Cellular and synaptic correlates of learning and memory and their impairment in a mouse model of Alzheimer's disease

Alzheimer's disease (AD) is characterized by synaptic dysfunction and progressive memory loss. The hippocampus is indispensable for memory processes and early affected by disease-associated pathology. It is still debated how in particular encoding and retrieval of memories is impaired in AD. Therefore, the current study investigated how individual neurons in the hippocampus encode a memory and whether this process is disturbed under AD-like conditions in a pre-clinical model. To achieve this goal a cutting-edge technology – two-photon in vivo imaging – was used to repetitively analyze the activity of neurons in the hippocampus throughout a hippocampus-dependent memory test. Initially, this study revealed two populations of hippocampal CA1 neurons that differ in their long-term activity: a subset of neurons was continuously active over several days, whereas another population showed variable activity. The latter provided the population that responded to memory encoding as well as retrieval and hence, formed the cellular memory trace, also known as engram. Interestingly, network activity and engram formation under AD-like conditions (APP/PS1 mice) was intact. However, a further analysis of neurons composing the "retrieval network" identified an additional neuronal ensemble in CA1 that superimposed the memory trace suggesting a causal relationship of memory trace superimposition and memory impairment. Indeed, mimicking superimposition by artificial activation of a non-related memory trace coding a different context caused reduced memory performance in healthy mice and thus, presents a potential mechanism for impaired memory retrieval in APP/PS1 mice. Furthermore, parvalbumin-expressing (PV+) interneurons in CA1 were indispensable for successful memory encoding and retrieval in healthy mice. Their functional impairment represented a potential explanation of the observed engram superimposition in APP/PS1 mice. Finally, a learning-related loss of synaptic connections was discovered on dendrites of CA1 pyramidal neurons in healthy mice suggesting a mechanism of synaptic selection important for encoding of new information. Learning-induced changes of synaptic connectivity were absent in APP/PS1 mice indicating that synaptic connectivity deficits might be causally related to memory trace superimposition and ultimately memory impairment under AD-like conditions. Summarized, the present study provides a refinement of the engram's characteristics and furthermore, identifies a novel mechanism of memory impairment on the cellular and synaptic level in a enmouse model of AD.Die Alzheimer-Krankheit (AD) ist durch synaptische Fehlfunktionen, eine Dysregulation des neuronalen Netzwerkes und darauf folgende Gedächtnisstörungen gekennzeichnet. Der Hippocampus ist für Lern- und Gedächtnisfunktionen unverzichtbar und sehr früh von der charakteristischen Pathologie der Krankheit betroffen. Wie genau die Bildung oder auch das Abrufen von Gedächtnisinhalten gestört wird, wurde noch nicht hinreichend geklärt. Die vorliegende Studie untersuchte die Beteiligung individueller Nervenzellen an der Bildung und dem Abrufen von Erinnerungen und eruiert mögliche Fehlfunktionen in einem präklinischen AD Model. Die Zwei-Photonen Intravitalmikroskopie wurde benutzt um repetitiv die Aktivität individueller Nervenzellen während einer hippocampus-abhängigen Lern- und Gedächtnisaufgabe zu verfolgen. Die untersuchte CA1-Region des Hippocampus wies hierbei zwei unterschiedliche Nervenzellpopulationen auf. Diese unterschieden sich hinsichtlich ihrer stabilen beziehungsweise wechselhaften Einbindung in das aktive Netzwerk. Nervenzellen letzterer Population wurden während des Lernens und Erinnerns in das aktive Netzwerk rekrutiert und somit als Träger der Erinnerung identifiziert, als sogenanntes Engramm. In einem Mausmodell, das Aspekte der Alzheimer-Krankheit repräsentiert (APP/PS1 Mäuse), wies die generelle Aktivität der CA1 Pyramidenzellen sowie das für den Erinnerungsprozess wichtige Engramm keine Abweichungen auf. Jedoch wurden im Erinnerungsnetzwerk der APP/PS1 Tiere zusätzlich aktivierte Nervenzellen identifiziert, die zu einer Überlagerung der Erinnerung und einer damit verbundenen Gedächtnisstörung führten. Durch künstliches Erzeugen dieser überlagernden Aktivität in experimentell gesunden Mäusen konnte ihre Gedächtnisfähigkeit vermindert und die Hypothese der Erinnerungsüberlagerung bestätigt werden. Des Weiteren wurde die Bedeutung von hippocampalen PV-positiven (PV+) Interneuronen bei Lern- und Gedächtnisprozessen bewiesen. Eine mögliche Unterfunktion ihrer hemmenden Leistung auf CA1 Pyramidenzellen könnte der vorher beschriebenen Überlagerung zugrunde liegen. Abschließend wurde ein durch Lernen induzierter Verlust von dendritischen Dornenfortsätzen im Stratum Radiatum der CA1 Pyramidenzellen gesunder Mäuse untersucht. Diese strukturelle Veränderung stellt einen potentiellen Selektionsmechanismus dar, der nicht in APP/PS1 Tieren nachgewiesen wurde. Zusammenfassend liefert die vorliegende Arbeit wichtige Erkenntnisse bezüglich der Charakteristika eines Engramms und deckt einen neuen Mechanismus der hippocampalen Gedächtnisstörung bei der Alzheimer-Krankheit auf

A global database of soil microbial phospholipid fatty acids and enzyme activities

Soil microbes drive ecosystem function and play a critical role in how ecosystems respond to global change. Research surrounding soil microbial communities has rapidly increased in recent decades, and substantial data relating to phospholipid fatty acids (PLFAs) and potential enzyme activity have been collected and analysed. However, studies have mostly been restricted to local and regional scales, and their accuracy and usefulness are limited by the extent of accessible data. Here we aim to improve data availability by collating a global database of soil PLFA and potential enzyme activity measurements from 12,258 georeferenced samples located across all continents, 5.1% of which have not previously been published. The database contains data relating to 113 PLFAs and 26 enzyme activities, and includes metadata such as sampling date, sample depth, and soil pH, total carbon, and total nitrogen. This database will help researchers in conducting both global- and local-scale studies to better understand soil microbial biomass and function

