Striatal Subregion-selective Dysregulated Dopamine Receptor-mediated Intracellular Signaling in a Model of DOPA-responsive Dystonia.

Although the mechanisms underlying dystonia are largely unknown, dystonia is often associated with abnormal dopamine neurotransmission. DOPA-responsive dystonia (DRD) is a prototype disorder for understanding dopamine dysfunction in dystonia because it is caused by mutations in genes necessary for the synthesis of dopamine and alleviated by the indirect-acting dopamine agonist l-DOPA. Although adaptations in striatal dopamine receptor-mediated intracellular signaling have been studied extensively in models of Parkinson's disease, another movement disorders associated with dopamine deficiency, little is known about dopaminergic adaptations in dystonia. To identify the dopamine receptor-mediated intracellular signaling associated with dystonia, we used immunohistochemistry to quantify striatal protein kinase A activity and extracellular signal-related kinase (ERK) phosphorylation after dopaminergic challenges in a knockin mouse model of DRD. l-DOPA treatment induced the phosphorylation of both protein kinase A substrates and ERK largely in D1 dopamine receptor-expressing striatal neurons. As expected, this response was blocked by pretreatment with the D1 dopamine receptor antagonist SCH23390. The D2 dopamine receptor antagonist raclopride also significantly reduced the phosphorylation of ERK; this contrasts with models of parkinsonism in which l-DOPA-induced ERK phosphorylation is not mediated by D2 dopamine receptors. Further, the dysregulated signaling was dependent on striatal subdomains whereby ERK phosphorylation was largely confined to dorsomedial (associative) striatum while the dorsolateral (sensorimotor) striatum was unresponsive. This complex interaction between striatal functional domains and dysregulated dopamine-receptor mediated responses has not been observed in other models of dopamine deficiency, such as parkinsonism, suggesting that regional variation in dopamine-mediated neurotransmission may be a hallmark of dystonia.

Differential expression of striatal proteins in a mouse model of DOPA-responsive dystonia reveals shared mechanisms among dystonic disorders.

Dystonia is characterized by involuntary muscle contractions that cause debilitating twisting movements and postures. Although dysfunction of the basal ganglia, a brain region that mediates movement, is implicated in many forms of dystonia, the underlying mechanisms are unclear. The inherited metabolic disorder DOPA-responsive dystonia is considered a prototype for understanding basal ganglia dysfunction in dystonia because it is caused by mutations in genes necessary for the synthesis of the neurotransmitter dopamine, which mediates the activity of the basal ganglia. Therefore, to reveal abnormal striatal cellular processes and pathways implicated in dystonia, we used an unbiased proteomic approach in a knockin mouse model of DOPA-responsive dystonia, a model in which the striatum is known to play a central role in the expression of dystonia. Fifty-seven of the 1805 proteins identified were differentially regulated in DOPA-responsive dystonia mice compared to control mice. Most differentially regulated proteins were associated with gene ontology terms that implicated either mitochondrial or synaptic dysfunction whereby proteins associated with mitochondrial function were generally over-represented and proteins associated with synaptic function were largely under-represented. Remarkably, nearly 20% of the differentially regulated striatal proteins identified in our screen are associated with pathogenic variants that cause inherited disorders with dystonia as a sign in humans suggesting shared mechanisms across many different forms of dystonia.

Attention bias towards threat in African American children exposed to early life trauma.

