Automatic Construction of Predictive Neuron Models through Large Scale Assimilation of Electrophysiological Data.

We report on the construction of neuron models by assimilating electrophysiological data with large-scale constrained nonlinear optimization. The method implements interior point line parameter search to determine parameters from the responses to intracellular current injections of zebra finch HVC neurons. We incorporated these parameters into a nine ionic channel conductance model to obtain completed models which we then use to predict the state of the neuron under arbitrary current stimulation. Each model was validated by successfully predicting the dynamics of the membrane potential induced by 20-50 different current protocols. The dispersion of parameters extracted from different assimilation windows was studied. Differences in constraints from current protocols, stochastic variability in neuron output, and noise behave as a residual temperature which broadens the global minimum of the objective function to an ellipsoid domain whose principal axes follow an exponentially decaying distribution. The maximum likelihood expectation of extracted parameters was found to provide an excellent approximation of the global minimum and yields highly consistent kinetics for both neurons studied. Large scale assimilation absorbs the intrinsic variability of electrophysiological data over wide assimilation windows. It builds models in an automatic manner treating all data as equal quantities and requiring minimal additional insight

Organic Cation Transporter 3: A Cellular Mechanism Underlying Rapid, Non-Genomic Glucocorticoid Regulation of Monoaminergic Neurotransmission, Physiology, and Behavior

Corticosteroid hormones act at intracellular glucocorticoid receptors (GR) and mineralocorticoid receptors (MR) to alter gene expression, leading to diverse physiological and behavioral responses. In addition to these classical genomic effects, corticosteroid hormones also exert rapid actions on physiology and behavior through a variety of non-genomic mechanisms, some of which involve GR or MR, and others of which are independent of these receptors. One such GR-independent mechanism involves corticosteroid-induced inhibition of monoamine transport mediated by “uptake2” transporters, including organic cation transporter 3 (OCT3), a low-affinity, high-capacity transporter for norepinephrine, epinephrine, dopamine, serotonin and histamine. Corticosterone directly and acutely inhibits OCT3-mediated transport. This review describes the studies that initially characterized uptake2 processes in peripheral tissues, and outlines studies that demonstrated OCT3 expression and corticosterone-sensitive monoamine transport in the brain. Evidence is presented supporting the hypothesis that corticosterone can exert rapid, GR-independent actions on neuronal physiology and behavior by inhibiting OCT3-mediated monoamine clearance. Implications of this mechanism for glucocorticoid-monoamine interactions in the context-dependent regulation of behavior are discussed

Sex differences in behavioral traits related with high sensitivity to the reinforcing effects of cocaine

Cocaine is the most prevalent illegal stimulant drug in Europe among the adult population. Its abuse is characterized by a faster substance abuse disorder (SUD) development than other drugs, with high vulnerability to relapse. However, there does not exist an effective treatment for cocaine dependence. Sex differences have been reported in psychological disorders including SUD. For this reason, it is essential to identify risk factors that predict susceptibility or resilience to cocaine addiction for the development of effective prevention strategies considering sex differences. In the present study, the main objective was to determine more sensitive phenotypes to the conditioned reinforcing effects of cocaine in both sexes. Anxiety-like behavior and the locomotor response to novelty were evaluated in the elevated plus maze, and despair in the tail suspension test, as well as vulnerability traits linked with a high sensitivity to the reinforcing effects of a subthreshold dose of cocaine (1 mg/kg) in the conditioned place preference (CPP) paradigm in male and female mice. Our results indicated that only female mice with high anxiety, low locomotor response to novelty or low despair levels acquired CPP induced by cocaine, while male mice with low anxiety, high locomotor response to novelty or high despair levels presented a higher susceptibility to the rewarding effects of cocaine than others. These sex differences in the results reveal an opposite pattern in males and females on the relationship between anxiety- and depressive-like behaviors and cocaine vulnerability, demonstrating the need to include female mice in preclinical studies

