Addiction is a maladaptive pattern of behavior following repeated use of reinforcing drugs in predisposed individuals, leading to lifelong changes. Common among these changes are alterations of ...neurons releasing dopamine in the ventral and dorsal territories of the striatum. The serotonin 5-HT
receptor has been involved in various behaviors, including impulsivity, response to antidepressants, and response to psychostimulants, pointing toward putative interactions with the dopamine system. Despite these findings, it remains unknown whether 5-HT
receptors directly modulate dopaminergic activity and the possible mechanisms involved. To answer these questions, we investigated the contribution of 5-HT
receptors to cocaine-dependent behavioral responses. Male mice permanently lacking 5-HT
receptors, even restricted to dopamine neurons, developed heightened cocaine-induced locomotor responses. Retrograde tracing combined with single-cell mRNA amplification indicated that 5-HT
receptors are expressed by mesolimbic dopamine neurons.
and
electrophysiological recordings showed that 5-HT
-receptor inactivation in dopamine neurons affects their neuronal activity and increases AMPA-mediated over NMDA-mediated excitatory synaptic currents. These changes are associated with lower ventral striatum dopamine activity and blunted cocaine self-administration. These data identify the 5-HT
receptor as a pharmacological intermediate and provide mechanistic insight into attenuated dopamine tone following exposure to drugs of abuse.
Here we report that mice lacking 5-HT
receptors totally or exclusively in dopamine neurons exhibit heightened cocaine-induced locomotor responses. Despite the sensitized state of these mice, we found that associated changes include lower ventral striatum dopamine activity and lower cocaine operant self-administration. We described the selective expression of 5-HT
receptors in a subpopulation of dopamine neurons sending axons to the ventral striatum. Increased bursting
properties of these dopamine neurons and a concomitant increase in AMPA synaptic transmission to
dopamine neurons were found in mice lacking 5-HT
receptors. These data support the idea that the chronic 5-HT
-receptor inhibition makes mice behave like animals already exposed to cocaine with higher cocaine-induced locomotion associated with changes in dopamine neuron reactivity.
Autosomal aneuploidy is the leading cause of embryonic and foetal death in humans. This arises mainly from errors in meiosis I or II of oogenesis. A largely ignored source of error stems from ...germinal mosaicism, which leads to premeiotic aneuploidy. Molecular cytogenetic studies employing metaphase fluorescence
hybridization and comparative genomic hybridisation suggest that premeiotic aneuploidy may affect 10-20% of oocytes overall. Such studies have been criticised on technical grounds. We report here an independent study carried out on unmanipulated oocytes that have been analysed using next generation sequencing (NGS). This study confirms that the incidence of premeiotic aneuploidy in an unselected series of oocytes exceeds 10%. A total of 140 oocytes donated by 42 women gave conclusive results; of these, 124 (88.5%) were euploid. Sixteen out of 140 (11.4%) provided evidence of premeiotic aneuploidy. Of the 140, 112 oocytes were immature (germinal vesicle or metaphase I), of which 10 were aneuploid (8.93%); the remaining 28 were intact metaphase II - first polar body complexes, and six of these were aneuploid (21.4%). Of the 16 aneuploid cells, half contained simple errors (one or two abnormal chromosomes) and half contained complex errors. We conclude that germinal mosaicism leading to premeiotic aneuploidy is a consistent finding affecting at least 10% of unselected oocytes from women undergoing egg collection for a variety of reasons. The importance of premeiotic aneuploidy lies in the fact that, for individual oocytes, it greatly increases the risk of an aneuploid mature oocyte irrespective of maternal age. As such, this may account for some cases of aneuploid conceptions in very young women.
The biggest cell in the human body, the oocyte, encloses almost the complete machinery to start life. Despite all the research performed to date, defining oocyte quality is still a major goal of ...reproductive science. It is the consensus that mature oocytes are transcriptionally silent although, during their growth, the cell goes through stages of active transcription and translation, which will endow the oocyte with the competence to undergo nuclear maturation, and the oocyte and embryo to initiate timely translation before the embryonic genome is fully activated (cytoplasmic maturation). A systematic search was conducted across three electronic databases and the literature was critically appraised using the KMET score system. The aim was to identify quantitative differences in transcriptome of human oocytes that may link to patient demographics that could affect oocyte competence. Data was analysed following the principles of thematic analysis. Differences in the transcriptome were identified with respect to age or pathological conditions and affected chromosome mis segregation, perturbations of the nuclear envelope, premature maturation, and alterations in metabolic pathways—amongst others—in human oocytes.
