Only watching others making their experiences is insufficient to enhance adult neurogenesis and water maze performance in mice

In the context of television consumption and its opportunity costs the question arises how far experiencing mere representations of the outer world would have the same neural and cognitive consequences than actively interacting with that environment. Here we demonstrate that physical interaction and direct exposition are essential for the beneficial effects of environmental enrichment. In our experiment, the mice living in a simple standard cage placed in the centre of a large enriched environment only indirectly experiencing the stimulus-rich surroundings (IND) did not display increased adult hippocampal neurogenesis. In contrast, the mice living in and directly experiencing the surrounding enriched environment (DIR) and mice living in a similar enriched cage containing an uninhabited inner cage (ENR) showed enhanced neurogenesis compared to mice in control conditions (CTR). Similarly, the beneficial effects of environmental enrichment on learning performance in the Morris Water maze depended on the direct interaction of the individual with the enrichment. In contrast, indirectly experiencing a stimulus-rich environment failed to improve memory functions indicating that direct interaction and activity within the stimulus-rich environment are necessary to induce structural and functional changes in the hippocampus

Effects of environmental enrichment and physical activity on hippocampal neurogenesis and spatial memory under physiological and pathological conditions in adult mice

Einleitung: Neurodegenerative Erkrankungen und das Altern gehen mit neuronalen Verlusten und kognitiven Defiziten einher. Häufig betroffen sind der Hippokampus und die hippokampusabhängige spatiale Kognition. Die gezielte Steigerung der im Hippokampus lokalisierten adulten Neurogenese bietet die Perspektive, neurodegenerativen Prozessen durch den Aufbau einer neurogenen Reserve entgegenzuwirken. In dieser Arbeit evaluieren wir in vier Mausmodellen das pro-neurogene und -kognitive Potenzial von Lebensstilinterventionen auf die hippokampale Neurogenese und die spatiale Kognition unter physiologischen und pathologischen Bedingungen. Methodik: Zum einen untersuchten wir ob die alleinige Wahrnehmung einer reizreichen Umgebung ausreichend ist, um als pro- neurogener und -kognitiver Lebensstil zu wirken. Zum anderen verglichen wir die Wirkung einer reizreichen Umgebung mit dem Therapeutikum Melatonin in einem Modell zirkadianer Dysrhythmie. Den Einfluss physischer Aktivität als einzelne Komponente eines aktiven Lebensstils untersuchten wir zum einen im Mausmodell einer hochkalorischen Ernährung und zum anderen im Dopamindepletionsmodell. Zur Beurteilung der hippokampalen Neurogenese verwendeten wir die BrdU-Inkorporationsmethode und quantifizierten sowie phänotypisierten immunhistologisch die BrdU+-Zellen. Die Hochleistungsflüssigkeitschromatographie und Polymerasekettenreaktion nutzten wir zur Evaluation des Dopaminstoffwechsels und im ELISA bestimmten wir Neurotrophine. Die Motorik der Tiere testeten wir im Rotarod und die spatiale Kognition im Morris-Wasserlabyrinth. Ergebnisse: Wir stellten fest, dass nur ein aktiver Lebensstil mit direkter Interaktion mit einer reizreichen Umgebung – und nicht die alleinige Wahrnehmung dieser – ausreichend ist, um proneurogen und pro-kognitiv zu wirken. Ein aktiver Lebensstil wirkte zwar ebenfalls unter zirkadianer Dysrhythmie pro-neurogen und konnte eine defizitäre neuronale Regeneration ausgleichen, jedoch konnte nur Melatonin zusätzlich die kognitiven Folgen kompensieren. Physische Aktivität, die simultan zu einer hochkalorischen Ernährung begonnen wurde, kann den negativen Folgen der Diät auf die spatiale Kognition durch Förderung der adulten hippokampalen Neurogenese ohne Modulation durch BDNF vorbeugen. Ähnlich positiv wirkte physische Aktivität im Dopamindepletionsmodell, indem die negativen Folgen der Dopamindepletion auf die hippokampale Neurogenese und die spatiale Kognition reduziert wurden und der pathologisch gesteigerte Dopaminumsatz wieder herunterreguliert wurde. Schlussfolgerung: Diese Arbeit zeigt, dass ein aktiver Lebensstil und physische Aktivität die hippokampale Neurogenese und spatiale Kognition sowohl unter physiologischen, als auch unter pathologischen Bedingungen positiv beeinflussen. Dabei haben sie jedoch nicht immer das Potenzial neuronale und kognitive Defizite vollständig zu kompensieren.Introduction: Neurodegenerative diseases and aging come along with neuronal loss and cognitive decline. The hippocampus and the hippocampus-dependent spatial cognition are commonly affected. The specific promotion of adult neurogenesis, localized in the hippocampus, offers the perspective to generate a neurogenic reserve for preventing neurodegenerative processes. In this thesis, we evaluate the pro-neurogenic and -cognitive potential of lifestyle interventions on hippocampal neurogenesis and spatial cognition under physiological und pathological conditions in four different mouse models. Methods: First, we investigated if the mere perception of an enriched environment is sufficient to act as a pro-neurogenic and -cognitive lifestyle. Second, we compared the effects of the lifestyle intervention environmental enrichment with the hormone melatonin in a model of circadian dysrhythmia. Furthermore, we investigated the influence of physical activity in a high-fat diet mouse model and in a model of dopamine depletion. We applied the BrdU- incorporation method to immunohistologically quantify and typify hippocampal neurogenesis. We used highperformance liquid chromatography and the polymerase chain reaction to evaluate the dopamine metabolism and determined neurotrophins in the enzyme-linked immunosorbent assay. In the Rotarod, we analysed the motor-abilities of the mice and in the Morris water maze, we tested spatial cognition. Results: Contrary to direct interaction with environmental enrichment, the mere perception of an enriched environment was insufficient to induce pro-neurogenic and pro-cognitive potential. Furthermore, interaction with environmental enrichment, resembling an active lifestyle, compensated the detrimental influence of circadian dysrhythmia on neural regeneration, but not on cognition. Meanwhile, melatonin prevented both neural and cognitive deficits. Physical activity simultaneously initiated with a high-fat diet prevented the consequences of the diet on hippocampal neurogenesis and spatial cognition without modulation by BDNF. Similar, physical activity reduced the neural and cognitive deficits in a model of dopamine depletion and downregulated a pathologically increased dopamine turnover. Conclusion: An active lifestyle and physical activity positively influence hippocampal neurogenesis and spatial cognition under physiological and pathological conditions. However, lifestyle interventions do not always have the potential to completely compensate neural and cognitive deficits

