Maternal immune activation transgenerationally modulates maternal care and offspring depression-like behavior

AbstractGestational infection is increasingly being recognized for its involvement as causative mechanism in severe developmental brain abnormalities and its contribution to the pathogenesis of psychopathologies later in life. First observations in the widely accepted maternal immune activation (MIA) model based upon the systemic administration of the viral mimetic Polyinosinic:polycytidylic acid (poly(I:C)) have recently suggested a transmission of behavioral and transcriptional traits across generations. Although maternal care behavior (MCB) is known as essential mediator of the transgenerational effects of environmental challenges on offspring brain function and behavior, the possible propagation of alterations of MCB resulting from MIA to following generations has not yet been examined. Here we show that poly(I:C) stimulation at embryonic day 12.5 (E12.5) leads to aberrant MCB and that this effect is transmitted to the female F1 offspring. The transgenerational effects on MCB are paralleled by enhanced depression-like behavior in the second generation F2 offspring with contributions of both maternal and paternal heritages. Examination of offspring hippocampal expression of genes known as targets of MCB and relevant for ensuing non-genetic transmission of altered brain function and behavior revealed transgenerationally conserved and modified expressional patterns in the F1 and F2 generation.Collectively these data firstly demonstrate the transgenerational transmission of the impact of gestational immune activation on the reproductive care behavior of the mother. Behavioral and molecular characteristics of first and second generation offspring suggest transgenerationally imprinted consequences of gestational infection on psychopathological traits related to mood disorders which remain to be examined in future cross-fostering experiments

microRNA expression in learned safety

Hintergrund: Signale der Sicherheit zu identifizieren und darauf zu reagieren ist notwendig um chronischen Stress und entsprechende Psychopathologien vorzubeugen. Gelernte Sicherheit beinhaltet Lernprozesse, welche zur Hemmung von Angst führen können. Die Amygdala ist eine Gehirnregion in der ein für gelernte Sicherheit spezifisches Genexpressionsmuster nachgewiesen wurde. Das Ziel der hier vorliegenden Masterarbeit ist es zu untersuchen, wie Genexpression in der Amygdala während gelernter Sicherheit reguliert wird, mit einem auf microRNAs gerichteten Fokus. Methoden: In einem ersten Experiment wurden die Expressionslevels von elf microRNAs in Gewebe der Amygdala von gelernter Sicherheit und gelernter Angst trainierten Mäusen durch qRT-PCR analysiert. In einem zweiten Experiment wurde die Expression der selben elf microRNAs in für gelernte Angst trainierten Mäusen mit Ton-allein und Schock-allein Mäusen verglichen. Schlussendlich wurde eine bioinformatische Untersuchung durchgeführt um nach potentiell durch die microRNAs regulierten Genen zu suchen. Ergebnisse: Es wurde gefunden, dass sich die Expression von fünf microRNAs in der Amygdala von für gelernte Sicherheit und gelernte Angst trainierten Mäusen signifikant unterscheidet. Keine Unterschiede in der Expression dieser microRNAs wurde in der Amygdala von für gelernte Angst trainierten im Vergleich zu Ton-allein und Schock-allein Mäusen gefunden. Durch die bioinformatische Untersuchung wurden mehrere Gene entdeckt, die potentiell durch microRNAs mit für gelernte Sicherheit spezifischer Expression reguliert sein könnten. Diskussion: Die selektive Modulierung der Expression von fünf verschiedenen microRNAs in der Amygdala aufgrund von gelernter Sicherheit legt nahe, dass diese microRNAs für die Regulation von unterschiedlichen Genen verantwortlich sind, die die molekulare Basis der gelernter Sicherheit zugrunde liegenden neuronalen Mechanismen formen.Background: To detect and interpret safety signals and moreover to react appropriately to those signals is crucial for mental health. Learned safety involves learning about signals indicating protection from danger, thus modulating fear responses. The amygdala is a brain region where specific gene expression changes resulting from safety learning have been observed in mice. The aim of the present study is to try to understand how gene expression in the amygdala during learned safety is regulated focusing on the role of microRNAs. Methods: In a first experiment, expressional levels of 11 miRNAs were analyzed in amygdala tissue of learned safety and learned fear trained control mice by qRT-PCR. In a second experiment, expression of the same 11 miRNAs was analyzed in mice trained in a learned fear paradigm and compared to tone alone and shock alone controls. Finally, a bioinformatical scan was performed, to search for potential microRNA target genes. Results: Amygdala expression of 5 miRNAs has been found to differ significantly between learned safety and learned fear trained animals. No differences in the expression of these miRNAs were found between learned fear and tone-alone and shock-alone control groups. A bioinformatical scan revealed various potential target genes for the miRNAs with learned safety specific expression related to stress and depression. Discussion: The selective modulation of expression of 5 specific miRNAs in the amygdala following learned safety suggests that these miRNAs may account for the regulation of various target genes forming the molecular basis for the neural mechanisms underlying learned safety

