Biology subjects

Manuella, F.

Publications and source records attributed to Manuella, F..

6 recordsLinked to original sources

bioRxiv2025

Circulating extracellular vesicles can transport stress signals to the male germline

Extracellular vesicles (EVs) play a key role in cell-cell communication by transporting bioactive molecules from donor to recipient cells across the body. While their involvement in somatic cells communication is well described, somatic-to-germ cells communication remains understudied. We show that small EVs (sEVs) can vehicle signals of early life stress (ELS) from circulation to sperm consequentially for the offspring. In mice, ELS persistently modifies RNA, lipids and metabolites in plasma sEVs. Chronic injection of plasma sEVs from ELS-exposed males alters the sperm transcriptome and is reflected in the transcriptome of embryos. This leads to metabolic dysfunctions in the adult offspring. These findings highlight a role of circulating sEVs in soma-to-germline communication relevant for the intergenerational transmission of ELS effects.

cell biology↗

bioRxiv2022

Long-term effects of early postnatal stress on Sertoli cells functions

Sertoli cells are somatic cells in testes essential for spermatogenesis, as they support the development, maturation, and differentiation of germ cells. Sertoli cells are metabolically highly active and physiologically regulated by external signals, particularly factors in the blood stream. In disease conditions, circulating pathological signals may affect Sertoli cells and consequentially, alter germ cells and fertility. While the effects of stress on reproductive cells have been well studied, how Sertoli cells respond to stress remains poorly characterized. Therefore, we used a mouse model of early postnatal stress to assess the effects of stress on Sertoli cells. We developed an improved enrichment strategy based on intracellular stainings and obtained enriched preparations of adult Sertoli cells from exposed males. We show that adult Sertoli cells have impaired electron transport chain (ETC) pathways and that several components of ETC complexes I, III, and IV are persistently affected. We identify the circulation as a potential mediator of the effects of stress, since treatment of primary Sertoli cells with serum from stressed males induces similar ETC alterations. These results newly highlight Sertoli cells as cellular targets of early life stress, and suggest that they may contribute to the negative effects of stress on fertility. HighlightsO_LIWe present an improved method to obtain enriched preparations of Sertoli cells from adult mouse testis for molecular analyses C_LIO_LISertoli cells from adult males exposed to stress during early postnatal life have altered electron transport chain (ETC) expression, suggesting persistent effects of early life stress on Sertoli cells physiology C_LIO_LISerum from adult males exposed to early postnatal stress reproduces ETC gene dysregulation in cultured Sertoli cells. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=147 SRC="FIGDIR/small/501498v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@ba92e9org.highwire.dtl.DTLVardef@1032032org.highwire.dtl.DTLVardef@36bf72org.highwire.dtl.DTLVardef@52e3d6_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2022

Paternal transmission of behavioural and metabolic traits induced by postnatal stress to the 5th generation in mice

Life experiences and environmental conditions in childhood can change the physiology and behaviour of exposed individuals and in some cases, of their offspring. In rodent models, stress/trauma, poor diet and endocrine disruptors in a parent have been shown to cause phenotypes in the direct progeny, suggesting intergenerational inheritance. A few models also examined transmission to further offspring and suggested transgenerational inheritance, but such multi-generations inheritance is not well characterized. Our previous work in a mouse model of early postnatal stress showed that behaviour and metabolism are altered in the offspring of exposed males up to the 4th generation in the patriline and up to the 2nd generation in the matriline. The present study examined if in the patriline, symptoms can be transmitted beyond the 4th generation. Analyses of the 5th and 6th generation of mice revealed that altered risk-taking and glucose regulation caused by postnatal stress are still manifested in the 5th generation but are attenuated in the 6th generation. Some of the symptoms are expressed in both males and females, but some are sex-dependent and sometimes opposite. These results indicate that postnatal trauma can affect behaviour and metabolism over many generations, suggesting epigenetic mechanisms of transmission.

animal behavior and cognition↗

bioRxiv2022

EXPLORE: A novel deep learning-based analysis method for exploration behaviour in object recognition tests

Object recognition tests are widely used in neuroscience to assess memory function in rodents. Despite the experimental simplicity of the task, the interpretation of behavioural features that are counted as object exploration can be complicated. Thus, object exploration is often analysed by manual scoring, which is time-consuming and variable across researchers. Current software using tracking points often lacks precision in capturing complex ethological behaviour. Switching or losing tracking points can bias outcome measures. To overcome these limitations we developed "EXPLORE", a simple, ready-to use and open source pipeline. EXPLORE consists of a convolutional neural network trained in a supervised manner, that extracts features from images and classifies behaviour of rodents near a presented object. EXPLORE achieves human-level accuracy in identifying and scoring exploration behaviour and outperforms commercial software with higher precision, higher versatility and lower time investment, in particular in complex situations. By labeling the respective training data set, users decide by themselves, which types of animal interactions on objects are in- or excluded, ensuring a precise analysis of exploration behaviour. A set of graphical user interfaces (GUIs) provides a beginning-to-end analysis of object recognition tests, accelerating a fast and reproducible data analysis without the need of expertise in programming or deep learning.

animal behavior and cognition↗

bioRxiv2019

A novel mode of communication between blood and the germline for the inheritance of paternal experiences

In many species, environmental stimuli can affect the germline and contribute to phenotypic changes in the offspring, without altering the genetic code1-5. So far, little is known about which biological signals can link exposure to germ cells. Using a mouse model of postnatal trauma with transgenerational effects, we show that exposure alters lipid-based metabolites in blood of males and their non-exposed offspring. Comparable alterations are validated in serum and saliva of orphan children exposed to trauma. Peroxisome proliferator-activated receptor (PPAR) is identified as mediating the effects of metabolites alterations. Mimicking PPAR activation with a dual PPAR/{gamma} agonist in vivo induces changes in the sperm transcriptome similarly to trauma, and reproduces metabolic phenotypes in the offspring. Injecting serum collected from adult males exposed to postnatal trauma into controls recapitulates metabolic phenotypes in the offspring. These results suggest conserved effects of early life adversity on blood metabolites, and causally involve paternal blood factors and PPAR nuclear receptor in phenotype heritability.

molecular biology↗

bioRxiv2018

Alterations in sperm long RNA contribute to the epigenetic inheritance of the effects of postnatal trauma

Psychiatric diseases have a strong heritable component known to not be restricted to DNA sequence-based genetic inheritance alone but to also involve epigenetic factors in germ cells 1,2. Initial evidence suggested that sperm RNA is causally linked 2,3 to the transmission of symptoms induced by traumatic experiences. Here we show that alterations in long RNA in sperm contribute to the inheritance of specific trauma symptoms. Injection of long RNA fraction from sperm of males exposed to postnatal trauma recapitulates the effects on food intake, glucose response to insulin and risk-taking in adulthood whereas the small RNA fraction alters body weight and behavioral despair. Alterations in long RNA are maintained after fertilization, suggesting a direct link between sperm and embryo RNA.

developmental biology↗