MicroRNAs are small noncoding genes with gene expression regulatory function. Their emergence as potential diagnostic biomarker for many diseases has gained a specific interest among researchers. ...Observations of changes in miRNA levels correlating with aneuploidy in early embryos raise the prospective of employing miRNA as biomarkers to assess the embryo quality.
To identify and gather the miRNAs with potential link to chromosomal abnormalities in embryos from previous research, we conducted a systematic search using four databases, including Embase, Medline, Web of Science, and Cochrane databases in accordance with PRISMA guidelines.
Out of 200 identified records, only seven met the inclusion criteria. Seven miRNAs: miR-19b, miR-517c, miR-518e, miR-522, miR-92a, and miR-106a exhibited persistent downregulation in aneuploid blastocysts in the included studies. These miRNAs are members of important miRNA clusters, associated with abnormal expression in studies on reproductive failure. Pathway analysis revealed their involvement in regulating gene transcription, as well as cell cycle progression and apoptosis.
The changes detected in the miRNA expression in aneuploid embryos across different studies support the aneuploidy and miRNA relationship and prospect miRNA as a valuable tool for the assessment of embryo quality. Collectively, these observations highlight the role of miRNAs in embryonic development, and their involvement in genetic abnormalities that occur in embryos, such as aneuploidy, indicating their potential implementation to improve the embryo selection and reproductive outcomes.
Background: Chromosomal structural rearrangements can lead to fertility problems and recurrent miscarriages. The intricate interplay of genetics during human development can lead to subtle anomalies ...that may affect reproduction. Case Presentation: A 33-year-old woman sought fertility treatment after experiencing six miscarriages. Products of conception from the final pregnancy loss had been karyotyped, revealing a Robertsonian translocation (RT), involving chromosome 14. Fertility investigations showed low anti-Mullerian hormone (AMH) levels but otherwise normal female characteristics with normal sperm parameters of her husband were observed and both partners having a normal karyotype. Two embryos were transferred in an IVF cycle but neither resulted in a successful pregnancy. Subsequently, preimplantation genetic testing for aneuploidy (PGT-A) was applied to trophectoderm biopsy specimens from 4 embryos, which revealed abnormalities involving chromosome 14. Sperm aneuploidy testing failed to detect any increase in the incidence of aneuploidy affecting chromosome 14. Further embryos genetic testing indicated that all identified chromosome 14 abnormalities in the embryos had a maternal (oocyte) origin. Conclusion: This case underscores challenges in diagnosing and managing germline mosaicism in fertility. A maternal 14;14 Robertsonian translocation, undetected in the patient's blood but impacting oocytes, likely explains recurrent miscarriage and observed embryo aneuploidies. Genetic mosaicism in reproductive medicine highlights the necessity for advanced testing and personalized treatments. Data integration from various genetic analyses could enhance managing treatment expectations and improving fertility experiences. Keywords: In vitro fertilization, Miscarriage, Mosaicism.
Purpose
The aim of the study is to investigate how blastocyst contraction behaviour affects the reproductive competence in high-quality euploid embryos.
Methods
Eight hundred ninety-six high-quality ...blastocysts derived from 190 patients (mean age 38.05 (SD = 2.9) years) who underwent preimplantation genetic testing for aneuploidies (PGT-A) from January 2016 to October 2017 were included in this study. PGT-A results were reported as euploid or aneuploid. Aneuploid embryos were sub-classified into three categories: monosomy, trisomy and complex aneuploid. Retrospective studies of time-lapse monitoring (TLM) of those embryos were analysed and reproductive outcome of transferred embryos was collected.
Results
A total of 234/896 were euploid (26.1%) whilst 662/896 (73.9%) blastocysts were proven to be aneuploid from which 116 (17.6%) presented monosomies, 136 (20.5%) trisomies and 410 (61.9%) were complex aneuploid. The most frequent chromosomal complements were trisomies affecting chromosome 21 and monosomies involving chromosomes 16 and 22. Data analysis showed a statistical difference in the number of contractions being reported greater in aneuploid when compared to euploid embryos (0.6 vs 1.57;
p
< 0.001). Analysis of the aneuploid embryos showed that monosomies present less number of contractions when compared to embryos affected with trisomies or complex aneuploidies (1.23 vs 1.53 and 1.40;
p
< 0.05). No difference was observed when comparing the latter two groups. Euploid embryos presenting at least one contraction resulted in lower implantation and clinical pregnancy rates when compared to blastocysts that do not display this event (47.6 vs 78.5% and 40.0 vs 59.0% respectively).
