Real-time imaging of hippocampal network dynamics reveals trisynaptic induction of CA1 LTP and "circuit-level" effects of chronic stress and antidepressants

Today’s pervasive presence of stress renders stress-related psychiatric disorders (SRPDs), a relevant global health problem. Memory impairment is a major symptom likely mediated by the hippocampus (HIP), a limbic brain region highly vulnerable to stress. Recent evidence suggests that information processing problems within specific neuronal networks might underlie SRPDs. However, the precise functional neurocircuitry that mediates hippocampal CA1 long-term potentiation (LTP), a putative correlate of mammalian learning and memory, remains unknown at present. Furthermore, valuable assays for studying stress and drug effects on polysynaptic activity flow through the classical input/output circuit of the HIP are missing. To engage a circuit-centered approach, voltage-sensitive dye imaging was applied in mouse brain slices. Single pulse entorhinal cortex (EC) to dentate gyrus (DG) input, evoked by perforant path stimulation, entailed strong neuronal activity in the DG, but no distinct neuronal activity in the CA3 and CA1 subfield of the HIP. In contrast, a thetafrequency (5 Hz) stimulus train induced waves of neuronal activity percolating through the entire hippocampal trisynaptic circuit (HTC-waves). Spatially restricted blocking of glutamate release at CA3 mossy fiber synapses caused a complete disappearance of HTC-waves, suggesting frequency facilitation at DG to CA3 synapses the pivotal gating mechanism. In turn, non-theta frequency stimulations (0.2/1/20 Hz) proved much less effective at generating HTC-waves. CA1 long-term potentiation (CA1 LTP) is the best understood form of synaptic plasticity in the brain, but predominantly at the monosynaptic level. Here, HTC-waves comprise high-frequency firing of CA3 pyramidal neurons (>100 Hz), inducing NMDA receptordependent CA1 LTP within a few seconds. Detailed examination revealed the existence of an induction threshold for LTP. Consequently, baseline recordings with a reduced number of HTC-waves were carried out to test the effects of memory enhancing drugs and HPA axis hormones on hippocampal network dynamics. Bath application of caffeine (5 mM), corticosterone (100 nM) and corticotropin-releasing hormone (5 & 50 nM) rapidly boosted HTC-waves. Cognitive processes taking place within the HIP are challenged by stress exposure, but whether and how chronic stress shapes "net" neuronal activity flow through the HIP remains elusive. The HTC-wave assay, refined for group comparisons, revealed that chronic stress markedly lowers the strength of evoked neuronal activity propagation through the hippocampal trisynaptic circuit. In contrast, antidepressants (ADs) of several classes, the mood stabilizer lithium, the anesthetic ketamine, and the neurotrophin brainderived neurotrophic factor amplified HTC-waves. An opposite effect was obtained with the antipsychotic haloperidol and the anxiolytic diazepam. The tested ADs exert this effect at low micromolar concentrations, but not at 100 nM, and nearly always, also not at 500 nM. Furthermore, the AD fluoxetine was found to facilitate LTP of HTC-waves. Finally, pharmacological blockade of the tyrosine-related kinase B receptor abolished fluoxetine effects on HTC-waves. These results highlight a circuit-centered approach suggesting evoked synchronous theta rhythmical firing of EC principal cells as a valuable tool to investigate several aspects of neuronal activity flow through the HIP. The physiological relevance is emphasized by the finding that the resulting HTC-waves, which likely occur during EC theta oscillations, evoke NMDA receptor-dependent CA1 LTP within a few seconds. Furthermore, HTC-waves allow to integrate molecular, cellular and structural adaptations in the HIP, pointing to a monoaminergic neurotransmission-independent, "circuit-level" mechanism of ADs, to balance the detrimental effects of chronic stress on HIP-dependent cognitive abilities

High-Speed imaging reveals opposing effects of chronic stress and antidepressants on neuronal activity propagation through the hippocampal trisynaptic circuit

Antidepressants (ADs) are used as first-line treatment for most stress-related psychiatric disorders. The alterations in brain circuit dynamics that can arise from stress exposure and underlie therapeutic actions of ADs remain, however, poorly understood. Here, enabled by a recently developed voltage-sensitive dye imaging assay in mouse brain slices, we examined the impact of chronic stress and concentration-dependent effects of eight clinically used ADs (belonging to different chemical/functional classes) on evoked neuronal activity propagations through the hippocampal trisynaptic circuitry (HTC: perforant path - dentate gyrus - area CA3 - area CA1). Exposure of mice to chronic social defeat stress led to markedly weakened activity propagations (HTC-Waves). In contrast, at concentrations in the low micromolar range, all ADs, which were bath applied to slices, caused an amplification of HTC-Waves in CA regions (invariably in area CA1). The fast-acting antidepressant ketamine, the mood stabilizer lithium, and brain-derived neurotrophic factor (BDNF) exerted comparable enhancing effects, whereas the antipsychotic haloperidol and the anxiolytic diazepam attenuated HTC-Waves. Collectively, we provide direct experimental evidence that chronic stress can depress neuronal signal flow through the HTC and demonstrate shared opposing effects of ADs. Thus, our study points to a circuit-level mechanism of ADs to counteract stress-induced impairment of hippocampal network function. However, the observed effects of ADs are impossible to depend on enhanced neurogenesis

Hippo Signaling: Emerging Pathway in Stress-Related Psychiatric Disorders?

