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- Longo, Francesco, et al.
(författare)
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Cell-type-specific disruption of cortico-striatal circuitry drives repetitive patterns of behavior in fragile X syndrome model mice.
- 2023
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Ingår i: Cell reports. - 2211-1247. ; 42:8
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Tidskriftsartikel (refereegranskat)abstract
- Individuals with fragile X syndrome (FXS) are frequently diagnosed with autism spectrum disorder (ASD), including increased risk for restricted and repetitive behaviors (RRBs). Consistent with observations in humans, FXS model mice display distinct RRBs and hyperactivity that are consistent with dysfunctional cortico-striatal circuits, an area relatively unexplored in FXS. Using a multidisciplinary approach, we dissect the contribution of two populations of striatal medium spiny neurons (SPNs) in the expression of RRBs in FXS model mice. Here, we report that dysregulated protein synthesis at cortico-striatal synapses is a molecular culprit of the synaptic and ASD-associated motor phenotypes displayed by FXS model mice. Cell-type-specific translational profiling of the FXS mouse striatum reveals differentially translated mRNAs, providing critical information concerning potential therapeutic targets. Our findings uncover a cell-type-specific impact of the loss of fragile X messenger ribonucleoprotein (FMRP) on translation and the sequence of neuronal events in the striatum that drive RRBs in FXS.
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| 2. |
- Mercaldo, Valentina, et al.
(författare)
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Altered striatal actin dynamics drives behavioral inflexibility in a mouse model of fragile X syndrome.
- 2023
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Ingår i: Neuron. - : Elsevier BV. - 1097-4199 .- 0896-6273.
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Tidskriftsartikel (refereegranskat)abstract
- The proteome of glutamatergic synapses is diverse across the mammalian brain and involved in neurodevelopmental disorders (NDDs). Among those is fragile X syndrome (FXS), an NDD caused by the absence of the functional RNA-binding protein FMRP. Here, we demonstrate how the brain region-specific composition of postsynaptic density (PSD) contributes to FXS. In the striatum, the FXS mouse model shows an altered association of the PSD with the actin cytoskeleton, reflecting immature dendritic spine morphology and reduced synaptic actin dynamics. Enhancing actin turnover with constitutively active RAC1 ameliorates these deficits. At the behavioral level, the FXS model displays striatal-driven inflexibility, a typical feature of FXS individuals, which is rescued by exogenous RAC1. Striatal ablation of Fmr1 is sufficient to recapitulate behavioral impairments observed in the FXS model. These results indicate that dysregulation of synaptic actin dynamics in the striatum, a region largely unexplored in FXS, contributes to the manifestation of FXS behavioral phenotypes.
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| 3. |
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Position Paper No. 5: Empowerment and Participatory Health Research
- 2021
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Ingår i: ICPHR Position papers.
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Empowerment has been a key conceptual underpinning of participatory health research (PHR), both as a set of processes that inform how partners and diverse stakeholders engage with each other, as well as a set of outcomes that contribute to improved health and social equity. The concept of empowerment is present in a number of characteristics of PHR as described in Position Paper No. 1 of the ICPHR (2013) entitled "What is participatory health research?", namely: PHR is a participatory and collective process: One of the goals of PHR is to promote the empowerment of the people involved so that all can actively participate in the process of knowledge production. With this approach, the results of the research can contribute to the improvement of the health and life of the people involved, and to the strengthening of personal and collective capacities.PHR promotes critical reflexivity: Participatory research processes promote a better understanding and acceptance of differences, supporting the reflective capacity and dialogue between those involved. Critical reflexivity refers to ongoing critical reflection of how power or lack of power affects the daily life and practice of the people involved in the research. These dynamics also occur within the partnership itself which magnifies the importance of critical reflexivity to promote power sharing within and outside the partnership. PHR aims for transformation through the action of people: Participatory research in health seeks to produce social changes favorable to the lives of the people involved in the study. However, this approach understands that such changes can be more effective in the way that people assume an active role in the entire research process, thus experiencing a process of empowerment. People can claim their power or have their power expanded to act in favor of their own interests when they recognize issues that are meaningful to them and, through critical reflection, understand their causes and visualize opportunities for effective intervention, empowering themselves to act on the basis of this knowledge. PHR produces knowledge which is local, collective, co-created, dialogical and diverse: the shared production of knowledge -- know-how, insights, wisdom and practices -- that benefits all people and communities involved, ultimately supporting the new paradigm of knowledge democracy. One of the great benefits of PHR is that it can potentially provide a safe place for people to work together across sectors, disciplines, and hierarchies. Through research collaboration, people can claim their own power, their own knowledge, and their own agency for personal, organizational, community, policy, and political transformation. However, participation cannot be taken for granted, but requires a conscious collective effort to co-create equitable decision-making, equal production of knowledge from diverse stakeholders, and ultimately to engage in practices that share power and enable people who are in disadvantaged positions to act on and grow the power they have. This position paper seeks to deepen our understanding of empowerment and the implications for conducting participatory health research with an underlying empowerment approach. We write for a wide audience of stakeholders interested in the benefits of PHR, including researchers, practitioners, policy makers, social entrepreneurs, social activists, funders, students, and anyone who wants to contribute to social justice and health equity. We first briefly present some history and definitions, then potential critiques of the use and understanding of the term empowerment. Finally, we will present reflections of how we can enhance our integration of empowerment into our participatory health research practice.
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