Conclusions
Most aneuploid blastocysts diagnosed by PGT-A have complex aneuploidies, showing that aneuploid embryos can develop after genomic activation and reaching high morphological scores. It becomes clear that embryo contraction, despite being a physiological feature during blastulation, is conditioned by the ploidy status of the embryo. Furthermore, the presence of contractions may compromise implantation rates.
Background: The purpose of the current study was to assess if luteal support with intramuscular (IM) 7 alpha-hydroxyprogesterone caproate (7-OHPC) (Lentogest, IBSA, Italy) improves the pregnancy ...outcome in comparison to natural intramuscular progesterone (Prontogest, AMSA, Italy) when administered to recipients in a frozen embryo transfer cycle. Methods: A retrospective comparative study was performed to evaluate outcomes between two different intramuscular regimens used for luteal support in frozen embryo transfer cycles in patients underwent autologous in vitro fertilization (IVF) cycles (896 IVF cycles) and intracytoplasmic sperm injection (ICSI) who had a blastocyst transfer from February 20 4 to March 20 7 at the Centre for Reproductive and Genetic Health (CRGH) in London. Results: The live birth rates were significantly lower for the IM natural progesterone group when compared to 7-OHPC group (4 .8% vs. 50.9%, adjusted OR of 0.63 (0.3 -0.9)). The miscarriage rates were significantly lower in the 7-OHPC group compared to the IM natural progesterone group (4.5% vs. 9.2%, OR of .5, 95% CI of . 3-2.). The gestational age at birth and birth weight were similar in both groups (p=0.297 and p=0.966, respectively). Conclusion: It is known that both intramuscular and vaginal progesterone preparations are the standard of care for luteal phase support in women having frozen embryo transfer cycles. However, there is no clear scientific consensus regarding the optimal luteal support. In this study, it was revealed that live birth rates are significantly higher in women who received artificial progesterone compared to women who received natural progesterone in frozen embryo transfer cycles. Keywords: Frozen embryo transfer cycles, Luteal support, Progesterone.
Purpose
Utilising non-invasive imaging parameters to assess human oocyte fertilisation, development and implantation; and their influence on transcriptomic profiles.
Methods
A ranking tool was ...designed using imaging data from 957 metaphase II stage oocytes retrieved from 102 patients undergoing ART. Hoffman modulation contrast microscopy was conducted with an Olympus IX53 microscope. Images were acquired prior to ICSI and processed using ImageJ for optical density and grey-level co-occurrence matrices texture analysis. Single-cell RNA sequencing of twenty-three mature oocytes classified according to their competence was performed.
Result(s)
Overall fertilisation, blastulation and implantation rates were 73.0%, 62.6% and 50.8%, respectively. Three different algorithms were produced using binary logistic regression methods based on “optimal” quartiles, resulting in an accuracy of prediction of 76.6%, 67% and 80.7% for fertilisation, blastulation and implantation. Optical density, gradient, inverse difference moment (homogeneity) and entropy (structural complexity) were the parameters with highest predictive properties. The ranking tool showed high sensitivity (68.9–90.8%) but with limited specificity (26.5–62.5%) for outcome prediction. Furthermore, five differentially expressed genes were identified when comparing “good” versus “poor” competent oocytes.
Conclusion(s)
Imaging properties can be used as a tool to assess differences in the ooplasm and predict laboratory and clinical outcomes. Transcriptomic analysis suggested that oocytes with lower competence may have compromised cell cycle either by non-reparable DNA damage or insufficient ooplasmic maturation. Further development of algorithms based on image parameters is encouraged, with an increased balanced cohort and validated prospectively in multicentric studies.
Within the ovary, the optimal growth of the follicle, oocyte maturation and ovulation are highly conditioned by the two-way cross talk and interactions between the oocyte and the immediate somatic ...cells, known as cumulus cells (CCs). This biological communication between cell lines triggered the interest in the study of CCs as a biomarker of oocyte competence.
The findings of a 45,X mosaic pattern on CCs from a female patient with unremarkable medical history are reported in this study. The patient came to the Centre for Reproductive and Genetic Health, London on 14th August 2019 for her first visit and the follow up procedures were done for her to determine underlying genetic status. For this purpose, four sources of DNA including CCs, blood lymphocytes, buccal cells and immature oocytes were analyzed in the present report.
In the present case study, the hypothesis of the female patient being mosaic 45,X was confirmed although the degree of mosaicism and whether this was affecting the germinal line could not be determined. In the event of the discovery of a cell line with an apparently abnormal genetic makeup, genetic counselling is important in order to understand the implications from somatic to germinal cells for patients exploring fertility journeys.
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