BACKGROUND: Attentional bias is linked to a range of mood disorders, including posttraumatic stress disorder (PTSD). The present study examined attention bias patterns in African American children exposed to trauma, in order to better understand potential risk factors for PTSD. METHODS: 31 children (ages 8-14) completed an eye-tracking task to assess gaze bias patterns while viewing pairs of emotional and neutral faces. Trauma exposure and PTSD symptoms were assessed in a subsample of children (n = 24). RESULTS: Repeated measures analysis of variance (ANOVA) results examining attention bias indices and gender showed greater attention bias toward angry faces than happy faces (p < 0.01) and toward emotional faces in males than females (p < 0.05). Correlational analyses showed attention bias toward angry faces was associated with greater levels of child trauma exposure (p < 0.05). Based on linear regression analysis, child trauma exposure accounted for 17 % of variance in attention bias toward angry versus neutral faces independent of gender or posttraumatic stress symptoms (p < 0.05). CONCLUSIONS: Trauma exposure in children is related to altered attention bias, via enhanced attention towards threatening cues. Results contribute to evidence that males and females may exhibit different attentional patterns. This study highlights the importance of additional research on attention bias patterns and prospective mental health outcomes across gender and through development.

The role of negative affect in the association between attention bias to threat and posttraumatic stress: An eye-tracking study.

Biased processing of threatening stimuli, including attention toward and away from threat, has been implicated in the development and maintenance of PTSD symptoms. Research examining theoretically-derived mechanisms through which dysregulated processing of threat may be associated with PTSD is scarce. Negative affect, a transdiagnostic risk factor for many types of psychopathology, is one potential mechanism that has yet to be examined. Thus, the present study (n = 92) tested the indirect effect of attention bias on PTSD via negative affect using rigorous eye-tracking methodology in a sample of urban-dwelling, trauma-exposed African-American women. We found support for the hypothesis that attention bias toward threat was indirectly associated with PTSD symptoms through increased negative affect. These results suggest that negative affect may be an important etiological process through which attention bias patterns could impact PTSD symptom severity. Implications for psychological and pharmacological therapeutic interventions targeting threat-related attention biases and negative affect are discussed.

Attention bias toward threatening faces in women with PTSD: eye tracking correlates by symptom cluster.

Maladaptive patterns of attention to emotional stimuli are a common feature of posttraumatic stress disorder (PTSD), with growing evidence supporting sustained attention to threatening stimuli across trauma samples. However, it remains unclear how different PTSD symptom clusters are associated with attentional bias patterns, particularly in urban civilian settings with high rates of trauma exposure and PTSD. The present study examined associations among these variables in 70 traumatized primarily African American women. PTSD was measured using the Clinician Administered PTSD Scale, and eye tracking was used to measure patterns of attention as participants engaged in an attention bias (dot probe) task to emotional faces; average initial fixation (1 s) and dwell duration (overall time spent looking at emotional face versus neutral face across the 5 s task) were used to assess attention bias patterns toward emotional faces. Women with PTSD showed significantly longer dwell duration toward angry faces than women without PTSD (F = 5.16, p < .05). Bivariate correlation analyses with the PTSD symptom clusters showed a significant association between average initial fixation toward angry faces and higher levels of avoidance symptoms (r = 0.29, p < .05) as well as sustained attention to angry faces and higher levels of re-experiencing symptoms (r = 0.24, p < .05). Using separate linear regression models based on initial significant correlations, we found that PTSD avoidance symptoms were significantly related to average initial fixation toward angry faces (R 2 ∆ = 0.09, p < .05) and PTSD re-experiencing symptoms were significantly related to dwell duration toward angry faces (R 2 ∆ = 0.06, p < .05). These findings contribute to evidence that PTSD is related to both initial vigilance and sustained attention to threat and that certain symptom clusters may either drive or be more impacted by attentional biases, highlighting the benefits of addressing attentional biases within treatment.

