Altered Neurocircuitry in the Dopamine Transporter Knockout Mouse Brain

The plasma membrane transporters for the monoamine neurotransmitters dopamine, serotonin, and norepinephrine modulate the dynamics of these monoamine neurotransmitters. Thus, activity of these transporters has significant consequences for monoamine activity throughout the brain and for a number of neurological and psychiatric disorders. Gene knockout (KO) mice that reduce or eliminate expression of each of these monoamine transporters have provided a wealth of new information about the function of these proteins at molecular, physiological and behavioral levels. In the present work we use the unique properties of magnetic resonance imaging (MRI) to probe the effects of altered dopaminergic dynamics on meso-scale neuronal circuitry and overall brain morphology, since changes at these levels of organization might help to account for some of the extensive pharmacological and behavioral differences observed in dopamine transporter (DAT) KO mice. Despite the smaller size of these animals, voxel-wise statistical comparison of high resolution structural MR images indicated little morphological change as a consequence of DAT KO. Likewise, proton magnetic resonance spectra recorded in the striatum indicated no significant changes in detectable metabolite concentrations between DAT KO and wild-type (WT) mice. In contrast, alterations in the circuitry from the prefrontal cortex to the mesocortical limbic system, an important brain component intimately tied to function of mesolimbic/mesocortical dopamine reward pathways, were revealed by manganese-enhanced MRI (MEMRI). Analysis of co-registered MEMRI images taken over the 26 hours after introduction of Mn^(2+) into the prefrontal cortex indicated that DAT KO mice have a truncated Mn^(2+) distribution within this circuitry with little accumulation beyond the thalamus or contralateral to the injection site. By contrast, WT littermates exhibit Mn^(2+) transport into more posterior midbrain nuclei and contralateral mesolimbic structures at 26 hr post-injection. Thus, DAT KO mice appear, at this level of anatomic resolution, to have preserved cortico-striatal-thalamic connectivity but diminished robustness of reward-modulating circuitry distal to the thalamus. This is in contradistinction to the state of this circuitry in serotonin transporter KO mice where we observed more robust connectivity in more posterior brain regions using methods identical to those employed here

Counteractive effects of antenatal glucocorticoid treatment on D1 receptor modulation of spatial working memory

RATIONALE: Antenatal exposure to the glucocorticoid dexamethasone dramatically increases the number of mesencephalic dopaminergic neurons in rat offspring. However, the consequences of this expansion in midbrain dopamine (DA) neurons for behavioural processes in adulthood are poorly understood, including working memory that depends on DA transmission in the prefrontal cortex (PFC). OBJECTIVES: We therefore investigated the influence of antenatal glucocorticoid treatment (AGT) on the modulation of spatial working memory by a D1 receptor agonist and on D1 receptor binding and DA content in the PFC and striatum. METHODS: Pregnant rats received AGT on gestational days 16-19 by adding dexamethasone to their drinking water. Male offspring reared to adulthood were trained on a delayed alternation spatial working memory task and administered the partial D1 agonist SKF38393 (0.3-3 mg/kg) by systemic injection. In separate groups of control and AGT animals, D1 receptor binding and DA content were measured post-mortem in the PFC and striatum. RESULTS: SKF38393 impaired spatial working memory performance in control rats but had no effect in AGT rats. D1 binding was significantly reduced in the anterior cingulate cortex, prelimbic cortex, dorsal striatum and ventral pallidum of AGT rats compared with control animals. However, AGT had no significant effect on brain monoamine levels. CONCLUSIONS: These findings demonstrate that D1 receptors in corticostriatal circuitry down-regulate in response to AGT. This compensatory effect in D1 receptors may result from increased DA-ergic tone in AGT rats and underlie the resilience of these animals to the disruptive effects of D1 receptor activation on spatial working memory

Reduced Amygdala and Ventral Striatal Activity to Happy Faces in PTSD Is Associated with Emotional Numbing

There has been a growing recognition of the importance of reward processing in PTSD, yet little is known of the underlying neural networks. This study tested the predictions that (1) individuals with PTSD would display reduced responses to happy facial expressions in ventral striatal reward networks, and (2) that this reduction would be associated with emotional numbing symptoms. 23 treatment-seeking patients with Posttraumatic Stress Disorder were recruited from the treatment clinic at the Centre for Traumatic Stress Studies, Westmead Hospital, and 20 trauma-exposed controls were recruited from a community sample. We examined functional magnetic resonance imaging responses during the presentation of happy and neutral facial expressions in a passive viewing task. PTSD participants rated happy facial expression as less intense than trauma-exposed controls. Relative to controls, PTSD participants revealed lower activation to happy (-neutral) faces in ventral striatum and and a trend for reduced activation in left amygdala. A significant negative correlation was found between emotional numbing symptoms in PTSD and right ventral striatal regions after controlling for depression, anxiety and PTSD severity. This study provides initial evidence that individuals with PTSD have lower reactivity to happy facial expressions, and that lower activation in ventral striatal-limbic reward networks may be associated with symptoms of emotional numbing

Haloperidol differentially modulates prepulse inhibition and p50 suppression in healthy humans stratified for low and high gating levels

