Impact of Endocannabinoid Signaling on Cognitive Processing throughout Adolescence and Adulthood

The present thesis investigated the basal cognitive abilities, the influence of the endocannabinoid system (ECS), and developmental aspects throughout the adolescence in male Wistar rats. First, possible behavioral differences in three different lines of Wistar Han rats were analyzed and the W[rcc] line was selected for the subsequent experiments based on its best performance in the object recognition test and good performance in the prepulse inhibition (PPI) of the acoustic startle reflex (ASR). In the second project the basic ontogeny of various cognitive abilities was analyzed and the results revealed differential patterns of development across adolescence and early adulthood. Object recognition memory showed a non-linear development with a decrease in performance on postnatal (pd) 40, at the approx. onset of puberty. This decrease was ameliorated by the administration of the cannabinoid receptor 1 (CB1R) antagonist/inverse agonist SR141716 indicating an involvement of the developing ECS at this time point. Recency discrimination developed later than recognition memory but did not display variations across adolescence. In contrast, PPI of the ASR developed gradually revealing a continuing increase of startle amplitude and sensorimotor gating abilities until early adulthood (pd 100). Molecular analysis showed increased CB1R levels in the hippocampus (Hip) in early adolescence indicating an increased ECS around that age. Myelination, which is linked to improved cognitive skills, appeared to increase gradually in the Hip and in the caudate putamen (CPu). Altogether, different cognitive abilities displayed differential time-courses of development and alterations of the developing ECS are implicated underlying some of these behavioral patterns. Long-term effects of a chronic pubertal WIN 55,212-2 treatment on cognitive abilities in adulthood included a decreased object recognition memory in the W[rcc] line, which confirmed this animal model of schizophrenia for this rat line. Moreover, complex cognitive skills were investigated in an attentional set shift test (ASST) and an impaired reversal learning ability was found while other learning abilities did not differ from vehicle treated animals. This indicates specific deficits in reversal learning upon chronic interference with the developing ECS. Furthermore, molecular analysis showed increased CB1R levels in the medial prefrontal cortex (mPFC) indicating a possible developmental compensatory mechanism in this brain region after disturbances in this particular developmental time-window. In the fourth project no long-term effects of a chronic pubertal methylphenidate (MPH) treatment on various behavioral tests were observed in adulthood for locomotor activity, anxiety-related behavior, intake of liquids of variable palatability or cognitive processing. Thus, the presently employed MPH administration paradigm did not appear to cause long-term effects but further investigations may reveal other time-windows of vulnerability to MPH administration during development. Altogether, the present thesis revealed differential developmental patterns of cognitive abilities during adolescence of male Wistar rats which appear to be linked to the developing ECS and interference with this system at this vulnerable time period may impair cognitive skills in adulthood

AAV-Mediated Overexpression of the CB1 Receptor in the mPFC of Adult Rats Alters Cognitive Flexibility, Social Behavior, and Emotional Reactivity

The endocannabinoid (ECB) system is strongly involved in the regulation of cognitive processing and emotional behavior and evidence indicates that ECB signaling might affect these behavioral abilities by modulations of prefrontal cortical functions. The aim of the present study was to examine the role of the CB1 receptor in the medial prefrontal cortex (mPFC) on cognitive flexibility and emotional behavior. Therefore, the CB1 receptor was overexpressed by adeno-associated virus vector-mediated gene transfer specifically in the mPFC of adult Wistar rats. Animals were then tested in different anxiety-related paradigms for emotional reactivity [e.g., elevated plus maze (EPM), light/dark emergence test (EMT), social interaction] and the attentional set shift task (ASST) – an adaptation of the human Wisconsin card sorting test – for cognitive abilities and behavioral flexibility. A subtle increase in exploratory behavior was found in CB1 receptor overexpressing animals (CB1-R) compared to Empty vector injected controls (Empty) in the EMT and EPM, although general locomotor activity did not differ between the groups. During social interaction testing, social contact behavior toward the unknown conspecific was found to be decreased, whereas social withdrawal was increased in CB1-R animals and they showed an inadequate increase in exploratory behavior compared to control animals. In the ASST, impaired reversal learning abilities were detected in CB1-R animals compared to controls, indicating reduced behavioral flexibility. In conclusion, upregulation of the CB1 receptor specifically in the rat mPFC induces alterations in emotional reactivity, leads to inadequate social behavior, and impairs cognitive flexibility. These findings might be relevant for neuropsychiatric disorders, since higher cortical CB1 receptor expression levels as well as similar behavioral impairments as observed in the present study have been described in schizophrenic patients