Los patrones desaptativos de atención a estímulos emocionales son una característica común del trastorno de estrés postraumático (TEPT), con evidencias crecientes que respaldan el rol de la atención sostenida hacia estímulos amenazadores a través de muestras de traumas. Sin embargo, aún permanece poco claro cómo diferentes conglomerados de síntomas de TEPT se asocian con los patrones de sesgo atencional, especialmente en entornos civiles urbanos con altas tasas de exposición al trauma y TEPT. El presente estudio examinó las asociaciones entre estas variables en 70 mujeres traumatizadas principalmente afroamericanas. El TEPT se midió utilizando la Escala de TEPT Administrada por el Medico, y el seguimiento ocular se usó para medir los patrones de atención cuando los participantes se involucraron en una tarea de sesgo atencional (sonda de puntos) a las caras emocionales; la fijación inicial promedio (1 segundo) y la duración de permanencia (tiempo total dedicado a mirar la cara emocional en contraste a la cara neutral en la tarea de 5 segundos) se utilizaron para evaluar los patrones de sesgo de atención hacia las caras emocionales. Las mujeres con TEPT mostraron una duración de permanencia de la mirada significativamente más prolongada hacia las caras enojadas que las mujeres sin TEPT (F = 5.16, p <.05). Los análisis de correlación bivariada con los conglomerados de síntomas de TEPT mostraron una asociación significativa entre la fijación inicial promedio hacia las caras enojadas y los niveles más altos de síntomas de evitación (r = 0.29, p <.05), así como la atención sostenida a las caras enojadas y niveles más altos los síntomas de re-experimentación (r = 0.24, p <.05). Usando modelos de regresión lineal separados basados en correlaciones significativas iniciales, encontramos que los síntomas de evitación de TEPT se relacionaron significativamente con la fijación inicial promedio hacia caras de enojo (R2∆=0.09, p<0.05) y los síntomas de re-experimentación de TEPT se relacionaron significativamente con la duración de permanencia hacia caras enojadas (R2∆=0.06, p<0.05). Estos hallazgos contribuyen a la evidencia de que el TEPT está relacionado con la vigilancia inicial y la atención sostenida a la amenaza y que ciertos conglomerados de síntomas pueden impulsar o verse más afectados por los sesgos atencionales, destacando los beneficios de abordar los sesgos atencionales dentro del tratamiento.

Psychological resilience is associated with more intact social functioning in veterans with post-traumatic stress disorder and depression.

Patients with depression or post-traumatic stress disorder (PTSD), common sequelae among individuals exposed to stressful or traumatic events, often report impairment in social functioning. Resilience is a multidimensional construct that enables adaptive coping with life adversity. Relationship between resilience and social functioning among veterans with depression and PTSD is not entirely clear and is the focus of this report. Resilience was assessed in 264 veterans using the Connor-Davidson Resilience Scale, PTSD with the PTSD Symptom Scale, depression with the Beck Depression Inventory, and social functioning with the Short Form Health Survey. Higher resilience was associated with more intact social functioning after PTSD and depression severity, childhood maltreatment, physical health, gender, education, marital status, and employment were simultaneously adjusted for. Childhood maltreatment, gender, marital status, education, and employment did not predict social functioning; however, greater severity of PTSD, depression, or physical health problems was each significantly associated with more impaired social functioning. Our findings suggest that higher resilience was associated with more intact social functioning regardless of the severity of PTSD and depression. Given the importance of social functioning in depression and/or PTSD recovery, studies are needed to examine if enhancing resilience presents a complementary approach to alleviating impaired social functioning.

Generalization of fear-potentiated startle in the presence of auditory cues: a parametric analysis.

Intense fear responses observed in trauma-, stressor-, and anxiety-related disorders can be elicited by a wide range of stimuli similar to those that were present during the traumatic event. The present study investigated the experimental utility of fear-potentiated startle paradigms to study this phenomenon, known as stimulus generalization, in healthy volunteers. Fear-potentiated startle refers to a relative increase in the acoustic startle response to a previously neutral stimulus that has been paired with an aversive stimulus. Specifically, in Experiment 1 an auditory pure tone (500 Hz) was used as the conditioned stimulus (CS+) and was reinforced with an unconditioned stimulus (US), an airblast to the larynx. A distinct tone (4000 Hz) was used as the nonreinforced stimulus (CS-) and was never paired with an airblast. Twenty-four hours later subjects underwent Re-training followed by a Generalization test, during which subjects were exposed to a range of generalization stimuli (GS) (250, 1000, 2000, 4000, 8000 Hz). In order to further examine the point at which fear no longer generalizes, a follow-up experiment (Experiment 2) was performed where a 4000 Hz pure tone was used as the CS+, and during the Generalization test, 2000 and 8000 Hz were used as GS. In both Experiment 1 and 2 there was significant discrimination in US expectancy responses on all stimuli during the Generalization Test, indicating the stimuli were perceptually distinct. In Experiment 1, participants showed similar levels of fear-potentiated startle to the GS that were adjacent to the CS+, and discriminated between stimuli that were 2 or more degrees from the CS+. Experiment 2 demonstrated no fear-potentiated startle generalization. The current study is the first to use auditory cues to test generalization of conditioned fear responses; such cues may be especially relevant to combat posttraumatic stress disorder (PTSD) where much of the traumatic exposure may involve sounds.

