Sexual differences in hippocampal microglia of adult mice subjected to maternal separation stress.

Introduction: It is well known that early life adversities could a"ect brain development and increase the vulnerability to stress-related disorders later in adulthood. Nevertheless, the neurobiological mechanisms underlying this susceptibility have been poorly characterized and sex could be an important variable. Recently, microglia, which is involved in many neurodevelopmental processes such as neurogenesis and synaptic plasticity, has been proposed as a mediator of this stress response and early life stress could “prime” microglia to be over- responsive in future challenges. Objective: The analysis of hippocampal microglia morphology and distribution in the dentate gyrus (DG) of mice subjected to early stress. Methods: Female and male C57BL/6J mice were subjected to 3h daily maternal separation (MS) for 21 days. In postnatal day 60, adult mice undertook a single 2h restriction stress (RS). Accordingly, the experimental groups were as follows: CTRL, RS, MS, MS+RS. The DG was analyzed using immunohistochemistry techniques against Iba1 (microglia) following image analysis (ImageJ) to obtain morphological and distribution data of microglial somas and DG surface area. Results: Smaller DG surface area was observed in MS male mice compared with the CTRL group, but not in female. Furthermore, microglial soma area changed in a sex-dependent manner, having female mice from MS group an increased soma area than those of MS male mice. This was also observed to be region-specific, with a larger microglia soma in DG subgranular zone (SGZ) of MS female compared to MS male. Since microglia in this DG zone is involved in neurogenesis, this might suggest a possible change in the formation of new born neurons. Conclusion: These results revealed a di"erent microglial response to stress depending on the animal sex and open the door to a better understanding of neurobiological basis in pathologies like depression. .University of Málaga, the project PID2020-117464RB-I00 from Ministerio de Ciencia e Innovación (MCIN/AEI) Spain, awarded to Pedraza, C. and Pérez-Martín, M. ; the project P20_00460 from Consejería de Conocimiento, Investigación y Universidades, Junta de Andalucía awarded to Pedraza, C. and predoctoral fellowship FPU21/01318 awarded to Munoz- Martin, J. funded by MCIN/AEI, Spain. Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Mild juvenile stress increases resilience to the development of anxious behaviors and prevents neurogenic reduction after stress exposure in adulthood.

Stress, especially during sensitive periods of development, can induce neuroplastic changes in brain regions such as the hippocampus, which increases vulnerability to the negative effects of a second stressor during adulthood, precipitating the development of depressive symptoms. For this reason, C57BL/6J mice were subjected to two stress protocols, the first in the juvenile period and the second in adulthood. Neurogenic and behavioral changes (saccharin preference test and social behavior test) were analyzed. The results revealed that juvenile stress increased basal saccharin preference in adulthood. However, animals subjected to stress in both juvenile and adulthood showed anhedonic behavior. In addition, stress in adulthood resulted in increased anxious behavior without affecting interest in social relationships. Stress in adulthood reduced neurogenesis. In contrast, juvenile stress prevented the development of anxious behavior and the reduction of hippocampal neurogenesis induced by stress in adulthood. In conclusion, juvenile stress increases the risk of developing anhedonia after exposure to a second stress, but, in contrast to our expectations, mild stress during the juvenile period increases resilience to the development of anxious behaviors and prevents neurogenic reduction after stress exposure in adulthoodUniversidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

New insights into hypothalamic neurogenesis disruption after acute and intense stress: implications for microglia and inflammation

