Molecular mechanisms in mood regulation involving the circadian clock

The circadian system coordinates activities and functions in cells and tissues in order to optimize body functions in anticipation to daily changes in the environment. Disruption of the circadian system, due to irregular lifestyle such as rotating shift work, frequent travel across time-zones, or chronic stress, is correlated with several diseases such as obesity, cancer, and neurological disorders. Molecular mechanisms linking the circadian clock with neurological functions have been uncovered suggesting that disruption of the clock may be critically involved in the development of mood disorders. In this mini-review, I will summarize molecular mechanisms in which clock components play a central role for mood regulation. Such mechanisms have been identified in the monoaminergic system, the HPA axis, and neurogenesis.A plethora of human genetic studies have identified polymorphisms in clock genes that associate with psychiatric disorders [reviewed in Ref. (1)]. This suggested that abnormalities in clock genes may be one of the causes for the development of mood disorders. At the cellular level, clock genes (Bmal1, Clock, Per, Cry, Rev-erb, and Ror) make up an autoregulatory transcriptional/translational feedback loop with a period of about 24 h (Figure 1, top gray circle) [reviewed in Ref. (2)]. These clock genes and their proteins not only self-promote their own temporally fluctuating transcription but they also regulate transcription of target genes (Figure 1) and/or modulate key molecular pathways via protein–protein interactions, such as the monoaminergic system, the HPA axis, or neurogenic pathways

Orchestration of gene expression and physiology by the circadian clock

In mammals, the master circadian clock that drives many biochemical, physiological and behavioral rhythms is located in the suprachiasmatic nuclei (SCN) of the hypothalamus. Generation and maintenance of circadian rhythms rely on complex interlaced feedback loops based on transcriptional and posttranscriptional events involving clock genes and kinases. This clock serves the purpose to organize an organism’s biochemistry on a 24 h time scale thereby avoiding interference between biochemical pathways and optimizing performance. Synchronization to environmental 24 h oscillations tunes physiological processes optimally with nature. In this review, I briefly describe the principle of the clock mechanism, its synchronization to the environment and consequences on health when the circadian clock is disrupted

Circadian rhythms and sleep—the metabolic connection

The circadian system coordinates mammalian physiology and behavior with the environmental light-dark cycle. It allocates sleep to the inactivity phase using various mechanisms involving neurotransmitters, nuclear receptors, and protein kinases. These pathways are related to metabolism, indicating that the circadian system and sleep are connected via metabolic parameters. This suggests that organs other than the brain may "sleep.” A hypothetic view on this aspect is presented providing a different perspective on sleep regulatio

The Circadian Clock, Reward, and Memory

During our daily activities, we experience variations in our cognitive performance, which is often accompanied by cravings for small rewards, such as consuming coffee or chocolate. This indicates that the time of day, cognitive performance, and reward may be related to one another. This review will summarize data that describe the influence of the circadian clock on addiction and mood-related behavior and put the data into perspective in relation to memory processes

Circadian rhythms in murine pups develop in absence of a functional maternal circadian clock

A genetic approach was used to investigate whether the emergence of circadian rhythms in murine pups is dependent on a functional maternal clock. Arrhythmic females bearing either the mPer1Brdm1/Per2Brdm1 or mPer2Brdm1/Cry1-/- double-mutant genotype were crossed with wild-type males under constant darkness. The heterozygous offspring have the genetic constitution for a functional circadian clock. Individual pups born to arrhythmic mPer1Brdm1/Per2Brdm1 and mPer2Brdm1/Cry1-/- mothers in constant darkness without external zeitgeber developed normal circadian rhythms, but their clocks were less synchronized to each other compared to wild-type animals. These findings indicate that development of circadian rhythms does not depend on a functional circadian clock in maternal tissue, extending previous findings obtained from pups born to SCN-lesioned mothers

High amplitude phase resetting in Rev-Erba/Per1 double mutant mice

Over time, organisms developed various strategies to adapt to their environment. Circadian clocks are thought to have evolved to adjust to the predictable rhythms of the light-dark cycle caused by the rotation of the Earth around its own axis. The rhythms these clocks generate persist even in the absence of environmental cues with a period of about 24 hours. To tick in time, they continuously synchronize themselves to the prevailing photoperiod by appropriate phase shifts. In this study, we disrupted two molecular components of the mammalian circadian oscillator, Rev-Erbα and Period1 (Per1). We found that mice lacking these genes displayed robust circadian rhythms with significantly shorter periods under constant darkness conditions. Strikingly, they showed high amplitude resetting in response to a brief light pulse at the end of their subjective night phase, which is rare in mammals. Surprisingly, Cry1, a clock component not inducible by light in mammals, became slightly inducible in these mice. Taken together, Rev-Erbα and Per1 may be part of a mechanism preventing drastic phase shifts in mammals

