Persistent Hyperdopaminergia Decreases the Peak Frequency of Hippocampal Theta Oscillations during Quiet Waking and REM Sleep

Long-term changes in dopaminergic signaling are thought to underlie the pathophysiology of a number of psychiatric disorders. Several conditions are associated with cognitive deficits such as disturbances in attention processes and learning and memory, suggesting that persistent changes in dopaminergic signaling may alter neural mechanisms underlying these processes. Dopamine transporter knockout (DAT-KO) mice exhibit a persistent five-fold increase in extracellular dopamine levels. Here, we demonstrate that DAT-KO mice display lower hippocampal theta oscillation frequencies during baseline periods of waking and rapid-eye movement sleep. These altered theta oscillations are not reversed via treatment with the antidopaminergic agent haloperidol. Thus, we propose that persistent hyperdopaminergia, together with secondary alterations in other neuromodulatory systems, results in lower frequency activity in neural systems responsible for various cognitive processes

Mice with reduced DAT levels recreate seasonal-induced switching between states in bipolar disorder.

Developing novel therapeutics for bipolar disorder (BD) has been hampered by limited mechanistic knowledge how sufferers switch between mania and depression-how the same brain can switch between extreme states-described as the "holy grail" of BD research. Strong evidence implicates seasonally-induced switching between states, with mania associated with summer-onset, depression with winter-onset. Determining mechanisms of and sensitivity to such switching is required. C57BL/6J and dopamine transporter hypomorphic (DAT-HY 50% expression) mice performed a battery of psychiatry-relevant behavioral tasks following 2-week housing in chambers under seasonally relevant photoperiod extremes. Summer-like and winter-like photoperiod exposure induced mania-relevant and depression-relevant behaviors respectively in mice. This behavioral switch paralleled neurotransmitter switching from dopamine to somatostatin in hypothalamic neurons (receiving direct input from the photoperiod-processing center, the suprachiasmatic nucleus). Mice with reduced DAT expression exhibited hypersensitivity to these summer-like and winter-like photoperiods, including more extreme mania-relevant (including reward sensitivity during reinforcement learning), and depression-relevant (including punishment-sensitivity and loss-sensitivity during reinforcement learning) behaviors. DAT mRNA levels switched in wildtype littermate mice across photoperiods, an effect not replicated in DAT hypomorphic mice. This inability to adjust DAT levels to match photoperiod-induced neurotransmitter switching as a homeostatic control likely contributes to the susceptibility of DAT hypormophic mice to these switching photoperiods. These data reveal the potential contribution of photoperiod-induced neuroplasticity within an identified circuit of the hypothalamus, linked with reduced DAT function, underlying switching between states in BD. Further investigations of the circuit will likely identify novel therapeutic targets to block switching between states

GBR 12909 administration as a mouse model of bipolar disorder mania: mimicking quantitative assessment of manic behavior

Mania is a core feature of bipolar disorder (BD) that traditionally is assessed using rating scales. Studies using a new human behavioral pattern monitor (BPM) recently demonstrated that manic BD patients exhibit a specific profile of behavior that differs from schizophrenia and is characterized by increased motor activity, increased specific exploration, and perseverative locomotor patterns as assessed by spatial d. It was hypothesized that disrupting dopaminergic homeostasis by inhibiting dopamine transporter (DAT) function would produce a BD mania-like phenotype in mice as assessed by the mouse BPM. We compared the spontaneous locomotor and exploratory behavior of C57BL/6J mice treated with the catecholamine transporter inhibitor amphetamine or the selective DAT inhibitor GBR 12909 in the mouse BPM. We also assessed the duration of the effect of GBR 12909 by testing mice in the BPM for 3 h and its potential strain dependency by testing 129/SvJ mice. Amphetamine produced hyperactivity and increased perseverative patterns of locomotion as reflected in reduced spatial d values but reduced exploratory activity in contrast to the increased exploration observed in BD patients. GBR 12909 increased activity and reduced spatial d in combination with increased exploratory behavior, irrespective of inbred strain. These effects persisted for at least 3 h. Thus, selectively inhibiting the DAT produced a long-lasting cross-strain behavioral profile in mice that was consistent with that observed in manic BD patients. These findings support the use of selective DAT inhibition in animal models of the impaired dopaminergic homeostasis putatively involved in the pathophysiology of BD mania

