Conflict Processing in the Rat Brain: Behavioral Analysis and Functional μPET Imaging Using [18F]Fluorodeoxyglucose

Conflicts in spatial stimulus–response tasks occur when the task-relevant feature of a stimulus implies a response toward a certain location which does not match the location of stimulus presentation. This conflict leads to increased error rates and longer reaction times, which has been termed Simon effect. A model of dual route processing (automatic and intentional) of stimulus features has been proposed, predicting response conflicts if the two routes are incongruent. Although there is evidence that the prefrontal cortex, notably the anterior cingulate cortex (ACC), plays a crucial role in conflict processing, the neuronal basis of dual route architecture is still unknown. In this study, we pursue a novel approach using positron emission tomography (PET) to identify relevant brain areas in a rat model of an auditory Simon task, a neuropsychological interference task, which is commonly used to study conflict processing in humans. For combination with PET we used the metabolic tracer [18F]fluorodeoxyglucose, which accumulates in metabolically active brain cells during the behavioral task. Brain areas involved in conflict processing are supposed to be activated when automatic and intentional route processing lead to different responses (dual route model). Analysis of PET data revealed specific activation patterns for different task settings applicable to the dual route model as established for response conflict processing. The rat motor cortex (M1) may be part of the automatic route or involved in its facilitation, while premotor (M2), prelimbic, and ACC seemed to be essential for inhibiting the incorrect, automatic response, indicating conflict monitoring functions. Our findings and the remarkable similarities to the pattern of activated regions reported during conflict processing in humans demonstrate that our rodent model opens novel opportunities to investigate the anatomical basis of conflict processing and dual route architecture

Identification and climatology of alpine pumping from a regional climate simulation

The thermally driven circulation between the European Alps and the alpine foreland - named Alpine pumping – occurs regularly under clear and calm weather conditions. While previous studies focused on the impact of Alpine pumping on moist convection and transport of air pollutants, this study was motivated by its ventilation effect for Munich, located about 50 km north of the Alps in undulating and only slightly inclined terrain, where local thermal circulations are weak. Hourly data from a reanalysis driven regional climate simulation with COSMO-CLM model for the period 1989 to 2008 were analysed to identify days with Alpine pumping and to determine the mean diurnal characteristics of this regional thermal circulation. Four literature derived combinations of meteorological criteria were tested to identify days favorable for Alpine pumping from COSMO-CLM results. The first criterion selects days with a daily sum of solar radiation ≥20 MJ/m2 and has been used in an earlier observational study. On average 60 d/y are fulfilling the criterion in the model simulation, which compares well to the 67 d/y determined from observations. The other three criteria combinations consider a maximum wind velocity at 850 hPa, a maximum daily precipitation sum, and/or a maximum mean cloud cover. The mean annual number of selected days is lower for these criteria combinations and ranges between 20 and 52. Diurnal wind reversals occur on 77 to 81% of the selected days, depending on the criteria combinationThe daily solar radiation sum of 20 MJ/m2 is only exceeded during April to September, while days satisfying the criteria combinations without the radiation threshold occur all year round. In agreement with observations, the simulated regional thermally driven wind field extends up to ~100 km north of the Alps with average near-surface wind speeds of 0.5-1.5 m/s in the Munich area. With increasing distance from the Alps, the diurnal cycle of Alpine pumping is delayed by up to 3 hours. The simulated mean depth of the daytime inflow layer ranges between 500 m and 1500 m, whereas the depth of the nocturnal outflow layer typically reaches up to a few hundred meters

Infants generalize representations of statistically segmented words

The acoustic variation in language presents learners with a substantial challenge. To learn by tracking statistical regularities in speech, infants must recognize words across tokens that differ based on characteristics such as the speaker’s voice, affect, or the sentence context. Previous statistical learning studies have not investigated how these types of surface form variation affect learning. The present experiments used tasks tailored to two distinct developmental levels to investigate the robustness of statistical learning to variation. Experiment 1 examined statistical word segmentation in 11-month-olds and found that infants can recognize statistically segmented words across a change in the speaker’s voice from segmentation to testing. The direction of infants’ preferences suggests that recognizing words across a voice change is more difficult than recognizing them in a consistent voice. Experiment 2 tested whether 17-month-olds can generalize the output of statistical learning across variation to support word learning. The infants were successful in their generalization; they associated referents with statistically defined words despite a change in voice from segmentation to label learning. Infants’ learning patterns also indicate that they formed representations of across-word syllable sequences during segmentation. Thus, low probability sequences can act as object labels in some conditions. The findings of these experiments suggest that the units that emerge during statistical learning are not perceptually constrained, but rather are robust to naturalistic acoustic variation

Identification of Iron and Heme Utilization Genes in Aeromonas and their Role in the Colonization of the Leech Digestive Tract