Multisensory input modulates memory-guided spatial navigation

Open source data, matlab-functions and R-scripts for box-plots and statistical analysis. XLSX-table contains data used for evaluation how multisensory input modulates spatial navigation. R-script for statistical analysis and R-script for box-plots. Matlab-functions to extract relevant parameters of memory-guided spatial navigation

Melatonin restores hippocampal neural precursor cell proliferation and prevents cognitive deficits induced by jet lag simulation in adult mice

Frequent flyers and shift workers undergo circadian dysrhythmia with adverse impact on body and mind. The circadian rhythm disorder jet lag disturbs hippocampal neurogenesis and spatial cognition, which represent morphological and functional adult brain plasticity. This raises the question if pro-neurogenic stimuli might prevent those consequences. However, suitable measures to mitigate jet lag-induced adverse effects on brain plasticity have been neglected so far. Here, we used adult C57Bl6 mice to investigate the pro-neurogenic stimuli melatonin (8 mg/kg i.p.) as well as environmental enrichment as potential measures. We applied photoperiod alterations to simulate jet lag by shortening the dark period every third day by 6 hours for 3 weeks. We found that jet lag simulation reduced hippocampal neural precursor cell proliferation by 24% and impaired spatial memory performance in the water maze indicated by a prolonged swim path to the target (similar to 23%). While melatonin prevented both the cellular (similar to 1%) as well as the cognitive deficits (similar to 5%), environmental enrichment only preserved precursor cell proliferation (similar to 12%). Our results indicate that lifestyle interventions are insufficient to completely compensate jet lag-induced consequences. Instead, melatonin is required to prevent cognitive impairment caused by the same environmental factors to which frequent flyers and shift workers are typically exposed to