Koaptation der Mitralklappensegel während des MitraClip-Eingriffs - Relevanz für die Reduktion der Mitralklappeninsuffizienz

Da es viele Menschen gibt, die unter einer Mitralinsuffizienz leiden und eine Ope- ration für einen beachtlichen Teil dieser Patienten aufgrund ihrer Erkrankungen ein großes Risiko darstellt, sind kathetergestützte Alternativen essentiell. Eine hiervon ist der MitraClip®, dessen Effektivität Gegenstand der Untersuchungen in dieser Studie war. Dabei wurden verschiedene Parameter an der Mitralklappe ausgemessen und diese zu verschiedenen Zeitpunkten miteinander und mit dem klinischen Outcome des Eingriffs verglichen. Es konnte gezeigt werden, dass die Implantation eines MitraClips® durch eine Verkleinerung des Klappendurchmes- sers und die Verkürzung der Segel zu einer deutlichen Verbesserung der Mitra- linsuffizienz führen kann. Der MitraClip® ist somit weiterhin aus der Behandlung der Mitralinsuffizienz nicht mehr wegzudenken. Zudem wurden die Länge des vorderen Mitralsegels und die Größe des anterio-posterioren Durchmessers als geeignete Parameter für eine Prognose bezüglich des Erfolgs eines Eingriffs her- ausgearbeitet. Die Länge des vorderen Mitralsegels kann zusätzlich für eine Vor- hersage über die Anzahl der benötigten Griffversuche zum Implantieren eines Clips herangezogen werden

Government Arms Exports Behavior as a Predictor of Importance of Foreign Policy Goals: The Case of Germany's Arms Exports to the Middle East

武器出口與外交政策: 以德國為例Informed by realist and liberalist theory, conditions for a logical relationship between arms exports and the relative importance of foreign policy goals are evaluated as part of a case study of Germany’s arms export behavior to three Middle Eastern states. Apparent contradictions between foreign policy goals are resolved, using only data of arms export behavior and constructing a gradient of importance of different policy goals, some consistent with realist predictions, some consistent with liberal predictions. Overall, no theoretical framework describes German government behavior to a degree of being able to make reliable predictions for future action. Therefore usage of empirical data including actions with significant political ramifications, such as arms export behavior, is highly suggested for future research on German foreign policy instead

Impact of preconditioning with retinoic acid during early development on morphological and functional characteristics of human induced pluripotent stem cell-derived neurons

Human induced pluripotent stem cells (hiPSCs) are a suitable tool to study basic molecular and cellular mechanisms of neurodevelopment. The directed differentiation of hiPSCs via the generation of a self-renewable neuronal precursor cell line allows the standardization of defined differentiation protocols. Here, we have investigated whether preconditioning with retinoic acid during early neural induction impacts on morphological and functional characteristics of the neuronal culture after terminal differentiation. For this purpose we have analyzed neuronal and glial cell markers, neuronal outgrowth, soma size, depolarization-induced distal shifts of the axon initial segment as well as glutamate-evoked calcium influx. Retinoic acid preconditioning led to a higher yield of neurons vs. glia cells and longer axons than unconditioned controls. In contrast, glutamatergic activation and depolarization induced structural plasticity were unchanged. Our results show that the treatment of neuroectodermal cells with retinoic acid during early development, i.e. during the neurulation phase, increases the yield of neuronal phenotypes, but does not impact on the functionality of terminally differentiated neuronal cells