Bridget Allen

The identification of mutations in the Tau gene in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) has made it possible to express human tau protein with pathogenic mutations in transgenic animals. Here we report on the production and characterization of a line of mice transgenic for the 383 aa isoform of human tau with the P301S mutation. At 5-6 months of age, homozygous animals from this line developed a neurological phenotype dominated by a severe paraparesis. According to light microscopy, many nerve cells in brain and spinal cord were strongly immunoreactive for hyperphosphorylated tau. According to electron microscopy, abundant filaments made of hyperphosphorylated tau protein were present. The majority of filaments resembled the half-twisted ribbons described previously in cases of FTDP-17, with a minority of filaments resembling the paired helical filaments of Alzheimer's disease. Sarkosyl-insoluble tau from brains and spinal cords of transgenic mice ran as a hyperphosphorylated 64 kDa band, the same apparent molecular mass as that of the 383 aa tau isoform in the human tauopathies. Perchloric acid-soluble tau was also phosphorylated at many sites, with the notable exception of serine 214. In the spinal cord, neurodegeneration was present, as indicated by a 49% reduction in the number of motor neurons. No evidence for apoptosis was obtained, despite the extensive colocalization of hyperphosphorylated tau protein with activated MAP kinase family members. The latter may be involved in the hyperphosphorylation of tau.

In mammals, mothers are the primary caregiver, programmed, in part, by hormones produced during pregnancy. High-quality maternal care is essential for the survival and lifelong health of offspring. We previously showed that the paternally silenced imprinted gene pleckstrin homology-like domain family A member 2 (Phlda2) functions to negatively regulate a single lineage in the mouse placenta called the spongiotrophoblast, a major source of hormones in pregnancy. Consequently, the offspring's Phlda2 gene dosage may influence the quality of care provided by the mother. Here, we show that wild-type (WT) female mice exposed to offspring with three different doses of the maternally expressed Phlda2 gene-two active alleles, one active allele (the extant state), and loss of function-show changes in the maternal hypothalamus and hippocampus during pregnancy, regions important for maternal-care behaviour. After birth, WT dams exposed in utero to offspring with the highest Phlda2 dose exhibit decreased nursing and grooming of pups and increased focus on nest building. Conversely, 'paternalised' dams, exposed to the lowest Phlda2 dose, showed increased nurturing of their pups, increased self-directed behaviour, and a decreased focus on nest building, behaviour that was robustly maintained in the absence of genetically modified pups. This work raises the intriguing possibility that imprinting of Phlda2 contributed to increased maternal care during the evolution of mammals.

Hypocretin/orexin (HCRT) and melanin concentrating hormone (MCH) neuropeptides are exclusively produced by the lateral hypothalamus and play important roles in sleep, metabolism, reward, and motivation. Loss of HCRT (ligands or receptors) causes the sleep disorder narcolepsy with cataplexy in humans and in animal models. How these neuropeptides are produced and involved in diverse functions remain unknown. Here, we developed methods to sort and purify HCRT and MCH neurons from the mouse late embryonic hypothalamus. RNA sequencing revealed key factors of fate determination for HCRT ( Peg3 , Ahr1 , Six6 , Nr2f2 , and Prrx1 ) and MCH ( Lmx1 , Gbx2 , and Peg3 ) neurons. Loss of Peg3 in mice significantly reduces HCRT and MCH cell numbers, while knock-down of a Peg3 ortholog in zebrafish completely abolishes their expression, resulting in a 2-fold increase in sleep amount. We also found that loss of HCRT neurons in Hcrt-ataxin-3 mice results in a specific 50% decrease in another orexigenic neuropeptide, QRFP, that might explain the metabolic syndrome in narcolepsy. The transcriptome results were used to develop protocols for the production of HCRT and MCH neurons from induced pluripotent stem cells and ascorbic acid was found necessary for HCRT and BMP7 for MCH cell differentiation. Our results provide a platform to understand the development and expression of HCRT and MCH and their multiple functions in health and disease.

Physical activity has cultural significance and population health benefits. However, Aboriginal and Torres Strait Islander adults may experience challenges in participating in physical activity. This mixed methods systematic review aimed to synthetize existing evidence on facilitators and barriers for physical activity participation experienced by Aboriginal and Torres Strait Islander adults in Australia. The Joanna Briggs Institute methodology was used. A systematic search was undertaken of 11 databases and 14 grey literature websites during 2020. The included studies reported physical activity facilitators and barriers experienced by Aboriginal or Torres Strait Islander participants aged 18+ years, living in the community. Twenty-seven studies met the inclusion criteria. Sixty-two facilitators were identified: 23 individual, 18 interpersonal, 8 community/environmental and 13 policy/program facilitators. Additionally, 63 barriers were identified: 21 individual, 17 interpersonal, 15 community/environmental and 10 policy/program barriers. Prominent facilitators included support from family, friends, and program staff, and opportunities to connect with community or culture. Prominent barriers included a lack of transport, financial constraints, lack of time, and competing work, family or cultural commitments. Aboriginal and Torres Strait Islander adults experience multiple facilitators and barriers to physical activity participation. Strategies to increase participation should seek to enhance facilitators and address barriers, collaboratively with communities, with consideration to the local context.

Optimising brain health for older Aboriginal and Torres Strait Islander peoples is important given the high rates of cognitive impairment and dementia (CI/D) in this population. To achieve this, effective models of care for the primary care setting are needed. This paper reports on the process evaluation of a stepped-wedge cluster randomised controlled trial conducted with 12 Aboriginal Community Controlled Health Services (ACCHSs) across four states of Australia. The study implemented a culturally responsive, co-designed best-practice model of CI/D care for Aboriginal and Torres Strait Islander peoples. Utilising the integrated-Promoting Action on Research Implementation in Health Services (i-PARIHS) Framework, the process evaluation aimed to identify the components of a “successful implementation” for this type of intervention. Qualitative and quantitative data collected included interviews, workshop evaluation forms, implementation checklists, and researcher observational notes. Fidelity to the intervention (scored as low, medium or high) was medium overall. Dose delivered across ACCHSs and intervention activities varied markedly. The project's reach was high and ACCHS staff demonstrated high engagement. Major themes derived from the qualitative data were: 1. ‘Aboriginal health and diverse environmental ecosystems’; 2. ‘Reciprocal relationships built on collaboration and cultural responsiveness’; 3. ‘Community knowledges and understandings of memory and thinking problems’. Despite encountering several challenges, the intervention improved management of dementia, and had high uptake and acceptability among ACCHS staff. Identified factors affecting the intervention, notably related to context, will inform future initiatives to improve dementia care in primary care settings. • The first process evaluation of a culturally responsive, co-designed best-practice model of dementia care implemented in Aboriginal and Torres Strait Islander primary care. • The cultural reframing of i-PARIHS constructs, to reflect and incorporate Indigenous epistemology. • Identification of key elements for successful implementation of complex interventions in primary care of Aboriginal and Torres Strait Islander peoples.