Medizin
Filtern
Dokumenttyp
Sprache
- Englisch (15)
Volltext vorhanden
- ja (15)
Gehört zur Bibliographie
- nein (15)
Schlagworte
- Parkinson's disease (2)
- Action potential (1)
- Autophagy (1)
- Axon (1)
- Burst (1)
- Cancer (1)
- Cellular neuroscience (1)
- Critical Online Reasoning Assessment (1)
- Developmental disorders (1)
- Dopamine (1)
Institut
To successfully learn using open Internet resources, students must be able to critically search, evaluate and select online information, and verify sources. Defined as critical online reasoning (COR), this construct is operationalized on two levels in our study: (1) the student level using the newly developed Critical Online Reasoning Assessment (CORA), and (2) the online information processing level using event log data, including gaze durations and fixations. The written responses of 32 students for one CORA task were scored by three independent raters. The resulting score was operationalized as “task performance,” whereas the gaze fixations and durations were defined as indicators of “process performance.” Following a person-oriented approach, we conducted a process mining (PM) analysis, as well as a latent class analysis (LCA) to test whether—following the dual-process theory—the undergraduates could be distinguished into two groups based on both their process and task performance. Using PM, the process performance of all 32 students was visualized and compared, indicating two distinct response process patterns. One group of students (11), defined as “strategic information processers,” processed online information more comprehensively, as well as more efficiently, which was also reflected in their higher task scores. In contrast, the distributions of the process performance variables for the other group (21), defined as “avoidance information processers,” indicated a poorer process performance, which was also reflected in their lower task scores. In the LCA, where two student groups were empirically distinguished by combining the process performance indicators and the task score as a joint discriminant criterion, we confirmed these two COR profiles, which were reflected in high vs. low process and task performances. The estimated parameters indicated that high-performing students were significantly more efficient at conducting strategic information processing, as reflected in their higher process performance. These findings are so far based on quantitative analyses using event log data. To enable a more differentiated analysis of students’ visual attention dynamics, more in-depth qualitative research of the identified student profiles in terms of COR will be required.
Background Parkinson's disease (PD) is an adult-onset movement disorder of largely unknown etiology. We have previously shown that loss-of-function mutations of the mitochondrial protein kinase PINK1 (PTEN induced putative kinase 1) cause the recessive PARK6 variant of PD. Methodology/Principal Findings Now we generated a PINK1 deficient mouse and observed several novel phenotypes: A progressive reduction of weight and of locomotor activity selectively for spontaneous movements occurred at old age. As in PD, abnormal dopamine levels in the aged nigrostriatal projection accompanied the reduced movements. Possibly in line with the PARK6 syndrome but in contrast to sporadic PD, a reduced lifespan, dysfunction of brainstem and sympathetic nerves, visible aggregates of alpha-synuclein within Lewy bodies or nigrostriatal neurodegeneration were not present in aged PINK1-deficient mice. However, we demonstrate PINK1 mutant mice to exhibit a progressive reduction in mitochondrial preprotein import correlating with defects of core mitochondrial functions like ATP-generation and respiration. In contrast to the strong effect of PINK1 on mitochondrial dynamics in Drosophila melanogaster and in spite of reduced expression of fission factor Mtp18, we show reduced fission and increased aggregation of mitochondria only under stress in PINK1-deficient mouse neurons. Conclusion Thus, aging Pink1 -/- mice show increasing mitochondrial dysfunction resulting in impaired neural activity similar to PD, in absence of overt neuronal death.
Communication with the hematopoietic system is a vital component of regulating brain function in health and disease. Traditionally, the major routes considered for this neuroimmune communication are by individual molecules such as cytokines carried by blood, by neural transmission, or, in more severe pathologies, by the entry of peripheral immune cells into the brain. In addition, functional mRNA from peripheral blood can be directly transferred to neurons via extracellular vesicles (EVs), but the parameters that determine their uptake are unknown. Using varied animal models that stimulate neuronal activity by peripheral inflammation, optogenetics, and selective proteasome inhibition of dopaminergic (DA) neurons, we show that the transfer of EVs from blood is triggered by neuronal activity in vivo. Importantly, this transfer occurs not only in pathological stimulation but also by neuronal activation caused by the physiological stimulus of novel object placement. This discovery suggests a continuous role of EVs under pathological conditions as well as during routine cognitive tasks in the healthy brain.