The role of microRNAs in learned safety

Entsprechend der Tatsache dass Angst durch Lernprozesse generiert und verstärkt werden kann, ist es möglich Angst durch Lernvorgänge spezifisch zu inhibieren. Konditionierte Inhibierung von Angst beinhaltet das Lernen von Signalen die Sicherheit bedeuten und wird aus diesem Grund „Gelernte Sicherheit“ genannt. Gelernte Sicherheitssignale inhibieren Angstreaktionen und führen zu Episoden von Sicherheit, doch darüber hinaus sind sie mit positiven Gefühlszuständen und dem Belohnungssystem verbunden und reduzieren depressionsartiges Verhalten in Mäusen. Dementsprechend kann Gelernte Sicherheit als Paradigma in dem Sub-Konstrukt der „Belohnungsvorhersage“ des positiven Wertigkeitssystem in dem neu etablierten „Research Domain criteria“ System für Neuropsychiatrische Forschung eingeordnet werden. Während einige der zugrundeliegenden neuralen Prozesse der Gelernten Sicherheit schon bekannt sind, sind die molekularen Mechanismen noch unvollständig aufgeklärt. In der vorliegende Dissertation wurde die Rolle von microRNAs (miRNAs)- kurze RNAs welche die Genexpression auf post-transkriptioneller Ebene regulieren- in der Gelernten Sicherheit untersucht. Im Detail wurde der Einfluss von ausgewählten miRNA Spezies (aus der miR-212/-132 Familie) auf die Verhaltensäußerung in Gelernter Sicherheit untersucht. In-silico und in-vitro Experimente wurden dann angewendet um mögliche für die Gelernte Sicherheit relevante und durch miR-132 regulierte Gene zu finden. Die vorliegenden Ergebnisse beinhalten eine Vielfalt von Analytischen Ebenen des Verhaltenszustandes bei der Gelernten Sicherheit, mit dem Schwerpunkt auf mehreren relevanten molekularen Prozessen.As fear can be generated and increased by learning processes, likewise also learned fear inhibition mechanisms do exist. Conditioned inhibition of fear is a fear inhibitory mechanism which involves learning of safety signals and is therefore also referred to as “learned safety”. Learned safety signals exert effects beyond the regulation of fear responses and the identification of episodes of security: they also relate to positive affective states, elicit reward-related approach and a reduction of depression-like behavior in mice. Hence, learned safety can be used as paradigm within the sub-construct “reward prediction” of the “positive valence” system along the newly established Research Domain Criteria system (RDoc) for neuropsychiatric research While some selected insights into the mediating neural underpininngs have been obtained and evidence for its translational potential exist, the molecular mechanisms of learned safety remain incompletely understood. The present thesis examined the role of microRNAs (miRNAs) - small noncoding RNAs which modulate gene expression at the posttranscriptional level - in learned safety. Specifically, the contribution of selected miRNA species (of the miR-212/132 family) to the behavioral expression of learned safety was investigated. In-silico and in-vitro approaches were then combined to identify possible relevant target genes of miRNA-132 which could be mediating the neural effects of learned safety. The present data integrate a wide range of analytical levels of the behavioral state of learned safety with a focus on some relevant molecular processes. Within the RDoc framework, the obtained information may contribute to enhance our understanding of one of the basic domains of functioning which is present along a grading spectrum of behavior - from physiology to pathology of the brain and its behavioral expression.submitted by Marianne Ronovsky, MSc.Zusammenfassung in deutscher SpracheAbweichender Titel laut Übersetzung der Verfasserin/des VerfassersMedizinische Universität Wien, Dissertation, 2017OeB