It is known that many pathogens produce high-affinity iron uptake systems like siderophores and/or genes for utilizing iron bound to heme-containing molecules, which facilitate iron-acquisition inside a host. In mutualistic digestive-tract associations, iron uptake systems have not been as well studied. We investigated the importance of two iron utilization systems within the beneficial digestive-tract association Aeromonas veronii and the medicinal leech, Hirudo verbana. Siderophores were detected in A. veronii using chrome azurol S. Using a mTn5, a transposon insertion in viuB generated a mutant unable to acquire iron using siderophores. The A. veronii genome was then searched for genes potentially involved in iron utilization bound to heme-containing molecules. A putative outer membrane heme receptor (hgpB) was identified with a transcriptional activator, termed hgpR, downstream. The hgpB gene was interrupted in both the parent strain and the viuB mutant with an antibiotic resistance cassette, yielding a hgpB mutant and a mutant with both iron uptake systems inactivated. In vitro assays indicated that hgpB is involved in utilizing iron bound to heme and that both iron utilization systems are important for A. veronii to grow in blood. In vivo colonization assays revealed that the ability to acquire iron from heme-containing molecules is critical for A.veronii to colonize the leech gut. Since iron and specifically heme utilization is important in this mutualistic relationship and has a role as a possible virulence factor in other organisms, genomes from different Aeromonas strains (both clinical and environmental) were queried with iron utilization genes of A. veronii. This analysis revealed the heme utilization genes are widely distributed among aeromonads. In addition, aeromonads posses a suite of genes involved in iron acquisition. These data further confirm symbiotic and pathogenic relationships possess similar mechanisms for interacting with animal hosts

Exposure to pairs of Aeromonas strains enhances virulence in the Caenorhabditis elegans infection model

Aeromonad virulence remains poorly understood, and is difficult to predict from strain characteristics. In addition, infections are often polymicrobial (i.e., are mixed infections), and 5-10% of such infections include two distinct aeromonads, which has an unknown impact on virulence. In this work, we studied the virulence of aeromonads recovered from human mixed infections. We tested them individually and in association with other strains with the aim of improving our understanding of aeromonosis. Twelve strains that were recovered in pairs from six mixed infections were tested in a virulence model of the worm Caenorhabditis elegans. Nine isolates were weak worm killers (median time to death, TD50, ≥7 days) when administered alone. Two pairs showed enhanced virulence, as indicated by a significantly shortened TD50 after co-infection versus infection with a single strain. Enhanced virulence was also observed for five of the 14 additional experimental pairs, and each of these pairs included one strain from a natural synergistic pair. These experiments indicated that synergistic effects were frequent and were limited to pairs that were composed of strains belonging to different species. The genome content of virulence-associated genes failed to explain virulence synergy, although some virulence-associated genes that were present in some strains were absent from their companion strain (e.g., T3SS). The synergy observed in virulence when 2 Aeromonas isolates were co-infected stresses the idea that consideration should be given to the fact that infection does not depend only on single strain virulence but is instead the result of a more complex interaction between the microbes involved, the host and the environment. These results are of interest for other diseases in which mixed infections are likely and in particular for water-borne diseases (e.g., legionellosis, vibriosis), in which pathogens may display enhanced virulence in the presence of the right partner. This study contributes to the current shift in infectiology paradigms from a premise that assumes a monomicrobial origin for infection to one more in line with the current pathobiome era

Recognition memory across the lifespan: the impact of word frequency and study-test interval on estimates of familiarity and recollection

The goal of this study was to investigate recognition memory performance across the lifespan and to determine how estimates of recollection and familiarity contribute to performance. In each of three experiments, participants from five groups from 14 up to 85 years of age (children, young adults, middle-aged adults, young-old adults, and old-old adults) were presented with high- and low-frequency words in a study phase and were tested immediately afterwards and/or after a one day retention interval. The results showed that word frequency and retention interval affected recognition memory performance as well as estimates of recollection and familiarity. Across the lifespan, the trajectory of recognition memory followed an inverse u-shape function that was neither affected by word frequency nor by retention interval. The trajectory of estimates of recollection also followed an inverse u-shape function, and was especially pronounced for low-frequency words. In contrast, estimates of familiarity did not differ across the lifespan. The results indicate that age differences in recognition memory are mainly due to differences in processes related to recollection while the contribution of familiarity-based processes seems to be age-invariant

Differences in conformational dynamics within the Hsp90 chaperone family reveal mechanistic insights