A global database of soil microbial phospholipid fatty acids and enzyme activities

Soil microbes drive ecosystem function and play a critical role in how ecosystems respond to global change. Research surrounding soil microbial communities has rapidly increased in recent decades, and substantial data relating to phospholipid fatty acids (PLFAs) and potential enzyme activity have been collected and analysed. However, studies have mostly been restricted to local and regional scales, and their accuracy and usefulness are limited by the extent of accessible data. Here we aim to improve data availability by collating a global database of soil PLFA and potential enzyme activity measurements from 12,258 georeferenced samples located across all continents, 5.1% of which have not previously been published. The database contains data relating to 113 PLFAs and 26 enzyme activities, and includes metadata such as sampling date, sample depth, and soil pH, total carbon, and total nitrogen. This database will help researchers in conducting both global- and local-scale studies to better understand soil microbial biomass and function

Effizientes Schmieren der Spanbildungszone/Controlled use of cooling lubricants for tribological optimization of machining processes – Efficient lubrication of the chip formation zone

Konventioneller Kühlschmierstoffeinsatz in der spanenden Fertigung führt zur Belastung von Umwelt und Gesundheit sowie zu erhöhten Fertigungskosten. Entsprechend weist der zielgerichtete Einsatz von Kühlschmierstoffen ein großes Potenzial zur nachhaltigen Gestaltung der Produktion auf, bringt jedoch auch zahlreiche technologische Herausforderungen mit sich. Durch die Kombination von experimenteller und simulativer Prozessanalyse lässt sich das Verhalten des Kühlschmierstoffs im Zerspanprozess verstehen und so ein gezielter Kühlschmierstoffeinsatz erreichen. &amp;nbsp; Conventional use of cutting fluids in machining processes leads to environmental pollution, causes health problems and increases production costs. Accordingly, controlled cutting fluid use shows a huge potential for a sustainable design of production. However, this entails technological challenges. A combination of experiments and simulations leads to a better understanding of the cutting fluid behavior and therefore, to a controlled cutting fluid application. </p

Chronic 2P-STED imaging reveals high turnover of dendritic spines in the hippocampus in vivo

Rewiring neural circuits by the formation and elimination of synapses is thought to be a key cellular mechanism of learning and memory in the mammalian brain. Dendritic spines are the postsynaptic structural component of excitatory synapses, and their experience-dependent plasticity has been extensively studied in mouse superficial cortex using two-photon microscopy in vivo. By contrast, very little is known about spine plasticity in the hippocampus, which is the archetypical memory center of the brain, mostly because it is difficult to visualize dendritic spines in this deeply embedded structure with sufficient spatial resolution. We developed chronic 2P-STED microscopy in mouse hippocampus, using a ‘hippocampal window’ based on resection of cortical tissue and a long working distance objective for optical access. We observed a two-fold higher spine density than previous studies and measured a spine turnover of ~40% within 4 days, which depended on spine size. We thus provide direct evidence for a high level of structural rewiring of synaptic circuits and new insights into the structure-dynamics relationship of hippocampal spines. Having established chronic super-resolution microscopy in the hippocampus in vivo, our study enables longitudinal and correlative analyses of nanoscale neuroanatomical structures with genetic, molecular and behavioral experiments

Tagger-A Swiss army knife for multiomics to dissect cell type-specific mechanisms of gene expression in mice

A deep understanding of how regulation of the multiple levels of gene expression in mammalian tissues give rise to complex phenotypes has been impeded by cellular diversity. A handful of techniques were developed to tag-select nucleic acids of interest in specific cell types, thereby enabling their capture. We expanded this strategy by developing the Tagger knock-in mouse line bearing a quad-cistronic transgene combining enrichment tools for nuclei, nascent RNA, translating mRNA, and mature microRNA (miRNA). We demonstrate that Tagger can capture the desired nucleic acids, enabling multiple omics approaches to be applied to specific cell types in vivo using a single transgenic mouse line.Funding Agencies|Knut and Alice Wallenberg Foundation; German Center for Neurodegenerative Diseases; German Research Foundation [SFB 1089]; ERA-NET NEURON (MicroSynDep, MicroSchiz); DFG; BMBF (IDSN) grant [BO4221, SFB 1286 Z2]; Helmholtz iMed grant; VW German-Israeli grant</p

THE EUROPEAN SHOCK SOCIETY MEETS THE IMMUNOSEP CONSORTIUM FOR PERSONALIZED SEPSIS TREATMENT

The unacceptable high mortality of severe infections and sepsis led over the years to understand the need for adjunctive immunotherapy to modulate the dysregulated host response of the host. However, not all patients should receive the same type of treatment. The immune function may largely differ from one patient to the other. The principles of precision medicine require that some biomarker is used to capture the immune function of the host and guide the best candidate therapy. This is the approach of the ImmunoSep randomized clinical trial (NCT04990232) where patients are allocated to treatment with anakinra or recombinant interferon gamma tailored to immune signs of macrophage activation-like syndrome and immunoparalysis respectively. ImmunoSep is a first-in-class paradigm of precision medicine for sepsis. Other approaches need to consider classification by sepsis endotypes, targeting T cell and application of stem cells. Basic principle for any trial to be successful is the delivery of appropriate antimicrobial therapy as standard-of-care taking into consideration not just the likelihood for resistant pathogens but also the pharmacokinetic/pharmacodynamic mode of action of the administered antimicrobial