610 Medizin und Gesundheit
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Abstract
Inhibition of midbrain dopamine neurons is thought to underlie the signaling of events that are less rewarding than expected and drive learning based on these negative prediction errors. It has recently been shown that Kv4.3 channels influence the integration of inhibitory inputs in specific subpopulations of dopamine neurons. The functional properties of Kv4.3 channels are themselves strongly determined by the binding of auxiliary β-subunits; among them KChIP4a stands-out for its unique combination of modulatory effects. These include decreasing surface membrane trafficking and slowing inactivation kinetics. Therefore, we hypothesized that KChIP4a expression in dopamine neurons could play a crucial role in behavior, in particular by affecting the computation of negative prediction errors. We developed a mouse line where the alternative exon that codes for the KChIP4a splice variant was selectively deleted in midbrain dopamine neurons. In a reward-based reinforcement learning task, we observed that dopamine neuron-specific KChIP4a deletion selectively accelerated the rate of extinction learning, without impacting the acquisition of conditioned responses. We further found that this effect was due to a faster decrease in the initiation rate of goal-directed behaviors, and not faster increases in action disengagement. Furthermore, computational fitting of the behavioral data with a Rescorla-Wagner model confirmed that the observed phenotype was attributable to a selective increase in the learning rate from negative prediction errors. Finally, KChIP4a deletion did not affect performance in other dopamine-sensitive behavioral tasks that did not involve learning from disappointing events, including an absence of effects on working memory, locomotion and novelty preference. Taken together, our results demonstrate that an exon- and midbrain dopamine neuron-specific deletion of an A-type K+ channel β-subunit leads to a selective gain of function in extinction learning.
One Sentence Summary
Exon- and midbrain dopamine neuron-specific deletion of the Kv4 channel β-subunit KChIP4a selectively accelerates extinction learning
Background: Dialectical behaviour therapy for posttraumatic stress disorder (DBT-PTSD), which is tailored to treat adults with PTSD and co-occurring emotion regulation difficulties, has already demonstrated its efficacy, acceptance and safety in an inpatient treatment setting. It combines elements of DBT with trauma-focused cognitive behavioural interventions.
Objective: To investigate the feasibility, acceptance and safety of DBT-PTSD in an outpatient treatment setting by therapists who were novice to the treatment, we treated 21 female patients suffering from PTSD following childhood sexual abuse (CSA) plus difficulties in emotion regulation in an uncontrolled clinical trial.
Method: The Clinician Administered PTSD Symptom Scale (CAPS), the Davidson Trauma Scale (DTS), the Borderline Section of the International Personality Disorder Examination (IPDE) and the Borderline Symptom List (BSL-23) were used as primary outcomes. For secondary outcomes, depression and dissociation were assessed. Assessments were administered at pretreatment, post-treatment and six-week follow-up.
Results: Improvement was significant for PTSD as well as for borderline personality symptomatology, with large pretreatment to follow-up effect sizes for completers based on the CAPS (Cohens d = 1.30), DTS (d = 1.50), IPDE (d = 1.60) and BSL-23 (d = 1.20).
Conclusion: The outcome suggests that outpatient DBT-PTSD can safely be used to reduce PTSD symptoms and comorbid psychopathology in adults who have experienced CSA.
Attention-deficit/hyperactivity disorder (ADHD) is highly heritable and the most common neurodevelopmental disorder in childhood. In recent decades, it has been appreciated that in a substantial number of cases the disorder does not remit in puberty, but persists into adulthood. Both in childhood and adulthood, ADHD is characterised by substantial comorbidity including substance use, depression, anxiety, and accidents. However, course and symptoms of the disorder and the comorbidities may fluctuate and change over time, and even age of onset in childhood has recently been questioned. Available evidence to date is poor and largely inconsistent with regard to the predictors of persistence versus remittance. Likewise, the development of comorbid disorders cannot be foreseen early on, hampering preventive measures. These facts call for a lifespan perspective on ADHD from childhood to old age. In this selective review, we summarise current knowledge of the long-term course of ADHD, with an emphasis on clinical symptom and cognitive trajectories, treatment effects over the lifespan, and the development of comorbidities. Also, we summarise current knowledge and important unresolved issues on biological factors underlying different ADHD trajectories. We conclude that a severe lack of knowledge on lifespan aspects in ADHD still exists for nearly every aspect reviewed. We encourage large-scale research efforts to overcome those knowledge gaps through appropriately granular longitudinal studies.
