Biology subjects

Dale, R. C.

Publications and source records attributed to Dale, R. C..

4 recordsLinked to original sources

bioRxiv2025

Cumulative pregnancy and postnatal environmental exposures impact social behaviour in male mice associated with epigenetic, ribosomal, and immune dysregulation

Environmental exposures across critical developmental windows can significantly influence brain development and contribute to the pathogenesis of neurodevelopmental disorders (NDDs). Emerging clinical evidence suggests that cumulative environmental factors during early development result in more pronounced disease phenotypes in offspring. Here, we developed a triple-hit model using C57Bl/6JAusb mice to examine the cumulative effects of antenatal social stress, antenatal chronic high-fat diet consumption, and postnatal poly(I:C) exposure on neurodevelopmental outcomes in offspring. Male triple-hit offspring displayed autism-like social deficits and an overall increased susceptibility to neurodevelopmental behavioural alterations in adulthood compared to male non-stressed controls. Conversely, these behavioural changes were not observed amongst female triple-hit offspring. Single-cell RNA (scRNA) transcriptomic and bulk proteomic sequencing were performed in male triple-hit offspring across peripheral blood immune cells and brain tissue. scRNA sequencing in microglia, astrocytes, and oligodendrocytes revealed dysregulation in critical glial cell processes, ribosomal functions, and chromatin remodelling. Similar functional themes were observed across peripheral blood macrophages, neutrophils, and naive B cells - displaying immune and ribosomal dysregulation at the transcriptional level. Proteomics pathway enrichment analyses revealed significantly reduced protein abundance in ribosomal biogenesis, translation, and chromatin remodelling functions in both peripheral blood immune cells and brain tissue. We also observed synaptic dysfunction in the blood and brain proteome. Overall, using our unique triple-hit model, we demonstrate that multiple early life environmental exposures drive NDD-associated behaviours in a sex-specific manner; and is associated with overlapping central and peripheral molecular mechanisms that have clinical relevance to NDD pathogenesis.

developmental biology↗

bioRxiv2024

A humanized neuronal model system reveals key roles for manganese in neuronal endocytosis, calcium flux and mitochondrial bioenergetics

Manganese (Mn) is an essential trace metal that is necessary for life. Its duality as both a crucial micronutrient and potential neurotoxicant necessitates tight control of intracellular and extracellular Mn levels. Dysregulation of Mn is implicated in a broad range of human diseases, from neurodevelopmental sequelae related to Mn levels in drinking water, to acquired forms of manganism, rare inherited Mn transportopathies and more common disorders such as Parkinsons and Alzheimers disease. Despite the clear association between Mn dysregulation and neurodevelopmental or neurodegenerative diseases, the underlying cellular mechanisms that govern neuropathology remain poorly understood. We established an induced pluripotent stem cells-derived midbrain neuronal system from SLC39A14, SLC39A8, and SLC30A10 patients to better understand the neuronal sequelae of Mn dysregulation. By integrating transcriptomic and functional approaches, we show that Mn dyshomeostasis leads to dysregulation of key cellular pathways that are crucial to normal neuronal function, including defects in mitochondrial bioenergetics, calcium signalling, endocytosis, and glycosylation, as well as cellular stress and early neurodegeneration. Our humanized model has enhanced understanding of the role of Mn in the human brain, and the consequences of both acquired and genetic disorders associated with Mn dysregulation. Better understanding of these underlying pathophysiological processes will identify potential targets for future therapeutic intervention.

neuroscience↗

bioRxiv2024

High fat diet consumption and social instability stress impair stress adaptation and maternal care in C57Bl/6 mice

Poor maternal diet and psychosocial stress represent two environmental factors that can significantly impact maternal health during pregnancy. While various mouse models have been developed to study the relationship between maternal health and offspring development, few incorporate multiple sources of stress that mirror the complexity of human experiences. Maternal high-fat diet (HF) models in rodents are well-established, whereas maternal psychosocial stress models are still emerging. The social instability stress (SIS) paradigm, serves as a chronic and unpredictable form of social stress. To evaluate the combined effects of a poor maternal diet and social stress on maternal health and behaviour, we developed a novel maternal stress model in adult female C57Bl/6 mice. We observed that all HF+ mice demonstrated rapid weight gain, elevated fasting blood glucose levels and impaired glucose tolerance independent of the presence (+) or absence (-) of SIS. Behavioural testing revealed anxiety-like behaviors remained across all groups prior to pregnancy. However, we did observe a trend of poorer nest quality among all HF+ mice compared to HF-mice following nest building testing. Unlike the other HF+ and HF-stress groups, which exhibited significantly reduced plasma ACTH and corticosterone levels following SIS exposure, we did not observe this reduction in HF+/SIS+ females. In addition, HF+/SIS+ females demonstrated significant postpartum maternal neglect, resulting in fewer numbers of live offspring. These findings suggest that prolonged maternal HF diet consumption, coupled with SIS, places a significant burden on the maternal stress response system, resulting in reduced parental investment and negative postpartum behaviour towards offspring.

animal behavior and cognition↗

bioRxiv2021

Diagnosis and analysis of unexplained cases of childhood encephalitis in Australia using metagenomic next-generation sequencing

Encephalitis is most often caused by a variety of infectious agents, the identity of which is commonly determined through diagnostic tests utilising cerebrospinal fluid (CSF). Immune-mediated disorders are also a differential in encephalitis cases. We investigated the clinical characteristics and potential aetiological agents of unexplained encephalitis through metagenomic next-generation sequencing of residual clinical samples of multiple tissue types and independent clinical review. A total of 43 specimens, from both sterile and non-sterile sites, were collected from 18 encephalitis cases with no cause identified by the Australian Childhood Encephalitis study. Samples were subjected to total RNA sequencing to determine the presence and abundance of potential pathogens, to reveal mixed infections, pathogen genotypes, and epidemiological origins, and to describe the possible aetiologies of unexplained encephalitis. From this, we identified five RNA and two DNA viruses associated with human infection from both non-sterile (nasopharyngeal aspirates, nose/throat swabs, urine, stool rectal swab) and sterile (cerebrospinal fluid, blood) sites. These comprised two human rhinoviruses, two human seasonal coronaviruses, two polyomaviruses and one picobirnavirus. With the exception of picobirnavirus all have been previously associated with respiratory disease. Human rhinovirus and seasonal coronaviruses may be responsible for five of the encephalitis cases reported here. Immune-mediated encephalitis was considered clinically likely in six cases and RNA sequencing did not identify a possible pathogen in these cases. The aetiology remained unknown in nine cases. Our study emphasises the importance of respiratory viruses in the aetiology of unexplained child encephalitis and suggests that the routine inclusion of non-CNS sampling in encephalitis clinical guidelines/protocols could improve the diagnostic yield. Author SummaryEncephalitis is caused by both infectious agents and auto-immune disorders. However, the aetiological agents, including viruses, remain unknown in around half the cases of encephalitis in many cohorts. Importantly, diagnostic tests are usually based on the analysis of cerebrospinal fluid which may limit their utility. We used a combination of meta-transcriptomic sequencing and independent clinical review to identify the potential causative pathogens in cases of unexplained childhood encephalitis. Accordingly, we identified seven viruses associated with both sterile and non-sterile sampling sites. Human rhinovirus and seasonal coronaviruses were considered as most likely responsible for five of the 18 encephalitis cases studied, while immune-mediated encephalitis was considered the cause in six cases, and we were unable to determine the aetiology in nine cases. Overall, we demonstrate the role of respiratory viruses as a cause of unexplained encephalitis and that sampling sites other than cerebrospinal fluid is of diagnostic value.

microbiology↗