The molecular chaperones of the Hsp90 family are essential in all eukaryotic cells. They assist late folding steps and maturation of many different proteins, called clients, that are not related in sequence or structure. Hsp90 interaction with its clients appears to be coupled to a series of conformational changes. Using hydrogen exchange mass spectrometry (HX-MS) we investigated the structural dynamics of human Hsp90β (hHsp90) and yeast Hsp90 (yHsp90). We found that eukaryotic Hsp90s are much more flexible than the previously studied Escherichia coli homolog (EcHsp90) and that nucleotides induce much smaller changes. More stable conformations in yHsp90 are obtained in presence of co-chaperones. The tetratricopeptide repeat (TPR) domain protein Cpr6 causes a different amide proton protection pattern in yHsp90 than the previously studied TPR-domain protein Sti1. In the simultaneous presence of Sti1 and Cpr6, protection levels are observed that are intermediate between the Sti1 and the Cpr6 induced changes. Surprisingly, no bimodal distributions of the isotope peaks are detected, suggesting that both co-chaperones affect both protomers of the Hsp90 dimer in a similar way. The cochaperones Sba1 was found previously in the crystal structure bound to the ATP hydrolysis-competent conformation of Hsp90, which did not allow to distinguish the mode of Sba1-mediated inhibition of Hsp90’s ATPase activity by stabilizing the pre- or post-hydrolysis step. Our HX-MS experiments now show that Sba1 binding leads to a protection of the ATP binding lid, suggesting that it inhibits Hsp90’s ATPase activity by slowing down product release. This hypothesis was verified by a single-turnover ATPase assay. Together, our data suggest that there are much smaller energy barriers between conformational states in eukaryotic Hsp90s than in EcHsp90 and that co-chaperones are necessary in addition to nucleotides to stabilize defined conformational states

Role of Anticonvulsants in the Management of Posttraumatic Epilepsy

Posttraumatic seizures have been recognized as a major complication of traumatic brain injury. The annual incidence of traumatic brain injury in the United States is 1.7 million. The role of anticonvulsants in the treatment of posttraumatic epilepsy remains uncertain. Based on current studies however, anticonvulsants have been shown to reduce early posttraumatic seizures occurring within the first seven days, but little to no benefits have been shown in late posttraumatic seizures occurring after 7 days. In this paper, we provide a minireview of the role of anticonvulsants and current advances in the management of posttraumatic epilepsy

Neural correlates of sensorimotor gating: a metabolic positron emission tomography study in awake rats

Impaired sensorimotor gating occurs in neuropsychiatric disorders such as schizophrenia and can be measured using the prepulse inhibition (PPI) paradigm of the acoustic startle response. This assay is frequently used to validate animal models of neuropsychiatric disorders and to explore the therapeutic potential of new drugs. The underlying neural network of PPI has been extensively studied with invasive methods and genetic modifications. However, its relevance for healthy untreated animals and the functional interplay between startle- and PPI-related areas during a PPI session is so far unknown. Therefore, we studied awake rats in a PPI paradigm, startle control and background noise control, combined with behavioral [18F]fluoro-2-deoxyglucose positron emission tomography (FDG-PET). Subtractive analyses between conditions were used to identify brain regions involved in startle and PPI processing in well-hearing Black hooded rats. For correlative analysis with regard to the amount of PPI we also included hearing-impaired Lister hooded rats that startled more often, because their hearing threshold was just below the lowest prepulses. Metabolic imaging showed that the brain areas proposed for startle and PPI mediation are active during PPI paradigms in healthy untreated rats. More importantly, we show for the first time that the whole PPI modulation network is active during passive PPI sessions, where no selective attention to prepulse or startle stimulus is required. We conclude that this reflects ongoing monitoring of stimulus significance and constant adjustment of sensorimotor gating

The neurocognitive basis for impaired dual-task performance in senior fallers

Falls are a major health-care concern, and while dual-task performance is widely recognized as being impaired in those at-risk for falls, the underlying neurocognitive mechanisms remain unknown. A better understanding of the underlying mechanisms could lead to the refinement and development of behavioural, cognitive, or neuropharmacological interventions for falls prevention. Therefore, we conducted a cross-sectional study with community-dwelling older adults aged 70-80 years with a history of falls (i.e., two or more falls in the past 12 months) or no history of falls (i.e., zero falls in the past 12 months); n = 28 per group. We compared functional activation during cognitive-based dual-task performance between fallers and non-fallers using functional magnetic resonance imaging (fMRI). Executive cognitive functioning was assessed via Stroop, Trail Making, and Digit Span. Mobility was assessed via the Timed Up and Go test. We found that non-fallers exhibited significantly greater functional activation compared with fallers during dual-task performance in key regions responsible for resolving dual-task interference, including precentral, postcentral, and lingual gyri. Further, we report slower reaction times during dual-task performance in fallers and significant correlations between level of functional activation and independent measures of executive cognitive functioning and mobility. Our study is the first neuroimaging study to examine dual-task performance in fallers, and supports the notion that fallers have reduced functional brain activation compared with non-fallers. Given that dual-task performance – and the underlying neural concomitants – appears to be malleable with relevant training, our study serves as a launching point for promising strategies to reduce falls in the future