The digital and information age has fundamentally transformed the way in which students learn and the study material they have at their disposal, especially in higher education. Students need to possess a number of higher-order cognitive and metacognitive skills, including effective information processing and critical reasoning to be able to navigate the Internet and use online sources, even those found outside of academically curated domains and in the depths of the Internet, and to solve (domain-specific) problems. Linking qualitative and quantitative research and connecting the humanities to empirical educational science studies, this article investigates the role of narratives and their impact on university students’ information seeking and their critical online reasoning (COR). This study focuses on the link between students’ online navigation skills, information seeking behavior and critical reasoning with regard to the specific domains: economics and medicine. For the empirical analysis in this article, we draw on a study that assesses the COR skills of undergraduate students of economics and medicine at two German universities. To measure COR skills, we used five tasks from the computer-based assessment “Critical Online Reasoning Assessment” (CORA), which assesses students’ skills in critically evaluating online sources and reasoning using evidence on contentious issues. The conceptual framework of this study is based on an existing methodology – narrative economics and medicine – and discusses its instructional potential and how it can be used to develop a new tool of “wise interventions” to enhance students’ COR in higher education. Based on qualitative content analyses of the students’ written responses, i.e., short essays, three distinct patterns of information seeking behavior among students have been identified. These three patterns – “Unambiguous Fact-Checking,” “Perspective-Taking Without Fact-Checking,” and “Web Credibility-Evaluating” – differ substantially in their potential connection to underlying narratives of information used by students to solve the CORA tasks. This analysis suggests that training university students in narrative analysis can strongly contribute to enhancing their critical online reasoning.
Background: Repetitive transcranial magnetic stimulation (rTMS) allows non-invasive stimulation of the human brain. However, no suitable marker has yet been established to monitor the immediate rTMS effects on cortical areas in children.
Objective: TMS-evoked EEG potentials (TEPs) could present a well-suited marker for real-time monitoring. Monitoring is particularly important in children where only few data about rTMS effects and safety are currently available.
Methods: In a single-blind sham-controlled study, twenty-five school-aged children with ADHD received subthreshold 1 Hz-rTMS to the primary motor cortex. The TMS-evoked N100 was measured by 64-channel-EEG pre, during and post rTMS, and compared to sham stimulation as an intraindividual control condition.
Results: TMS-evoked N100 amplitude decreased during 1 Hz-rTMS and, at the group level, reached a stable plateau after approximately 500 pulses. N100 amplitude to supra-threshold single pulses post rTMS confirmed the amplitude reduction in comparison to the pre-rTMS level while sham stimulation had no influence. EEG source analysis indicated that the TMS-evoked N100 change reflected rTMS effects in the stimulated motor cortex. Amplitude changes in TMS-evoked N100 and MEPs (pre versus post 1 Hz-rTMS) correlated significantly, but this correlation was also found for pre versus post sham stimulation.
Conclusion: The TMS-evoked N100 represents a promising candidate marker to monitor rTMS effects on cortical excitability in children with ADHD. TMS-evoked N100 can be employed to monitor real-time effects of TMS for subthreshold intensities. Though TMS-evoked N100 was a more sensitive parameter for rTMS-specific changes than MEPs in our sample, further studies are necessary to demonstrate whether clinical rTMS effects can be predicted from rTMS-induced changes in TMS-evoked N100 amplitude and to clarify the relationship between rTMS-induced changes in TMS-evoked N100 and MEP amplitudes. The TMS-evoked N100 amplitude reduction after 1 Hz-rTMS could either reflect a globally decreased cortical response to the TMS pulse or a specific decrease in inhibition.