Low-threshold analysis of CDMS shallow-site data

Data taken during the final shallow-site run of the first tower of the Cryogenic Dark Matter Search (CDMS II) detectors have been reanalyzed with improved sensitivity to small energy depositions. Four ~224 g germanium and two ~105 g silicon detectors were operated at the Stanford Underground Facility (SUF) between December 2001 and June 2002, yielding 118 live days of raw exposure. Three of the germanium and both silicon detectors were analyzed with a new low-threshold technique, making it possible to lower the germanium and silicon analysis thresholds down to the actual trigger thresholds of ~1 keV and ~2 keV, respectively. Limits on the spin-independent cross section for weakly interacting massive particles (WIMPs) to elastically scatter from nuclei based on these data exclude interesting parameter space for WIMPs with masses below 9 GeV/c^2. Under standard halo assumptions, these data partially exclude parameter space favored by interpretations of the DAMA/LIBRA and CoGeNT experiments' data as WIMP signals, and exclude new parameter space for WIMP masses between 3 GeV/c^2 and 4 GeV/c^2.Comment: 18 pages, 12 figures, 5 table

A systematic review of reviews on the prevalence of anxiety disorders in adult populations.

BACKGROUND: A fragmented research field exists on the prevalence of anxiety disorders. Here, we present the results of a systematic review of reviews on this topic. We included the highest quality studies to inform practice and policy on this issue. METHOD: Using PRISMA methodology, extensive electronic and manual citation searches were performed to identify relevant reviews. Screening, data extraction, and quality assessment were undertaken by two reviewers. Inclusion criteria consisted of systematic reviews or meta-analyses on the prevalence of anxiety disorders that fulfilled at least half of the AMSTAR quality criteria. RESULTS: We identified a total of 48 reviews and described the prevalence of anxiety across population subgroups and settings, as reported by these studies. Despite the high heterogeneity of prevalence estimates across primary studies, there was emerging and compelling evidence of substantial prevalence of anxiety disorders generally (3.8-25%), and particularly in women (5.2-8.7%); young adults (2.5-9.1%); people with chronic diseases (1.4-70%); and individuals from Euro/Anglo cultures (3.8-10.4%) versus individuals from Indo/Asian (2.8%), African (4.4%), Central/Eastern European (3.2%), North African/Middle Eastern (4.9%), and Ibero/Latin cultures (6.2%). CONCLUSIONS: The prevalence of anxiety disorders is high in population subgroups across the globe. Recent research has expanded its focus to Asian countries, an increasingly greater number of physical and psychiatric conditions, and traumatic events associated with anxiety. Further research on illness trajectories and anxiety levels pre- and post-treatment is needed. Few studies have been conducted in developing and under-developed parts of the world and have little representation in the global literature.This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1002/brb3.497

Fear Memory Recall Potentiates Opiate Reward Sensitivity through Dissociable Dopamine D1 versus D4 Receptor-Dependent Memory Mechanisms in the Prefrontal Cortex.

Disturbances in prefrontal cortical (PFC) dopamine (DA) transmission are well established features of psychiatric disorders involving pathological memory processing, such as post-traumatic stress disorder and opioid addiction. Transmission through PFC DA D4 receptors (D4Rs) has been shown to potentiate the emotional salience of normally nonsalient emotional memories, whereas transmission through PFC DA D1 receptors (D1Rs) has been demonstrated to selectively block recall of reward- or aversion-related associative memories. In the present study, using a combination of fear conditioning and opiate reward conditioning in male rats, we examined the role of PFC D4/D1R signaling during the processing of fear-related memory acquisition and recall and subsequent sensitivity to opiate reward memory formation. We report that PFC D4R activation potentiates the salience of normally subthreshold fear conditioning memory cues and simultaneously potentiates the rewarding effects of systemic or intra-ventral tegmental area (VTA) morphine conditioning cues. In contrast, blocking the recall of salient fear memories with intra-PFC D1R activation, blocks the ability of fear memory recall to potentiate systemic or intra-VTA morphine place preference. These effects were dependent upon dissociable PFC phosphorylation states involving calcium-calmodulin-kinase II or extracellular signal-related kinase 1-2, following intra-PFC D4 or D1R activation, respectively. Together, these findings reveal new insights into how aberrant PFC DAergic transmission and associated downstream molecular signaling pathways may modulate fear-related emotional memory processing and concomitantly increase opioid addiction vulnerability. Disturbances in prefrontal cortical (PFC) dopamine (DA) transmission are well established features of psychiatric disorders involving pathological memory processing, such as post-traumatic stress disorder and opioid addiction. Transmission through PFC DA D4 receptors (D4Rs) has been shown to potentiate the emotional salience of normally nonsalient emotional memories, whereas transmission through PFC DA D1 receptors (D1Rs) has been demonstrated to selectively block recall of reward-or aversion-related associative memories. In the present study, using a combination of fear conditioning and opiate reward conditioning in male rats, we examined the role of PFC D4/D1R signaling during the processing of fear-related memory acquisition and recall and subsequent sensitivity to opiate reward memory formation. We report that PFC D4R activation potentiates the salience of normally subthreshold fear conditioning memory cues and simultaneously potentiates the rewarding effects of systemic or intra-ventral tegmental area (VTA) morphine conditioning cues. In contrast, blocking the recall of salient fear memories with intra-PFC D1R activation, blocks the ability of fear memory recall to potentiate systemic or intra-VTA morphine place preference. These effects were dependent upon dissociable PFC phosphorylation states involving calcium-calmodulin-kinase II or extracellular signal-related kinase 1-2, following intra-PFC D4 or D1Ractivation, respectively. Together, these findings reveal new insights into how aberrant PFC DAergic transmission and associated downstream molecular signaling pathways may modulate fear-related emotional memory processing and concomitantly increase opioid addiction vulnerability

