Spatiotemporal development of the forebrain in the Dp(16)1Yey/+ mouse model of Down syndrome

Down syndrome (DS), or trisomy 21 (Ts21), is the most common genetic developmental disorder with a prevalence of about one in 700 live births. The triplication of human chromosome 21 (Hsa21) that characterizes this disorder results in a constellation of cognitive and physical alterations. The cognitive deficits range from mild to severe, and persist throughout life. Post-mortem studies of individuals with DS have revealed various neuropathologic abnormalities that are thought to underlie cognitive dysfunction, including: disruption of neurogenesis, corticogenesis, synapse formation, and myelination. However, the etiology of these alterations remains largely unknown. In order to elucidate the genetic basis of DS-phenotypes, several mouse models have been developed. The Ts65Dn, Ts1Cje, and Ts16 models, recapitulate DS-related phenotypes and have extended our knowledge of the associated pathological changes. Despite this progress, genetic dissimilarities in mouse models may confound phenotypic comparisons between mouse models and human DS. Specifically, the aforementioned models have a limited subset of triplicated Hsa-21 homologs or contain non-syntenic genes. Recently, a novel mouse model, the Dp(16)1Yey/+ (or Dp16), that has the entire Hsa-21 syntenic region of Mmu16 triplicated and no non-syntenic genes has been developed, suggesting that Dp16 may present phenotypes more closely matching the human disorder. In this study, we present the first comprehensive analysis of Dp16 embryonic, young and adult brains that includes a focus on the proliferative, inhibitory/excitatory neuronal and oligodendrocyte-lineage phenotypes using histological, immunohistochemical, and behavioral assessments. We hypothesize that due to the larger triplicated segment, the Dp16 mouse model better recapitulates DS-related neuropathologies relative to other mouse models. Despite the extended triplication, Dp16 animals lack DS-related embryonic phenotypes, however, behavioral and cellular phenotypes arise during the 2nd week following birth. The Dp16 is the first model of DS to develop postnatal phenotypes in the absence of changes to embryonic brain development, as such, Dp16 may not be a reliable model to further understand brain development in the DS fetus. However, when used in conjuncture with other models, the Dp16 will be a useful tool in understanding the contribution of aneuploidy and gene dosage to DS-phenotypes in mouse models of DS

26th Annual Computational Neuroscience Meeting (CNS*2017): Part 3 - Meeting Abstracts - Antwerp, Belgium. 15–20 July 2017

This work was produced as part of the activities of FAPESP Research,\ud Disseminations and Innovation Center for Neuromathematics (grant\ud 2013/07699-0, S. Paulo Research Foundation). NLK is supported by a\ud FAPESP postdoctoral fellowship (grant 2016/03855-5). ACR is partially\ud supported by a CNPq fellowship (grant 306251/2014-0)

Differential changes to D1 and D2 medium spiny neurons in the 12-month-old Q175+/- mouse model of Huntington's Disease.

Huntington's Disease (HD) is an autosomal dominant, progressive neurodegenerative disorder caused by deleterious expansion of CAG repeats in the Huntingtin gene and production of neurotoxic mutant Huntingtin protein (mHTT). The key pathological feature of HD is a profound degeneration of the striatum and a loss of cortical volume. The initial loss of indirect pathway (D2) medium spiny neuron (MSN) projections in early stages of HD, followed by a loss of direct pathway (D1) projections in advanced stages has important implications for the trajectory of motor and cognitive dysfunction in HD, but is not yet understood. Mouse models of HD have yielded important information on the effects and mechanisms of mHTT toxicity; however, whether these models recapitulate differential vulnerability of D1 vs. D2 MSNs is unknown. Here, we employed 12-month-old Q175+/- x D2-eGFP mice to examine the detailed structural and functional properties of D1 vs. D2 MSNs. While both D1 and D2 MSNs exhibited increased input resistance, depolarized resting membrane potentials and action potential threshold, only D1 MSNs showed reduced rheobase, action potential amplitude and frequency of spontaneous excitatory postsynaptic currents. Furthermore, D1 but not D2 MSNs showed marked proliferative changes to their dendritic arbors and reductions in spine density. Immunohistochemical assessment showed no loss of glutamatergic afferent inputs from cortical and subcortical sources onto identified D1 and D2 MSNs. Computational models constrained by empirical data predict that the increased dendritic complexity in Q175+/- D1 MSNs likely leads to greater dendritic filtering and attenuation of signals propagating to the soma from the dendrites. Together these findings reveal that, by twelve months, D1 and D2 MSNs exhibit distinctive responses to the presence of mHTT in this important mouse model of HD. This further highlights the need to incorporate findings from D1 and D2 MSNs independently in the context of HD models

Treatment with Mesenchymal-Derived Extracellular Vesicles Reduces Injury-Related Pathology in Pyramidal Neurons of Monkey Perilesional Ventral Premotor Cortex

Functional recovery after cortical injury, such as stroke, is associated with neural circuit reorganization, but the underlying mechanisms and efficacy of therapeutic interventions promoting neural plasticity in primates are not well understood. Bone marrow mesenchymal stem cell-derived extracellular vesicles (MSC-EVs), which mediate cell-to-cell inflammatory and trophic signaling, are thought be viable therapeutic targets. We recently showed, in aged female rhesus monkeys, that systemic administration of MSC-EVs enhances recovery of function after injury of the primary motor cortex, likely through enhancing plasticity in perilesional motor and premotor cortices. Here, usin

Do wearable alcohol-based handrub dispensers increase hand hygiene compliance? - a mixed-methods study

Abstract Background Hand Hygiene (HH) compliance was shown to be poor in several studies. Improving the availability of alcohol-based hand rub (ABHR) is a cornerstone for increasing HH compliance. Methods In this study, we introduced wearable dispensers for ABHR in an Emergency Department (ED) well equipped with mounted ABHR dispensers and accompanied this single-modal intervention by a quasi-experimental mixed-method study. The study was performed in the ED of the University Hospital Zurich, Switzerland, a 950-bed tertiary teaching hospital. During a five-week baseline period and a seven-week intervention period, we observed HH compliance according to the WHO ‘Five Moments’ concept, measured ABHR consumption, and investigated perceived ABHR availability, self-reported HH compliance and knowledge of HH indications by questionnaire. Multivariable logistic regression was used to identify independent determinants for HH compliance. In addition, semi-structured interviews were conducted and thematically analyzed to assess barriers and facilitators for the use of the newly introduced dispensers. Results Across 811 observed HH opportunities, the HH compliance for all moments was 56% (95% confidence interval (CI), 51–62%) during baseline and 64% (CI, 59–68%) during intervention period, respectively. In the multivariable analysis adjusted for sex, profession, and WHO HH moment, there was no difference in HH compliance between baseline and intervention (adjusted Odds ratio: 1.22 (0.89–1.66), p = 0.22), No significant changes were observed in consumption and perceived availability of ABHR. During intervention, 7.5% ABHR was consumed using wearable dispensers. HCP perceived wearable dispensers as unnecessary since mounted dispensers were readily accessible. Poor ergonomic design of the wearable dispenser emerged as a main barrier, especially its lid and fastening mechanism. Interviewees identified two ideal situations for wearable dispensers, HCP who accompany patients from ED to other wards, and HCP approaching a patient from a non-patient areas in the ED such as the central working station or the meeting room. Conclusion The introduction of wearable dispensers did not increase observed hand hygiene compliance or ABHR consumption in an ED already well equipped with mounted dispensers. For broader acceptance and use, wearable dispensers might benefit from an optimized ergonomic design