Conditioned fear associated phenotypes as robust, translational indices of trauma-, stressor-, and anxiety-related behaviors.

Post-traumatic stress disorder (PTSD) is a heterogeneous disorder that affects individuals exposed to trauma (e.g., combat, interpersonal violence, and natural disasters). It is characterized by hyperarousal, intrusive reminders of the trauma, avoidance of trauma-related cues, and negative cognition and mood. This heterogeneity indicates the presence of multiple neurobiological mechanisms underlying the development and maintenance of PTSD. Fear conditioning is a robust, translational experimental paradigm that can be employed to elucidate these mechanisms by allowing for the study of fear-related dimensions of PTSD (e.g., fear extinction, fear inhibition, and generalization of fear) across multiple units of analysis. Fear conditioning experiments have identified varying trajectories of the dimensions described, highlighting exciting new avenues of targeted, focused study. Additionally, fear conditioning studies provide a translational platform to develop novel interventions. The current review highlights the versatility of fear conditioning paradigms, the implications for pharmacological and non-pharmacological treatments, the robustness of these paradigms to span an array of neuroscientific measures (e.g., genetic studies), and finally the need to understand the boundary conditions under which these paradigms are effective. Further understanding these paradigms will ultimately allow for optimization of fear conditioning paradigms, a necessary step towards the advancement of PTSD treatment methods.

Age-dependent MDPV-induced taste aversions and thermoregulation in adolescent and adult rats.

Adolescent rats are more sensitive to the rewarding and less sensitive to the aversive properties of various drugs of abuse than their adult counterparts. Given a nationwide increase in use of "bath salts," the present experiment employed the conditioned taste aversion procedure to assess the aversive effects of 3,4-methylenedioxypyrovalerone (MDPV; 0, 1.0, 1.8, or 3.2 mg/kg), a common constituent in "bath salts," in adult and adolescent rats. As similar drugs induce thermoregulatory changes in rats, temperature was recorded following MDPV administration to assess if thermoregulatory changes were related to taste aversion conditioning. Both age groups acquired taste aversions, although these aversions were weaker and developed at a slower rate in the adolescent subjects. Adolescents increased and adults decreased body temperature following MDPV administration with no correlation to aversions. The relative insensitivity of adolescents to the aversive effects of MDPV suggests that MDPV may confer an increased risk in this population.

The effects of the 5-HT3 receptor antagonist tropisetron on cocaine-induced conditioned taste aversions.

Although cocaine readily induces taste aversions, little is known about the mechanisms underlying this effect. Recent work has shown that cocaine's actions on serotonin (5-HT) may be involved. To address this possibility, the present experiments examined a role of the specific 5-HT receptor, 5-HT3, in this effect given that it is implicated in a variety of behavioral effects of cocaine. This series of investigations first assessed the aversive effects of the 5-HT3 receptor antagonist tropisetron alone (Experiment 1). Specifically, in Experiment 1 male Sprague-Dawley rats were given repeated pairings of a novel saccharin solution and tropisetron (0, 0.056, 0.18 and 0.56mg/kg). Following this, a non-aversion-inducing dose of tropisetron (0.18mg/kg) was assessed for its ability to block aversions induced by a range of doses of cocaine (Experiment 2). Specifically, in Experiment 2 animals were given access to a novel saccharin solution and then injected with tropisetron (0 or 0.18mg/kg) followed by an injection of various doses of cocaine (0, 10, 18 and 32mg/kg). Cocaine induced dose-dependent taste aversions that were not blocked by tropisetron, suggesting that cocaine's aversive effects are not mediated by 5-HT, at least at this specific receptor subtype. At the intermediate dose of cocaine, aversions appeared to be potentiated, suggesting 5-HT3 may play a limiting role in cocaine's aversive effects. These data are discussed in the context of previous examinations of the roles of serotonin, dopamine, and norepinephrine in cocaine-induced aversions.