Discovery of the Hippo pathway and its core components has made a significant impact on our progress in the understanding of organ development, tissue homeostasis, and regeneration. Upon diverse extracellular and intracellular stimuli, Hippo signaling regulates stemness, cell proliferation and apoptosis by a well-conserved signaling cascade, and disruption of these systems has been implicated in cancer as well as metabolic and neurodegenerative diseases. The central role of Hippo signaling in cell biology also results in prominent links to stress-regulated pathways. Genetic variations, epigenetically provoked upregulation of Hippo pathway members and dysregulation of cellular processes implicated in learning and memory, are linked to an increased risk of stress-related psychiatric disorders (SRPDs). In this review, we summarize recent findings, supporting the role of Hippo signaling in SRPDs by canonical and non-canonical Hippo pathway interactions

Aid Effectiveness in the Democratic Republic of Congo: A Case Study Investigating the Factors Influencing Ineffective Aid

This article examines aid effectiveness in the Democratic Republic of Congo (DRC). It first discusses how to best measure aid effectiveness. Then, it investigates several contributing factors to the DRC’s current developmental predicaments. To accomplish these, the concepts of Paul Collier’s traps, Erik Reinert’s development theory, and the indicators of the Paris Declaration on Aid Effectiveness are utilised as explanatory tools. These variables are combined to seek a holistic approach in investigating the reasons behind the lack of aid effectiveness. A history of conflict is explored and constructs a setting for the DRC’s precarious reality and it is argued that the DRC’s sustained, long-term conflict is one of the main reasons for aid ineffectiveness. Furthermore, the state of industry and the idea of welfare colonialism as detrimental to aid effectiveness in the context of the DRC are explored. Additionally, an investigation of the implementation of the Paris Declaration on Aid Effectiveness and the actions of donor countries is provided. This leads to a critique of the practical implementation of aid in the DRC. The conclusion argues for an overall lack of aid effectiveness which has been aggravated by long-term conflict, poor governance, lack of industry, and a dysfunctional Paris Declaration

The use of the laryngeal tube disposable by paramedics during out-of-hospital cardiac arrest: a prospectively observational study (2008–2012

Summary: In the previous and the current guidelines of the European Resuscitation Council (ERC), endotracheal intubation (ETI), as an instrument for ventilation during resuscitation, was confirmed as less important for paramedics not trained in this method. For those, during resuscitation, the laryngeal tube is recommended by the ERC as a supraglottic airway device. The present study investigated prospectively the use of the laryngeal tube disposable (LT-D) by paramedics in prehospital emergency cases. Methods: During a 42-month period (Sept 2008–Feb 2012), we prospectively registered all prehospital cardiac arrest situations in which the LT-D had been applied by paramedics (from one emergency medical service in Germany). Results: During the defined period, 133 attempts, recorded on standardised data sheets, were enrolled into the investigation. Three were excluded from the study because of use during a trauma situation. Therefore, 130 patients were evaluated in this study. For this, the LT-D was used in 98% of all cases during resuscitation, and in about 2% of other emergencies (eg, trauma). With regard to resuscitation, adequate ventilation/oxygenation was described as possible in 83% of all included cases. In 66% of all cases, no problems concerning the insertion of the LT-D were described by the paramedics. No significant problems were reported in 93%. In 7% (n=9 cases), no insertion of the LT-D was possible. Instead of bag-mask-valve ventilation, the LT-D was used as a first-line airway device in about 66%. Between the two defined groups, no statistically significant differences were found (p>0.05). Conclusions: As an alternative airway device during resuscitation, recommended by the ERC in 2005 and 2010, the LT-D may enable ventilation rapidly and, as in most of our described cases, effectively. Additionally, by using the LT-D in a case of cardiac arrest, a reduced ‘hands-off time’ and, therefore, a high chest compression rate may be possible. Our investigation showed that the LT-D was often used as an alternative to bag-mask-ventilation and to ETI as well. However, we were able to describe more problems in the use of the LT-D than earlier investigations. Therefore, in future, more studies concerning the use of alternative airway devices in comparison with ETI and/or video-laryngoscopy seem to be necessary

Shaping a screening file for maximal lead discovery efficiency and effectiveness: elimination of molecular redundancy

High Throughput Screening (HTS) is a successful strategy for finding hits and leads that have the opportunity to be converted into drugs. In this paper we highlight novel computational methods used to select compounds to build a new screening file at Pfizer and the analytical methods we used to assess their quality. We also introduce the novel concept of molecular redundancy to help decide on the density of compounds required in any region of chemical space in order to be confident of running successful HTS campaigns

Populist Mobilization: A New Theoretical Approach to Populism*

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/112280/1/j.1467-9558.2011.01388.x.pd

Measurement of t(t)over-bar normalised multi-differential cross sections in pp collisions at root s=13 TeV, and simultaneous determination of the strong coupling strength, top quark pole mass, and parton distribution functions

Peer reviewe