Coarse--graining, fixed points, and scaling in a large population of neurons

We develop a phenomenological coarse--graining procedure for activity in a large network of neurons, and apply this to recordings from a population of 1000+ cells in the hippocampus. Distributions of coarse--grained variables seem to approach a fixed non--Gaussian form, and we see evidence of scaling in both static and dynamic quantities. These results suggest that the collective behavior of the network is described by a non--trivial fixed point

A Cortical Substrate for Memory-Guided Orienting in the Rat

SummaryAnatomical, stimulation, and lesion data have suggested a homology between the rat frontal orienting fields (FOF) (centered at +2 AP, ±1.3 ML mm from Bregma) and primate frontal cortices such as the frontal or supplementary eye fields. We investigated the functional role of the FOF using rats trained to perform a memory-guided orienting task, in which there was a delay period between the end of a sensory stimulus instructing orienting direction and the time of the allowed motor response. Unilateral inactivation of the FOF resulted in impaired contralateral responses. Extracellular recordings of single units revealed that 37% of FOF neurons had delay period firing rates that predicted the direction of the rats' later orienting motion. Our data provide the first electrophysiological and pharmacological evidence supporting the existence in the rat, as in the primate, of a frontal cortical area involved in the preparation and/or planning of orienting responses

Minimal Impairment in a Rat Model of Duration Discrimination Following Excitotoxic Lesions of Primary Auditory and Prefrontal Cortices

We present a behavioral paradigm for the study of duration perception in the rat, and report the result of neurotoxic lesions that have the goal of identifying sites that mediate duration perception. Using a two-alternative forced-choice paradigm, rats were either trained to discriminate durations of pure tones (range = [200,500] ms; boundary = 316 ms; Weber fraction after training = 0.24 ± 0.04), or were trained to discriminate frequencies of pure tones (range = [8,16] kHz; boundary = 11.3 kHz; Weber = 0.16 ± 0.11); the latter task is a control for non-timing-specific aspects of the former. Both groups discriminate the same class of sensory stimuli, use the same motions to indicate decisions, have identical trial structures, and are trained to psychophysical threshold; the tasks are thus matched in a number of sensorimotor and cognitive demands. We made neurotoxic lesions of candidate timing-perception areas in the cerebral cortex of both groups. Following extensive bilateral lesions of the auditory cortex, the performance of the frequency discrimination group was significantly more impaired than that of the duration discrimination group. We also found that extensive bilateral lesions of the medial prefrontal cortex resulted in little to no impairment of both groups. The behavioral framework presented here provides an audition-based approach to study the neural mechanisms of time estimation and memory for durations

The Impact of Recent Alcohol Use on Genome Wide DNA Methylation Signatures

Chronic alcohol intake is associated with a wide variety of adverse health outcomes including depression, diabetes, and heart disease. Unfortunately, the molecular mechanisms through which these effects are conveyed are not clearly understood. To examine the potential role of epigenetic factors in this process, we examined the relationship of recent alcohol intake to genome wide methylation patterns using the Illumina 450 Methylation Bead Chip and lymphoblast DNA derived from 165 female subjects participating in the Iowa Adoption Studies. We found that the pattern of alcohol use over the 6-months immediately prior to phlebotomy was associated with, severity-dependent changes in the degree of genome wide methylation that preferentially hypermethylate the central portion of CpG islands with methylation at cg05600126, a probe in ABR, and the 5′ untranslated region of BLCAP attaining genome wide significance in two point and sliding window analyses of probe methylation data, respectively. We conclude that recent alcohol use is associated with widespread changes in DNA methylation in women and that further study to confirm these findings and determine their relationship to somatic function are in order

Effects of Genotype and Child Abuse on DNA Methylation and Gene Expression at the Serotonin Transporter

Altered regulation of the serotonin transporter (SLC6A4) is hypothesized to be a key event in many forms of neuropsychiatric illness, yet our understanding of the molecular mechanisms through which changes in gene function could lead to illness remains incomplete. In prior studies, we and others have demonstrated that methylation of CpG residues in the promoter associated CpG island alters SLC6A4 gene expression, that the extent of that DNA methylation in child abuse is genotype dependent, and that adverse childhood experiences such as child sex abuse are related to methylation. However, we have not examined whether these effects are splice variant specific, whether the association of methylation to gene expression varies as a function of genotype, and whether methylation in other SLC6A4 gene regions are more likely candidates for GxE effects. In the current investigation we measured methylation in lymphoblast DNA from 158 female subjects in the Iowa Adoption Studies at 16 CpG residues spread across the SLC6A4 locus, and analyzed their relationship to gene expression for two SLC6A4 splice variants. Methylation of two CpG residues in the shore of the CpG island (cg22584138 and cg05951817), a location immediately upstream from exon 1A, predicted gene expression for the splice variant containing Exon 1A + 1B. Methylation at two residues in the CpG island itself (cg 25769822 and cg05016953) was associated with total SLC6A4 expression. Examination of these four CpG residues indicated that methylation of cg22584138 was influenced by both genotype and sex abuse, whereas methylation of cg05016953 was influenced only by sex abuse history. Factors influencing methylation at other CpG dinucleotide pairs were not identified. We conclude that methylation effects on transcription may vary as a function of underlying gene motif and splice variant, and that the shore of CpG islands, upstream of TSS, may be of particular interest in examining environmental effects on methylation

Unlocking biomarker discovery: Large scale application of aptamer proteomic technology for early detection of lung cancer

Lung cancer is the leading cause of cancer deaths, because ~84% of cases are diagnosed at an advanced stage. Worldwide in 2008, ~1.5 million people were diagnosed and ~1.3 million died – a survival rate unchanged since 1960. However, patients diagnosed at an early stage and have surgery experience an 86% overall 5-year survival. New diagnostics are therefore needed to identify lung cancer at this stage. Here we present the first large scale clinical use of aptamers to discover blood protein biomarkers in disease with our breakthrough proteomic technology. This multi-center case-control study was conducted in archived samples from 1,326 subjects from four independent studies of non-small cell lung cancer (NSCLC) in long-term tobacco-exposed populations. We measured >800 proteins in 15uL of serum, identified 44 candidate biomarkers, and developed a 12-protein panel that distinguished NSCLC from controls with 91% sensitivity and 84% specificity in a training set and 89% sensitivity and 83% specificity in a blinded, independent verification set. Performance was similar for early and late stage NSCLC. This is a significant advance in proteomics in an area of high clinical need

Bioethics Consultation in the Private Sector

The members of a task force on bioethics consultation report their conclusions. The task force was convened by the American Society for Bioethics and Humanities and the American Society of Law, Medicine, and Ethics, although these groups do not endorse the group\u27s conclusions. Two commentaries follow, and an essay by science reporter Nell Boyce sets the scene