In recent years, the hypothalamus has emerged as a new neurogenic area, capable of generating new neurons after development. Neurogenesis-dependent neuroplasticity seems to be critical to continuously adapt to internal and environmental changes. Stress is a potent environmental factor that can produce potent and enduring effects on brain structure and function. Acute and chronic stress is known to cause alterations in neurogenesis and microglia in classical adult neurogenic regions such as the hippocampus. The hypothalamus is one of the major brain regions implicated in homeostatic stress and emotional stress systems, but little is known about the effect of stress on the hypothalamus. Here, we studied the impact of acute and intense stress (water immersion and restrain stress, WIRS), which may be considered as an inducer of an animal model of posttraumatic stress disorder, on neurogenesis and neuroinflammation in the hypothalamus of adult male mice, focusing on three nuclei: PVN, VMN and ARC, and also in the periventricular area. Our data revealed that a unique stressor was sufficient to provoke a significant impact on hypothalamic neurogenesis by inducing a reduction in the proliferation and number of immature neurons identified as DCX+ cells. These differences were accompanied by marked microglial activation in the VMN and ARC, together with a concomitant increase in IL-6 levels, indicating that WIRS induced an inflammatory response. To investigate the possible molecular mechanisms responsible for neuroplastic and inflammatory changes, we tried to identify proteomic changes. The data revealed that WIRS induced changes in the hypothalamic proteome, modifying the abundance of three and four proteins after 1 h or 24 h of stress application, respectively. These changes were also accompanied by slight changes in the weight and food intake of the animals. These results are the first to show that even a short-term environmental stimulus such as acute and intense stress can have neuroplastic, inflammatory, functional and metabolic consequences on the adult hypothalamus

Gut microbiome specific changes in different behavioral profiles in a mouse social defeat stress model.

Comunicación de tipo PósterThe gut microbiome has arisen as one important modulator of general health, including brain function. In fact, disturbances in brain health are commonly mirrored in the microbiome, which could be contributing to pathology. One of the most common brain disorders is depression, which is tightly linked to environmental factors such as stress and drives alterations in regular behavior. However, not much is known about the role of the gut microbiome in response to stress and its relationship to behavior. In this study, the social defeat stress (SDS) paradigm was used as a depressive-like symptoms inducer in 8 w.o. male C57BL/6J mice for 10 days. Mice were segregated in stress resilient and sensitive according to behavior using K-means clustering and behavioral data was interpreted using principal component analysis. Then, the mice microbiome was extracted from fecal pellets after the stress protocol. DNA was extracted and purified followed by 16S (V3-V4) region amplification for sequencing. These data were analyzed to obtain diversity indexes and identify bacterial taxa within samples and groups. Data revealed that mice responded differently to the same stressor. Half the mice were found to have mild depressive-like symptoms whereas the other half showed profound alterations. Behavioral data was found to be explained in three factors: anhedonia, exploration, and motility. Stressed mice showed overall differences in their microbiome, being less diverse and populations associated with higher inflammation. Moreover, the healthy gut associated Verrucomicrobiae class was only identified in stress resilient mice, suggesting a possible relationship with their behavioral phenotype. Altogether, these results show a different behavioral response to stress in animals that reflects in their microbiome, which could be a key factor in determining stress resilience.This study was supported by Ministerio de Ciencia e Innovación - Plan Nacional I+D+I from Spain (PID2020-117464RB-I00) to CP and MP-M; FEDER/Junta de Andalucía - Proyectos I+D+I en el marco del Programa Operativo FEDER Andalucía 2014-2020 (UMA20-FEDERJA-112) to CP and MP-M; Consejería de Conocimiento, Investigación y Universidades, Junta de Andalucía (P20_00460) to CP. PC-P has been funded by the research project PID2020-117464RB-I00. Ministerio de Educación, Cultura y Deporte from Spain (FPU19/03629 to Infantes-López MI). Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Genetic landscape of 6089 inherited retinal dystrophies affected cases in Spain and their therapeutic and extended epidemiological implications