The family of lysosome-associated membrane proteins (LAMP) includes the ubiquitously expressed LAMP1 and LAMP2, which account for half of the proteins in the lysosomal membrane. Another member of the LAMP family is LAMP3, which is expressed only in certain cell types and differentiation stages. LAMP3 expression is linked with poor prognosis of certain cancers, and the locus where it is encoded was identified as a risk factor for Parkinson's disease (PD). Here, we investigated the role of LAMP3 in the two main cellular degradation pathways, the proteasome and autophagy. LAMP3 mRNA was not detected in mouse models of PD or in the brain of human patients. However, it was strongly induced upon proteasomal inhibition in the neuroblastoma cell line SH-SY5Y. Induction of LAMP3 mRNA following proteasomal inhibition was dependent on UPR transcription factor ATF4 signaling and induced autophagic flux. Prevention of LAMP3 induction enhanced apoptotic cell death. In summary, these data demonstrate that LAMP3 regulation as part of the UPR contributes to protein degradation and cell survival during proteasomal dysfunction. This link between autophagy and the proteasome may be of special importance for the treatment of tumor cells with proteasomal inhibitors.
Mutations in the actively expressed, maternal allele of the imprinted KCNK9 gene cause Birk-Barel intellectual disability syndrome (BBIDS). Using a BBIDS mouse model, we identify here a partial rescue of the BBIDS-like behavioral and neuronal phenotypes mediated via residual expression from the paternal Kcnk9 (Kcnk9pat) allele. We further demonstrate that the second-generation HDAC inhibitor CI-994 induces enhanced expression from the paternally silenced Kcnk9 allele and leads to a full rescue of the behavioral phenotype suggesting CI-994 as a promising molecule for BBIDS therapy. Thus, these findings suggest a potential approach to improve cognitive dysfunction in a mouse model of an imprinting disorder.
The in vivo firing patterns of ventral midbrain dopamine neurons are controlled by afferent and intrinsic activity to generate sensory cue and prediction error signals that are essential for reward-based learning. Given the absence of in vivo intracellular recordings during the last three decades, the subthreshold membrane potential events that cause changes in dopamine neuron firing patterns remain unknown. To address this, we established in vivo whole-cell recordings and obtained over 100 spontaneously active, immunocytochemically-defined midbrain dopamine neurons in isoflurane-anaesthetized adult mice. We identified a repertoire of subthreshold membrane potential signatures associated with distinct in vivo firing patterns. Dopamine neuron activity in vivo deviated from single-spike pacemaking by phasic increases in firing rate via two qualitatively distinct biophysical mechanisms: 1) a prolonged hyperpolarization preceding rebound bursts, accompanied by a hyperpolarizing shift in action potential threshold; and 2) a transient depolarization leading to high-frequency plateau bursts, associated with a depolarizing shift in action potential threshold. Our findings define a mechanistic framework for the biophysical implementation of dopamine neuron firing patterns in the intact brain.
In vivo functional diversity of midbrain dopamine neurons within identified axonal projections
(2019)
Functional diversity of midbrain dopamine (DA) neurons ranges across multiple scales, from differences in intrinsic properties and connectivity to selective task engagement in behaving animals. Distinct in vitro biophysical features of DA neurons have been associated with different axonal projection targets. However, it is unknown how this translates to different firing patterns of projection-defined DA subpopulations in the intact brain. We combined retrograde tracing with single-unit recording and labelling in mouse brain to create an in vivo functional topography of the midbrain DA system. We identified differences in burst firing among DA neurons projecting to dorsolateral striatum. Bursting also differentiated DA neurons in the medial substantia nigra (SN) projecting either to dorsal or ventral striatum. We found differences in mean firing rates and pause durations among ventral tegmental area (VTA) DA neurons projecting to lateral or medial shell of nucleus accumbens. Our data establishes a high-resolution functional in vivo landscape of midbrain DA neurons.
The dopamine (DA) system plays a major role in cognitive functions through its interactions with several brain regions including the prefrontal cortex (PFC). Conversely, disturbances in the DA system contribute to cognitive deficits in psychiatric diseases, yet exactly how they do so remains poorly understood. Here we show, using mice with disease-relevant alterations in DA signaling (D2R-OE mice), that deficits in working memory (WM) are associated with impairments in the WM-dependent firing patterns of DA neurons in the ventral tegmental area (VTA). The WM-dependent phase-locking of DA neurons to 4 Hz VTA-PFC oscillations is absent in D2R-OE mice and VTA-PFC synchrony deficits scale with their WM impairments. We also find reduced 4 Hz synchrony between VTA DA neurons and selective impairments in their representation of WM demand. These results identify how altered DA neuron activity—at the level of long-range network activity and task-related firing patterns—may underlie cognitive impairments.