbound, ligand-induced, and DNA-bound states, establishing a model system for the study of ligand-mediated effects on transcription factor function.

The Lombard effect-an increase in vocalization amplitude in response to an increase in background noise-is observed in a wide variety of animals. We investigated this basic form of vocal control in the cotton-top tamarin (Saguinus oedipus) by measuring the amplitude of a contact call, the combination long call (CLC), while simultaneously varying the background noise level. All subjects showed a significant increase in call amplitude and syllable duration in response to an increase in background noise amplitude. Together with prior results, this study shows that tamarins have greater vocal control in the context of auditory feedback perturbation than previously suspected.

Nud1p, a protein homologous to the mammalian centrosome and midbody component Centriolin, is a component of the budding yeast spindle pole body (SPB), with roles in anchorage of microtubules and regulation of the mitotic exit network during vegetative growth. Here we analyze the function of Nud1p during yeast meiosis. We find that a nud1-2 temperature-sensitive mutant has two meiosis-related defects that reflect genetically distinct functions of Nud1p. First, the mutation affects spore formation due to its late function during spore maturation. Second, and most important, the mutant loses its ability to distinguish between the ages of the four spindle pole bodies, which normally determine which SPB would be preferentially included in the mature spores. This affects the regulation of genome inheritance in starved meiotic cells and leads to the formation of random dyads instead of non-sister dyads under these conditions. Both functions of Nud1p are connected to the ability of Spc72p to bind to the outer plaque and half-bridge (via Kar1p) of the SPB.

Organisms adjust their rate of growth depending on the availability of nutrients. Thus, when environmental conditions limit nutrients, growth is slowed and is only restored after food again becomes abundant. Many aspects of the molecular mechanisms that govern this complex control system remain unknown. However, it has been shown that the insulin/IGF-1 (insulin-like growth factor 1) receptor pathway, together with the FOXO family of transcription factors, play an important role in this process. Recent studies with the fruit fly Drosophila melanogaster have provided new insights into the regulatory circuitry that controls both growth and gene expression in response to nutrient availability.

More than 50 years have passed since the first recording of neuronal responses to an odor stimulus from the primary olfactory brain area, the main olfactory bulb. During this time very little progress has been achieved in understanding neuronal dynamics in the olfactory bulb in awake behaving animals, which is very different from that in anesthetized preparations. In this paper we formulate a new framework containing the main reasons for studying olfactory neuronal dynamics in awake animals and review advances in the field within this new framework.

Experimental investigations have revealed that synapses possess interesting and, in some cases, unexpected properties. We propose a theoretical framework that accounts for three of these properties: typical central synapses are noisy, the distribution of synaptic weights among central synapses is wide, and synaptic connectivity between neurons is sparse. We also comment on the possibility that synaptic weights may vary in discrete steps. Our approach is based on maximizing information storage capacity of neural tissue under resource constraints. Based on previous experimental and theoretical work, we use volume as a limited resource and utilize the empirical relationship between volume and synaptic weight. Solutions of our constrained optimization problems are not only consistent with existing experimental measurements but also make nontrivial predictions.