Limitations in the recording of maternal mortality in Germany: An analysis of statistical challenges

Background: The World Health Organization (WHO) defines maternal mortality as the death of a woman during pregnancy or up to 42 days after delivery. The maternal mortality ratio (MMR) serves as an indicator of the quality of health care. In Germany, recording is based on the death certificate (ICD-10 code), with variations in documentation leading to underreporting. Studies indicate insufficient data in Berlin and queries in Germany. Method: 2,316 death certificates of women (aged 15 – 50) from the Berlin Central Archive (2019 – 2022) were analysed to identify maternal deaths and the quality of the information provided was assessed. In addition, the recording of pregnancy status on death certificates was examined nationwide. Results: Fourteen maternal deaths (excluding late cases according to the WHO) were identified. Only four cases were identifiable as maternal deaths solely on the basis of ICD-10 codes. The additional information ‘Is or was the woman pregnant?’ which is important for identification, was available in about a quarter of the death certificates reviewed. In 73.2 % of cases, the question ‘Is or was the woman pregnant?’ remained unanswered. A nationwide comparison of death certificates revealed considerable differences: only Bavaria and Bremen followed the WHO definition. Saxony-Anhalt does not record pregnancy status at all. Conclusion: The recording of maternal mortality in Germany is incomplete. Death certificates are often deficient. Many federal states record periods outside the WHO definition (3 –12 months after birth). A standardized national system for registering maternal deaths is required to improve data collection and enable better prevention.Peer Reviewe

Erfassungsdefizite bei der Müttersterblichkeit in Deutschland: Eine Analyse statistischer Herausforderungen

Hintergrund: Die Weltgesundheitsorganisation (WHO) definiert Müttersterblichkeit als den Tod einer Frau während der Schwangerschaft oder bis 42 Tage danach. Die maternale Mortalitätsrate (MMR) dient als Indikator für die Qualität der Gesundheitsversorgung. In Deutschland basiert die Erfassung auf dem Leichenschauschein (ICD-10-Code), wobei Variationen in der Dokumentation zu Untererfassung führen. Studien deuten auf unzureichende Angaben in Berlin und Abfragen in Deutschland hin. Methode: Es wurden 2.316 Leichenschauscheine von Frauen (15 – 50 Jahre) aus dem Berliner Zentralarchiv (2019 – 2022) zur Identifikation mütterlicher Todesfälle analysiert und die Ausfüllqualität bewertet. Zudem wurde bundesweit die Erfassung des Schwangerschaftsstatus auf den Leichenschauscheinen untersucht. Ergebnisse: 14 maternale Todesfälle (ohne späte Fälle laut WHO) wurden identifiziert. Nur vier Fälle waren allein durch ICD-10-Codes als mütterliche Todesfälle erkennbar. Die für die Identifikation wichtige Zusatzangabe „Ist oder war die Frau schwanger?“ war bei etwa einem Viertel der gesichteten Leichenschauscheine verfügbar. In 73,2 % der Fälle blieb die Frage „Ist oder war die Frau schwanger?“ unbeantwortet. Der bundesweite Vergleich der Leichenschauscheine zeigte erhebliche Unterschiede: Nur Bayern und Bremen folgten der WHO-Definition. Sachsen- Anhalt erfasst den Schwangerschaftsstatus gar nicht. Schlussfolgerung: Die Erfassung der Müttersterblichkeit in Deutschland ist lückenhaft. Leichenschauscheine sind häufig unvollständig ausgefüllt. Viele Bundesländer erfassen Zeiträume außerhalb der WHO-Definition (3 –12 Monate nach Geburt). Ein standardisiertes nationales System zur Registrierung von mütterlichen Todesfällen ist nötig, um die Datenerhebung zu verbessern und eine bessere Prävention zu ermöglichen.Peer Reviewe