Inherited retinal diseases (IRDs), defined by dysfunction or progressive loss of photoreceptors, are disorders characterized by elevated heterogeneity, both at the clinical and genetic levels. Our main goal was to address the genetic landscape of IRD in the largest cohort of Spanish patients reported to date. A retrospective hospital-based cross-sectional study was carried out on 6089 IRD affected individuals (from 4403 unrelated families), referred for genetic testing from all the Spanish autonomous communities. Clinical, demographic and familiar data were collected from each patient, including family pedigree, age of appearance of visual symptoms, presence of any systemic findings and geographical origin. Genetic studies were performed to the 3951 families with available DNA using different molecular techniques. Overall, 53.2% (2100/3951) of the studied families were genetically characterized, and 1549 different likely causative variants in 142 genes were identified. The most common phenotype encountered is retinitis pigmentosa (RP) (55.6% of families, 2447/4403). The most recurrently mutated genes were PRPH2, ABCA4 and RS1 in autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL) NON-RP cases, respectively; RHO, USH2A and RPGR in AD, AR and XL for non-syndromic RP; and USH2A and MYO7A in syndromic IRD. Pathogenic variants c.3386G > T (p.Arg1129Leu) in ABCA4 and c.2276G > T (p.Cys759Phe) in USH2A were the most frequent variants identified. Our study provides the general landscape for IRD in Spain, reporting the largest cohort ever presented. Our results have important implications for genetic diagnosis, counselling and new therapeutic strategies to both the Spanish population and other related populations.This work was supported by the Instituto de Salud Carlos III (ISCIII) of the Spanish Ministry of Health (FIS; PI16/00425 and PI19/00321), Centro de Investigación Biomédica en Red Enfermedades Raras (CIBERER, 06/07/0036), IIS-FJD BioBank (PT13/0010/0012), Comunidad de Madrid (CAM, RAREGenomics Project, B2017/BMD-3721), European Regional Development Fund (FEDER), the Organización Nacional de Ciegos Españoles (ONCE), Fundación Ramón Areces, Fundación Conchita Rábago and the University Chair UAM-IIS-FJD of Genomic Medicine. Irene Perea-Romero is supported by a PhD fellowship from the predoctoral Program from ISCIII (FI17/00192). Ionut F. Iancu is supported by a grant from the Comunidad de Madrid (CAM, PEJ-2017-AI/BMD7256). Marta del Pozo-Valero is supported by a PhD grant from the Fundación Conchita Rábago. Berta Almoguera is supported by a Juan Rodes program from ISCIII (JR17/00020). Pablo Minguez is supported by a Miguel Servet program from ISCIII (CP16/00116). Marta Corton is supported by a Miguel Servet program from ISCIII (CPII17/00006). The funders played no role in study design, data collection, data analysis, manuscript preparation and/or publication decisions

Unveiling the Secrets of the Stressed Hippocampus: Exploring Proteomic Changes and Neurobiology of Posttraumatic Stress Disorder

Intense stress, especially traumatic stress, can trigger disabling responses and in some cases even lead to the development of posttraumatic stress disorder (PTSD). PTSD is heterogeneous, accompanied by a range of distress symptoms and treatment-resistant disorders that may be associated with a number of other psychopathologies. PTSD is a very heterogeneous disorder with different subtypes that depend on, among other factors, the type of stressor that provokes it. However, the neurobiological mechanisms are poorly understood. The study of early stress responses may hint at the way PTSD develops and improve the understanding of the neurobiological mechanisms involved in its onset, opening the opportunity for possible preventive treatments. Proteomics is a promising strategy for characterizing these early mechanisms underlying the development of PTSD. The aim of the work was to understand how exposure to acute and intense stress using water immersion restraint stress (WIRS), which could be reminiscent of natural disaster, may induce several PTSD-associated symptoms and changes in the hippocampal proteomic profile. The results showed that exposure to WIRS induced behavioural symptoms and corticosterone levels reminiscent of PTSD. Moreover, the expression profiles of hippocampal proteins at 1 h and 24 h after stress were deregulated in favour of increased inflammation and reduced neuroplasticity, which was validated by histological studies and cytokine determination. Taken together, these results suggest that neuroplastic and inflammatory dysregulation may be a therapeutic target for the treatment of post-traumatic stress disorders