Concurrent zero-dimensional and one-dimensional biomineralization of gold from a solution of Au3+ and bovine serum albumin.

A technique was developed for preparing a novel material that consists of gold nanoparticles trapped within a fiber of unfolded proteins. These fibers are made in an aqueous solution that contains HAuCl4 and the protein, bovine serum albumin (BSA). By changing the ratio of gold to BSA in solution, two different types of outcomes are observed. At lower gold to BSA ratios (30-120), a purple solution results after heating the mixture at 80 °C for 4 h. At higher gold to BSA ratios (130-170), a clear solution containing purple fibers results after heating the mixture at 80 °C for 4 h. UV-Vis spectroscopy and light scattering techniques show growth in nanocolloid size as gold to BSA ratio rises above 100. Data indicate that, for the higher gold to BSA ratios, the gold is sequestered within the solid material. The material mass, visible by eye, appears to be an aggregation of smaller individual fibers. Scanning electron microscopy and transmission electron microscopy indicate that these fibers are primarily one-dimensional aggregates, which can display some branching, and can be as narrow as 400 nm in size. The likely mechanism for the synthesis of the novel material is discussed.

Dopamine mediates cocaine-induced conditioned taste aversions as demonstrated with cross-drug preexposure to GBR 12909.

Although cocaine readily induces taste aversions, little is known about the mechanisms underlying this effect. It has been suggested that its inhibitory effects at one of the monoamine transporters may be mediating this suppression. Using the cross-drug preexposure preparation, the present series of studies examined a possible role of dopamine (DA) in this effect. Male Sprague-Dawley rats were exposed to cocaine (18 mg/kg; Experiment 1) or the selective DA transporter (DAT) inhibitor GBR 12909 (50 mg/kg; Experiment 2) prior to the pairing of a novel saccharin solution with injections of GBR 12909 (32 mg/kg), cocaine (18 mg/kg) or vehicle in a conditioned taste aversion (CTA) procedure. Preexposure to cocaine attenuated aversions induced by itself but not aversions induced by GBR 12909 (Experiment 1). Conversely, preexposure to GBR 12909 attenuated aversions induced by itself and cocaine (Experiment 2). This asymmetry suggests that cocaine and GBR 12909 induce CTAs via similar, but non-identical, mechanisms. These data are discussed in the context of previous work demonstrating roles for dopamine, norepinephrine and serotonin in cocaine-induced CTAs.

The effects of haloperidol on cocaine-induced conditioned taste aversions.

Although the mechanism underlying the rewarding effects of cocaine has been well characterized, little is known about the mechanism underlying its aversive effects. Several reports have indicated a possible role of dopamine (DA) in the aversive effects; however, several procedural issues limit any conclusions regarding its specific role. In order to investigate a possible dopaminergic role in cocaine-induced CTAs using procedures that circumvented these possible issues, the present series of investigations assessed the aversive effects of the DA antagonist haloperidol alone (Experiment 1) and in combination with cocaine (Experiment 2). Haloperidol, at doses that were determined to be non-aversive, yet behaviorally active in a locomotor assessment, attenuated cocaine-induced taste aversions, suggesting that cocaine's aversive effects are mediated in part by dopaminergic activity. These findings were discussed in consideration with other evidence implicating DA and other neurotransmitter systems in cocaine-induced CTAs.