Memory consolidation affects the interplay of place and response navigation

Navigation through space is based on memory representations of landmarks (‘place’) or movement sequences (‘response’). Over time, memory representations transform through consolidation. However, it is unclear how the transformation affects place and response navigation in humans. In the present study, healthy adults navigated to target locations in a virtual maze. The preference for using place and response strategies and the ability to recall place and response memories were tested after a delay of one hour (n = 31), one day (n = 30), or two weeks (n = 32). The different delays captured early-phase synaptic changes, changes after one night of sleep, and long-delay changes due to the reorganization of navigation networks. Our results show that the relative contributions of place and response navigation changed as a function of time. After a short delay of up to one day, participants preferentially used a place strategy and exhibited a high degree of visual landmark exploration. After a longer delay of two weeks, place strategy use decreased significantly. Participants now equally relied on place and response strategy use and increasingly repeated previously taken paths. Further analyses indicate that response strategy use predominantly occurred as a compensatory strategy in the absence of sufficient place memory. Over time, place memory faded before response memory. We suggest that the observed shift from place to response navigation is context-dependent since detailed landmark information, which strongly relied on hippocampal function, decayed faster than sequence information, which required less detail and depended on extra-hippocampal areas. We conclude that changes in place and response navigation likely reflect the reorganization of navigation networks during systems consolidation

Memory-guided navigation in Amyotrophic Lateral Sclerosis

Previous studies provided conflicting results on hippocampal involvement in nondemented patients with amyotrophic lateral sclerosis (ALS). We investigated whether tests of memory-guided navigation, i.e., a behavior that depends heavily on the hippocampus, could reveal behavioral correlates of hippocampal dysfunction in non-demented ALS patients. We conducted a prospective study of spatial cognition in 43 ambulatory, non-demented ALS patients and 43 healthy controls. We used a virtual navigation task ("starmaze") derived from animal research and previously used in studies of hippocampal function. In addition, we performed the following neuropsychological tests: SPART, 10/36 Spatial Recall Test; 5PT, Five-Point Test; and PTSOT, Perspective Taking/Spatial Orientation Test. Here we store the data acquired in the experiment and analysed to gain insight into hippocampal dysfunction of patients with ALS. Furthermore, this storage contains the matlab-functions for data analysis

The dark matter of the cancer genome: aberrations in regulatory elements, untranslated regions, splice sites, non-coding RNA and synonymous mutations

This paper deals with the use of reported speech (RS) in Spanish criminal lawsuits (querellas) and police reports (denuncias) and argues about the most suitable strategies to translate such RS into Italian. In line of principle, the written record of the statements made by the individual(s) who filed the complaint is often the result of an oral cooperation between the plaintiff and the police officer and/or their attorney, whose subjectivity is reflected on the texts in a quite different fashion in the two legal cultures. The so-called ‘verbatim assumption’ of quotations in direct speech (DS) turns out to be a fallacy in the discussed genres, insofar as the locutor (i.e. the police officer or the attorney responsible for the drafting of the document) often normalizes the original utterances of the enunciator (i.e. the plaintiff whose point of view is represented in the report) in terms of cohesion, register and sentence length. Usually, these texts are translated following a strictly ‘interlinear approach’, so much so as to result almost illegible. An adequate command  of genre conventions – both in the source and in the target language – and the abidance by the translation universals of simplification and explicitation may help the translator produce a more efficient and readable target text, consistent with the expectations of a jurist in the target culture

The dark matter of the cancer genome: aberrations in regulatory elements, untranslated regions, splice sites, non-coding RNA and synonymous mutations

Cancer is a disease of the genome caused by oncogene activation and tumor suppressor gene inhibition. Deep sequencing studies including large consortia such as TCGA and ICGC identified numerous tumor‐specific mutations not only in protein‐coding sequences but also in non‐coding sequences. Although 98% of the genome is not translated into proteins, most studies have neglected the information hidden in this “dark matter” of the genome. Malignancy‐driving mutations can occur in all genetic elements outside the coding region, namely in enhancer, silencer, insulator, and promoter as well as in 5′‐UTR and 3′‐UTR. Intron or splice site mutations can alter the splicing pattern. Moreover, cancer genomes contain mutations within non‐coding RNA, such as microRNA, lncRNA, and lincRNA. A synonymous mutation changes the coding region in the DNA and RNA but not the protein sequence. Importantly, oncogenes such as TERT or miR‐21 as well as tumor suppressor genes such as TP53/p53,APC,BRCA1, or RB1 can be affected by these alterations. In summary, coding‐independent mutations can affect gene regulation from transcription, splicing, mRNA stability to translation, and hence, this largely neglected area needs functional studies to elucidate the mechanisms underlying tumorigenesis. This review will focus on the important role and novel mechanisms of these non‐coding or allegedly silent mutations in tumorigenesis