Prenatal and postnatal experiences associated with epigenetic changes in the adult mouse brain
(2018)
To analyze the influences of early-life history on the brain epigenome, the offspring of mouse dams kept in an enriched or standard environment were exposed postnatally to enriched, standard, or adverse conditions. The methylation patterns of 7 candidate genes (9 loci) involved in developmental programming of stress vulnerability/resilience and psychiatric disease were analyzed in 6 brain regions of adult male and female mice. Exposure to an enriched prenatal environment was associated with widespread epigenetic changes (all of small effect size), affecting 29 of 324 (9%) gene/region-specific methylation patterns. The effects of either adverse or enriched postnatal conditions were tested separately in the two prenatal cohorts. Significant changes were observed in 2 of 324 (0.6%) loci in offspring of dams in a standard environment and 6 of 324 (1.9%) loci in animals that were exposed prenatally to an enriched environment. Prenatal life experiences appear to have a bigger effect on the adult brain epigenome than postnatal experiences. Positive prenatal life experiences may increase epigenetic plasticity of the brain later in life. All observed between-group differences were sex-specific, consistent with largely different developmental trajectories of the male and female brain. Multiple changes of small effect size are consistent with a multifactorial model of developmental programming of adult behavior and disease susceptibility.
The enzyme acetyl-CoA carboxylase (ACC) plays a crucial role in fatty acid metabolism. In recent years, ACC has been recognized as a promising drug target for treating different diseases. However, the role of ACC in vascular endothelial cells (ECs) has been neglected so far. To characterize the role of ACC, we used the ACC inhibitor, soraphen A, as a chemical tool, and also a gene silencing approach. We found that ACC1 was the predominant isoform in human umbilical vein ECs as well as in human microvascular ECs and that soraphen A reduced the levels of malonyl-CoA. We revealed that ACC inhibition shifted the lipid composition of EC membranes. Accordingly, membrane fluidity, filopodia formation, and migratory capacity were reduced. The antimigratory action of soraphen A depended on an increase in the cellular proportion of PUFAs and, most importantly, on a decreased level of phosphatidylglycerol. Our study provides a causal link between ACC, membrane lipid composition, and cell migration in ECs. Soraphen A represents a useful chemical tool to investigate the role of fatty acid metabolism in ECs and ACC inhibition offers a new and valuable therapeutic perspective for the treatment of EC migration-related diseases.
Pseudomonas aeruginosa is a human pathogen that causes health-care associated blood stream infections (BSI). Although P. aeruginosa BSI are associated with high mortality rates, the clinical relevance of pathogen-derived prognostic biomarker to identify patients at risk for unfavorable outcome remains largely unexplored. We found novel pathogen-derived prognostic biomarker candidates by applying a multi-omics approach on a multicenter sepsis patient cohort. Multi-level Cox regression was used to investigate the relation between patient characteristics and pathogen features (2298 accessory genes, 1078 core protein levels, 107 parsimony-informative variations in reported virulence factors) with 30-day mortality. Our analysis revealed that presence of the helP gene encoding a putative DEAD-box helicase was independently associated with a fatal outcome (hazard ratio 2.01, p = 0.05). helP is located within a region related to the pathogenicity island PAPI-1 in close proximity to a pil gene cluster, which has been associated with horizontal gene transfer. Besides helP, elevated protein levels of the bacterial flagellum protein FliL (hazard ratio 3.44, p < 0.001) and of a bacterioferritin-like protein (hazard ratio 1.74, p = 0.003) increased the risk of death, while high protein levels of a putative aminotransferase were associated with an improved outcome (hazard ratio 0.12, p < 0.001). The prognostic potential of biomarker candidates and clinical factors was confirmed with different machine learning approaches using training and hold-out datasets. The helP genotype appeared the most attractive biomarker for clinical risk stratification due to its relevant predictive power and ease of detection.
Rhythmic neural spiking and attentional sampling arising from cortical receptive field interactions
(2018)
Summary: Growing evidence suggests that distributed spatial attention may invoke theta (3-9 Hz) rhythmic sampling processes. The neuronal basis of such attentional sampling is however not fully understood. Here we show using array recordings in visual cortical area V4 of two awake macaques that presenting separate visual stimuli to the excitatory center and suppressive surround of neuronal receptive fields elicits rhythmic multi-unit activity (MUA) at 3-6 Hz. This neuronal rhythm did not depend on small fixational eye movements. In the context of a distributed spatial attention task, during which the monkeys detected a spatially and temporally uncertain target, reaction times (RT) exhibited similar rhythmic fluctuations. RTs were fast or slow depending on the target occurrence during high or low MUA, resulting in rhythmic MUA-RT cross-correlations at at theta frequencies. These findings suggest that theta-rhythmic neuronal activity arises from competitive receptive field interactions and that this rhythm may subserve attentional sampling.