Schizophrenia patients exhibit deficits in sensory gating as indexed by reduced prepulse inhibition (PPI) and P50 suppression, which have been linked to psychotic symptom formation and cognitive deficits. Although recent evidence suggests that atypical antipsychotics might be superior over typical antipsychotics in reversing PPI and P50 suppression deficits not only in schizophrenia patients, but also in healthy volunteers exhibiting low levels of PPI, the impact of typical antipsychotics on these gating measures is less clear. To explore the impact of the dopamine D2-like receptor system on gating and cognition, the acute effects of haloperidol on PPI, P50 suppression, and cognition were assessed in 26 healthy male volunteers split into subgroups having low vs high PPI or P50 suppression levels using a placebo-controlled within-subject design. Haloperidol failed to increase PPI in subjects exhibiting low levels of PPI, but attenuated PPI in those subjects with high sensorimotor gating levels. Furthermore, haloperidol increased P50 suppression in subjects exhibiting low P50 gating and disrupted P50 suppression in individuals expressing high P50 gating levels. Independently of drug condition, high PPI levels were associated with superior strategy formation and execution times in a subset of cognitive tests. Moreover, haloperidol impaired spatial working memory performance and planning ability. These findings suggest that dopamine D2-like receptors are critically involved in the modulation of P50 suppression in healthy volunteers, and to a lesser extent also in PPI among subjects expressing high sensorimotor gating levels. Furthermore, the results suggest a relation between sensorimotor gating and working memory performance

Multi-dimensionality and variability in folk classification of stingless bees (Apidae: Meliponini)

Background: Not long ago Eugene Hunn suggested using a combination of cognitive, linguistic, ecological and evolutionary theories in order to account for the dynamic character of ethnoecology in the study of folk classification systems. In this way he intended to question certain homogeneity in folk classifications models and deepen in the analysis and interpretation of variability in folk classifications. This paper studies how a rural culturally mixed population of the Atlantic Forest of Misiones (Argentina) classified honey-producing stingless bees according to the linguistic, cognitive and ecological dimensions of folk classification. We also analyze the socio-ecological meaning of binomialization in naming and the meaning of general local variability in the appointment of stingless bees. Methods: We used three different approaches: the classical approach developed by Brent Berlin which relies heavily on linguistic criteria, the approach developed by Eleonor Rosch which relies on psychological (cognitive) principles of categorization and finally we have captured the ecological dimension of folk classification in local narratives. For the second approximation, we developed ways of measuring the degree of prototypicality based on a total of 107 comparisons of the type "X is similar to Y" identified in personal narratives. Results: Various logical and grouping strategies coexist and were identified as: graded of lateral linkage, hierarchical and functional. Similarity judgments among folk taxa resulted in an implicit logic of classification graded according to taxa's prototypicality. While there is a high agreement on naming stingless bees with monomial names, a considerable number of underrepresented binomial names and lack of names were observed. Two possible explanations about reported local naming variability are presented. Conclusions: We support the multidimensionality of folk classification systems. This confirms the specificity of local classification systems but also reflects the use of grouping strategies and mechanisms commonly observed in other cultural groups, such as the use of similarity judgments between more or less prototypical organisms. Also we support the idea that alternative naming results from a process of fragmentation of knowledge or incomplete transmission of knowledge. These processes lean on the facts that culturally based knowledge, on the one hand, and biologic knowledge of nature on the other, can be acquired through different learning pathways.Fil: Zamudio, Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Instituto Multidisciplinario de Biología Vegetal (p); ArgentinaFil: Hilgert, Norma Ines. Consejo Nacional de Investigaciones Cientiâ­ficas y Tecnicas. Centro Cientifico Tecnologico Nordeste. Instituto de Biologia Subtropical. Instituto de Biologia Subtropical - Nodo Puerto Iguazu; Argentin

Intra-arterial chemoradiation for T3-4 oral cavity cancer: Treatment outcomes in comparison to oropharyngeal and hypopharyngeal carcinoma

<p>Abstract</p> <p>Background</p> <p>Surgery followed by radiotherapy is the standard of care for resectable locally advanced oral cavity squamous cell carcinoma (SCC). We report the treatment outcomes of patients with T3-T4 SCC of the oral cavity treated with chemoradiation, an alternative approach.</p> <p>Patients and methods</p> <p>From a series of 240 patients with stage III-IV carcinoma of the upper aerodigestive tract who were treated consecutively according to the RADPLAT protocol, a subset analysis of 155 patients with T3-T4 SCC (Oral cavity SCC N = 22, oropharynx SCC N = 94 and hypopharynx SCC N = 39), was performed. The goal was to test the hypothesis that oral cavity SCC treated with chemoradiation has similar outcomes to the two comparison sites.</p> <p>Results</p> <p>With a median follow-up of 58 months, local disease control was 69% and the overall survival was 37%. In comparison, local disease control for the oropharynx and hypopharynx groups was 86% and 79% respectively. The overall survival rate for the oropharyngeal and hypopharyngeal groups were 41% and 6% respectively</p> <p>Conclusion</p> <p>Patients with locally advanced oral cavity cancer treated with the chemoradiation protocol RADPLAT have outcomes that are equal or better compared to patients with similar disease involving the oropharynx and hypopharynx</p

Оценка надежности высоконадежных систем с учетом ЗИП

Предложены приближенные верхние и нижние оценки коэффициента готовности высоконадежной восстанавливаемой системы со структурной избыточностью. Полученные расчетные соотношения могут использоваться для оценки надежности высоконадежных систем с учетом различных стратегий пополнения ЗИП

Single-cell analysis tools for drug discovery and development

The genetic, functional or compositional heterogeneity of healthy and diseased tissues presents major challenges in drug discovery and development. Such heterogeneity hinders the design of accurate disease models and can confound the interpretation of biomarker levels and of patient responses to specific therapies. The complex nature of virtually all tissues has motivated the development of tools for single-cell genomic, transcriptomic and multiplex proteomic analyses. Here, we review these tools and assess their advantages and limitations. Emerging applications of single cell analysis tools in drug discovery and development, particularly in the field of oncology, are discussed