Rationale

In der vorliegenden Arbeit sollen der Stand der Entwicklungen und der Nutzung sowie aktueller Trends im Bereich der Gesundheits-Apps dargelegt werden, wobei insbesondere vielversprechende Ansätze in der Prävention, Diagnostik/Therapie und Gesundheitsversorgung im Fokus stehen, wie beispielsweise die Versorgung chronisch kranker Patienten und älterer Menschen sowie der ländlichen Bevölkerung. Weitere Themenbereiche, auf die näher eingegangen werden soll, sind die Identifizierung von Risiken der Verwendung von Gesundheits-Apps, insbesondere im Hinblick auf Datenschutz und Datensicherheit, aber auch die Aufarbeitung von praktischen und regulatorischen Hürden für den Einsatz sinnvoller Anwendungen und Aufzeigen von Regelungsbedarfen. Zudem soll eine Übersicht über die ethischen Implikationen von Gesundheits-Apps und deren Anwendung in verschiedenen Kontexten gegeben werden. Um auf die Bedürfnisse einzelner Stakeholder, von Patientinnen und Patienten über professionelle Anwender bis hin zu Herstellern von Apps für den Bereich Gesundheit besser eingehen zu können, wird zusätzlich auf die mögliche Gestaltung notwendiger Hilfestellungen für jede der vorgenannten Gruppen eingegangen. Abschließend werden Handlungsfelder zur Beseitigung der identifizierten Hürden, die sowohl technischer als auch rechtlicher oder ethischer Natur sein können mit dem Ziel benannt, mögliche Risiken für alle Beteiligten zu minimieren und Möglichkeiten zur Förderung sinnvoller Anwendungen aufzuzeigen.The presented work is meant to provide insights into current developments and trends with respect to the use of mobile health apps. A special emphasis shall be placed on the areas of prevention, diagnostics and therapy as well as healthcare in general, for example regarding the care for patients with chronic conditions, elderly people or rural populations. Other important areas of interest are the identification of risks that may arise from using health apps, especially in the context of data protection and data security. An appraisal of the practical as well as regulatory hurdles one may encounter when using health related apps in various use cases is given along with a description of points where adaptations to existing regulations might be advised. In addition, the ethical implications of using health related apps in various contexts are outlined. In order to better respond to the needs of individual stakeholders, i.e. patients as well as medical professionals and developers of health apps, an outline of possible ways to support each of these groups is provided. Finally, the closing summary chapter describes important areas where action may be advised to be able to eliminate the identified hurdles, which may be technical in nature, but may also be due to legal or ethical concerns. This aims at minimizing potential risks for all those who are dealing with health related apps, but may also serve to provide insights into how relevant uses of mobile technologies in health contexts can be promoted

Chapter 13 – Orientation for Users of Health Apps

Eine Orientierung für Nutzerinnen und Nutzer ist nicht nur aufgrund der unübersichtlichen Marktsituation und der Marktdynamik vonnöten. Eine umfassende und aktuelle Überprüfung sämtlicher Gesundheits-Apps durch offizielle Stellen ist nicht realistisch. Zur Beurteilung und Einschätzung der Qualität und Vertrauenswürdigkeit von Apps gibt es variantenreiche Modelle mit unterschiedlichen Schwerpunkten, Methoden und Kennzeichnungen (Siegel, Kodizes, Zertifizierung), deren Ergebnisse Nutzerinnen und Nutzern eine Orientierungshilfe bieten sollen. Eine allumfassende, grenzübergreifende und praktikable Lösung gibt es bisher nicht. Es ist zu erwarten, dass auch in Zukunft mehrere Ansätze nötig sein werden, um den unterschiedlichen Anforderungen, die sich aus Einsatzart und -ort ergeben, gerecht zu werden. Zur Abhilfe wird die Förderung bzw. der Ausbau bestehender und die Implementierung neuer vertrauensbildender Maßnahmen empfohlen. Zunächst wäre ein Prozess aufzusetzen, der einen Konsens über Qualität und Vertrauenswürdigkeit unter allen Beteiligten erwirkt. Dieser soll die Basis für die Umsetzung von Maßnahmen bilden, die den transparenten Umgang mit Informationen zu Apps ebenso wie Prüfverfahren befördern und alle Beteiligten dazu befähigen, ihre jeweiligen Aufgaben im Kontext von Qualität und Vertrauenswürdigkeit verantwortungsbewusst wahrzunehmen. Zusätzlich müssen Maßnahmen, wie z.B. Kriterienkataloge geschaffen bzw. publik gemacht werden, die Anwenderinnen und Anwender in die Lage versetzen, sich selbst ein verlässliches Bild von den zur Verfügung stehenden Angeboten zu machen. Es wird die Einrichtung einer zentralen, öffentlichen und unabhängigen Informationsplattform empfohlen, die neben einer Informations- und Aufklärungsfunktion für alle Beteiligten auch als Austausch-, Planungs- und Koordinierungswerkzeug für die Initiierung, Abstimmung und Durchführung der Prozesse fungiert. Diese Plattform könnte vom Bundesministerium für Gesundheit (BMG), dem Bundesministerium für Wirtschaft und Energie (BMWi), dem Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM) und der Bundeszentrale für gesundheitliche Aufklärung (BZgA) betrieben werden.Providing orientation to users is a necessity, not least of all due to the complex and chaotic situation in the market and the market's dynamics. However, a comprehensive and up-to-date review of all health related apps by official bodies is not feasible. There are many different models that focus on various aspects and aim at providing users with insights into quality aspects as well as trustability of apps, for example codes of conduct, certifications or quality seals. However, there is currently no comprehensive and practical solution that works on an international level as well. It is to be expected that there will be a need for a number of different approaches to be able to adequately address all aspects arising from using apps in various settings. To remedy the situation, it is recommended to promote and implement new confidence building measures that include all stakeholders. First of all, it is necessary to reach consensus with respect to which aspects are to be included to adequately cover quality and trustability. This consensus will then serve as a basis for implementing measures that may support transparency on the one side, but may also be used to aid all those concerned in shouldering their responsibilities in the context of quality and trustability. This will require a clear definition of the necessary criteria users can employ and these must be compiled and made known. These criteria may also aid users with forming their own opinion with respect to the available apps. A central, publicly available and independent information platform should be established to be able to educate all stakeholders, but also to provide a means for communication as well as planning and coordination. This platform could for example be operated by the Federal Ministry of Health (BMG), the Federal Ministry for Economic Affairs and Energy (BMWi), the Federal Institute for Drugs and Medical Devices (BfArM) and Federal Centre for Health Education (BZgA)