Highlights:
* Center-surround interactions induce theta-rhythmic MUA of visual cortex neurons
* The MUA rhythm does not depend on small fixational eye movements
* Reaction time fluctuations lock to the neuronal rhythm under distributed attention
From August to November 2017, Madagascar endured an outbreak of plague. A total of 2417 cases of plague were confirmed, causing a death toll of 209. Public health intervention efforts were introduced and successfully stopped the epidemic at the end of November. The plague, however, is endemic in the region and occurs annually, posing the risk of future outbreaks. To understand the plague transmission, we collected real-time data from official reports, described the outbreak's characteristics, and estimated transmission parameters using statistical and mathematical models. The pneumonic plague epidemic curve exhibited multiple peaks, coinciding with sporadic introductions of new bubonic cases. Optimal climate conditions for rat flea to flourish were observed during the epidemic. Estimate of the plague basic reproduction number during the large wave of the epidemic was high, ranging from 5 to 7 depending on model assumptions. The incubation and infection periods for bubonic and pneumonic plague were 4.3 and 3.4 days and 3.8 and 2.9 days, respectively. Parameter estimation suggested that even with a small fraction of the population exposed to infected rat fleas (1/10,000) and a small probability of transition from a bubonic case to a secondary pneumonic case (3%), the high human-to-human transmission rate can still generate a large outbreak. Controlling rodent and fleas can prevent new index cases, but managing human-to-human transmission is key to prevent large-scale outbreaks.
Relevance of the natural HDAC inhibitor sulforaphane as a chemopreventive agent in urologic tumors
(2018)
Due to an increased understanding of molecular biology and the genomics of cancer, new and potent agents have been approved by the Food and Drug Administration (FDA) to fight this disease. However, all of these drugs cause severe side effects and resistance inevitably develops, re-activating tumor growth and dissemination. For this reason, patients turn to natural compounds as alternative or complementary treatment options, since it has been found that natural plant products may block, inhibit, or reverse cancer development. The present review focusses on the role of the natural compound sulforaphane (SFN) as an anti-tumor agent in urologic cancer. SFN is a natural compound found in cruciferous vegetables from the Brassicaceae family such as broccoli, cauliflower and cabbage. Several epidemiologic and clinical studies have documented chemopreventive properties of SFN, making it an interesting candidate for additive cancer treatment. SFN shows remarkable anti-tumor effects in vitro and in vivo without exerting toxicity. The review summarizes the current understanding of SFN and provides insights into its molecular mode of action with particular emphasis on epigenetic tumor control.
Delayed-onset muscle soreness (DOMS) is a common symptom in people participating in exercise, sport, or recreational physical activities. Several remedies have been proposed to prevent and alleviate DOMS. In 2008 and 2015, two studies have been conducted to investigate the effects of acupuncture on symptoms and muscle function in eccentric exercise-induced DOMS of the biceps brachii muscle. In 2008 a prospective, randomized, controlled, observer and subject-blinded trial was undertaken with 22 healthy subjects (22–30 years; 12 females) being randomly assigned to three treatment groups: real acupuncture (deep needling at classic acupuncture points and tender points; n = 7), sham-acupuncture (superficial needling at non-acupuncture points; n = 8), and control (n = 7). In 2015, a five-arm randomized controlled study was conducted with 60 subjects (22 females, 23.6 ± 2.8 years). Participants were randomly allocated to needle, laser, sham needle, sham laser acupuncture, and no intervention.
In both cases treatment was applied immediately, 24 and 48 hours after DOMS induction.
The outcome measures included pain perception (visual analogue scale; VAS), mechanical pain threshold (MPT), maximum isometric voluntary force (MIVF) and pressure pain threshold (PPT).
Results: In 2008, following nonparametric testing, there were no significant differences between groups in outcome measures at baseline. After 72 hours, pain perception (VAS) was significantly lower in the acupuncture group compared to the sham acupuncture and control subjects. However, the mean MPT and MIVF scores were not significantly different between groups. This lead to the conclusion, that acupuncture seemed to have no effects on MPT and muscle function, but reduced perceived pain arising from exercise-induced DOMS.
The more recent results from 2015 indicated that neither verum nor sham interventions significantly improved outcomes within 72 hours when compared with the no treatment control (P > 0.05).