Acceptability and Effectiveness of App-Based Interventions in Managing Symptoms of Depression, Self-Harm and Suicidal Ideation in Youth

This item is only available electronically.Depression during adolescence has been linked to an increased risk for non-suicidal self-harm and suicidal ideation both preceding risk factors for suicide. However, young people are unlikely to seek help for mental health problems. Given that this group routinely use online services to connect with others and seek information, smartphone applications (‘apps’) present a possible treatment modality. This review critically examines the development and application of apps in the self-guided treatment of depression, self-harm and suicidal ideation among youth. Findings in this area are promising, although inconsistent. Randomized controlled trials are needed to determine treatment safety and effectiveness.Thesis (M.Psych(Clinical)) -- University of Adelaide, School of Psychology, 202

Reduced fronto-striatal volume in attention-deficit/hyperactivity disorder in two cohorts across the lifespan

Attention-Deficit/Hyperactivity Disorder (ADHD) has been associated with altered brain anatomy in neuroimaging studies. However, small and heterogeneous study samples, and the use of region-of-interest and tissuespecific analyses have limited the consistency and replicability of these effects. We used a data-driven multivariate approach to investigate neuroanatomical features associated with ADHD in two independent cohorts: the Dutch NeuroIMAGE cohort (n = 890, 17.2 years) and the Brazilian IMpACT cohort (n = 180, 44.2 years). Using independent component analysis of whole-brain morphometry images, 375 neuroanatomical components were assessed for association with ADHD. In both discovery (corrected-p = 0.0085) and replication (p = 0.032) cohorts, ADHD was associated with reduced volume in frontal lobes, striatum, and their interconnecting whitematter. Current results provide further evidence for the role of the fronto-striatal circuit in ADHD in children, and for the first time show its relevance to ADHD in adults. The fact that the cohorts are from different continents and comprise different age ranges highlights the robustness of the findings

Doctor of Philosophy

dissertationThe interplay of dynamics and structure is a common theme in both mathematics and biology. In this thesis, the author develops and analyzes mathematical models that give insight into the dynamics and structure of a variety of biological applications. The author presents a variety of contributions in applications of mathematics to explore biological systems across several scales. First, she analyzes pattern formation in a partial differential equation model based on two interacting proteins that are undergoing passive and active transport, respectively. This work is inspired by a longstanding problem in identifying a biophysical mechanism for the control of synaptic density in C. elegans and leads to a novel mathematical formulation of Turing-type patterns in intracellular transport. The author also demonstrates the persistence of these patterns on growing domains, and discusses extensions for a two-dimensional model. She then presents two models that explore how stochastic processes affect intracellular dynamics. First, the author and her collaborators derive effective stochastic differential equations that describe intermittent virus trafficking. Next, she shows how ion channel fluctuations lead to subthreshold oscillations in neuron models. In the final chapter, she discusses two projects for ongoing and future work: one on modeling parasite infection on dynamic social networks, and another on the bifurcation structure of localized patterns on lattices. All of these projects, presented together, chronicle the journey of the author through her mathematical development and attempts to identify, discover, create, and communicate mathematics that inspires and excites