Biology subjects

Platt, B.

Publications and source records attributed to Platt, B..

3 recordsLinked to original sources

bioRxiv2023

How stra(i)nge are your controls? A comparative analysis of metabolic phenotypes in commonly used C57 substrains

In recent years, the use of insufficiently characterised control subjects has been a contributing factor to increasing irreproducibility in different areas of biomedical research including neuroscience and metabolism. There is now a growing awareness of phenotypic differences between the metabolic profiles of C57BL/6 substrains which are commonly used as control animals. We here investigated baseline metabolic characteristics such as glucose regulation, fasted serum insulin levels and hepatic insulin signalling in five different C57BL/6 sub-strains (N, J, JOla, JRcc) of both sexes, obtained from two commercial vendors Charles River Laboratories (Crl) and Envigo (Env). Our results indicated systematic and tissue-specific differences between substrains, modulated by both vendor and sex in all parameters investigated, not necessarily mediated by the presence of the Nnt mutation. Not only were there differences between 6J and 6N as expected, all three 6J sub-strains exhibited different profiles, even from the same breeder. Two distinct metabolic profiles were identified, one in which low insulin levels resulted in impaired glucose clearance (6JCrl; both sexes) and the other, where sustained elevations in fasted basal insulin levels led to glucose intolerance (male 6JRccEnv). Further, 6JRccEnv displayed sex differences in both glucose clearance and hepatic insulin signalling markers. In comparison, the two 6N substrains of either sex, irrespective of vendor, did not exhibit considerable differences, with 6NCrl animals presenting a good choice as a healthy baseline control for many types of experiments. Overall, our data emphasise the importance of selecting and characterising control subjects regarding background, sex, and supplier to ensure proper experimental outcomes in biomedical research.

physiology↗

bioRxiv2021

Pulsation changes link to impaired glymphatic function in a mouse model of vascular cognitive impairment

Large vessel disease and carotid stenosis are key mechanisms contributing to vascular cognitive impairment (VCI) and dementia. Our previous work, and that of others, using rodent models, demonstrated that bilateral common carotid stenosis (BCAS) leads to cognitive impairment via gradual deterioration of the glial-vascular unit and accumulation of amyloid-{beta} (A{beta}) protein. Since brain-wide drainage pathways (glymphatic) for waste clearance, including A{beta} removal, have been implicated in the pathophysiology of VCI via glial mechanisms, we hypothesized that glymphatic function would be impaired in a BCAS model and exacerbated in the presence of A{beta}. Male wild- type and Tg-SwDI (model of microvascular amyloid) mice were subjected to BCAS or sham surgery which led to a reduction in cerebral perfusion and impaired spatial learning and memory. After 3 months survival, glymphatic function was evaluated by cerebrospinal fluid (CSF) fluorescent tracer influx. We demonstrated that BCAS caused a marked regional reduction of CSF tracer influx in the dorsolateral cortex and CA1-DG molecular layer. In parallel to these changes increased reactive astrogliosis was observed post-BCAS. To further investigate the mechanisms that may lead to these changes, we measured the pulsation of cortical vessels. BCAS impaired vascular pulsation in pial arteries in WT and Tg-SwDI mice. Since our findings show that BCAS may influence VCI by impaired glymphatic drainage and reduced vascular pulsation we propose that these additional targets need to be considered when treating VCI.

neuroscience↗

bioRxiv2021

Sex differences in behaviour and molecular pathology in the 5XFAD model

BackgroundThe prevalence of Alzheimers Disease (AD) is greater in women compared to men, but the reasons for this remain unknown. This sex difference has been widely neglected in experimental studies using transgenic mouse models of AD. ObjectiveHere, we studied behaviour and molecular pathology of 5-month-old 5XFAD mice, which express mutated human amyloid precursor protein and presenilin-1 on a C57BL/6J background, vs. their wild-type littermate controls, to compared both sex- and genotype-dependent differences. MethodsA novel behavioural paradigm was utilised (OF-NO-SI), comprising activity measures (Open Field, OF) arena, followed by Novel Object exploration (NO) and Social Interaction (SI) of a sex-matched conspecific. Each segment consisted of two repeated trials to assess between-trial habituation. Subsequently, brain pathology (amyloid load, stress response and inflammation markers, synaptic integrity, trophic support) was assessed using qPCR and Western blotting. ResultsFemale 5XFAD mice had higher levels of human APP and beta-amyloid (A{beta}) and heightened inflammation vs males. These markers correlated with hyperactivity observed in both sexes, yet only female 5XFAD mice presented with deficits in object and social exploration. Male animals had higher expression of stress markers and neurotrophic factors irrespective of genotype, this correlated with cognitive performance. ConclusionThe impact of sex on AD-relevant phenotypes is in line with human data and emphasises the necessity of appropriate study design and reporting. Differential molecular profiles observed in male vs. female mice offer insights into possible protective mechanisms, and hence treatment strategies.

neuroscience↗