Classic and Inverse Compositional Gauss-Newton in Global DIC

International audienceToday, effective implementations of Digital Image Correlation (DIC) are based on iterative algorithms with constant linear operators. A relevant idea of the classic Finite Element (or more generally global) DIC (FE-DIC) solver consists in replacing the gradient of the deformed state image with that of the reference image, so as to obtain a constant operator. Different arguments (small strains, small deformations, equality of the two gradients close to the solution...) have been given in the literature to justify this approximation, but none of them are fully accurate. Indeed, the convergence of the optimization algorithm has to be investigated from its ability to produce descent directions. Through such a study, this paper attempts to explain why this approximation works and what is its domain of validity. Then an Inverse Compositional Gauss-Newton (ICGN) implementation of FE-DIC is proposed as a cost effective and mathematically sound alternative to this approximation

Impact of maternal immune activation on maternal care behavior, offspring emotionality and intergenerational transmission in C3H/He mice

Maternal immune activation (MIA) is a well-established model for the investigation of the deleterious effects of gestational infection on offspring mental health later in life. Hence, MIA represents a critical environmental variable determining brain development and the depending neural and behavioral functions in the progeny. Transgenerational transmission of some of the effects of MIA has been recently reported using the Polyinosinic:polycytidylic acid (Poly (I:C)) MIA model in C57BL/6 (C57) inbred mice. However, little is known about the underlying molecular mechanisms and the possible relevance of the specific genetic make-up of the inbred mouse strain used. Here we set out to characterize the effects of gestational Poly (I:C) treatment in C3H/HeNCrl mice (C3H), focusing on maternal care and offspring depression-like behavior and its intergenerational potential. miRNA expression in the offspring hippocampus in the F1 and F2 generations was examined as possible mechanism contributing to the observed behavioral effects. The impact of MIA on maternal care and its transmission to F1 females was previously observed in C57 mice was also found in C3H mice. Depression-like behavior in the adult offspring in C3H F1 and F2 females differed from reports of the C57 strain in the literature, suggesting a potential modulating role of the genetic background in the Poly(I:C) MIA mouse model. As the pattern of expression of selected candidate miRNAs in the F1 and F2 offspring hippocampus was not conserved between the two generations, it is unlikely to be a direct consequence of altered maternal care, or to be an immediate determinant of offspring emotionality.(VLID)469021

Animal Models of Maternal Immune Activation in Depression Research

Background: Depression and schizophrenia are debilitating mental illnesses with significant socio-economic impact. The high degree of comorbidity between the two disorders, and shared symptoms and risk factors, suggest partly common pathogenic mechanisms. Supported by human and animal studies, maternal immune activation (MIA) has been intimately associated with the development of schizophrenia. However, the link between MIA and depression has remained less clear, in part due to the lack of appropriate animal models. Objective: Here we aim to summarize findings obtained from studies using MIA animal models and discuss their relevance for preclinical depression research. Methods: Results on molecular, cellular and behavioral phenotypes in MIA animal models were collected by literature search (PubMed) and evaluated for their significance for depression. Results: Several reports on offspring depression-related behavioral alterations indicate an involvement of MIA in the development of depression later in life. Depression-related behavioral phenotypes were frequently paralleled by neurogenic and neurotrophic deficits and modulated by several genetic and environmental factors. Conclusion: Literature evidence analyzed in this review supports a relevance of MIA as animal model for a specific early life adversity, which may prime an individual for the development of distinct psychopathologies later life. MIA animal models may present a unique tool for the identification of additional exogenous and endogenous factors, which are required for the manifestation of a specific neuropsychiatric disorder, such as depression, later in life. Hereby, novel insights into the molecular mechanisms involved in the pathophysiology of depression may be obtained, supporting the identification of alternative therapeutic strategies.P 27520-B27(VLID)312728