5 research outputs found
The role of adenosine A2A receptors in the regulation of neuronal and immunological responses in rats with Experimental Autoimmune Myasthenia gravis (EAMG)
Do stars govern our actions? astrocyte involvement in rodent behavior
Do stars govern our actions? Astrocyte involvement in rodent behaviorAstrocytes have emerged as important partners of neurons in information processing. Important progress has been made in the past two decades in understanding the role of astrocytes in the generation of neuron–astrocyte network outputs resulting in behavior. We review evidence for astrocyte involvement across four different behavioral domains: cognition, emotion, motor, and sensory processing. Accumulating evidence from animal models has provided a wealth of data that largely supports a direct involvement of astrocytes on diverse aspects of behavior. The development of tools for selectively controlling the temporal and spatial properties of astrocyte activity will help to consolidate our knowledge of the mechanisms underlying this involvement.The authors acknowledge funding from the Marie Curie Fellowship FP7-PEOPLE-2010-IEF 273936 and BIAL Foundation Grant 6112010 to J.F.O.; Foundation for Science and Technology (FCT) project grant (PTDC/SAU-NSC/118194/2010) to J.F.O., V.M.S., and S.G.G.; and fellowships (SFRH/BD/89714/2012 to V.M.S., SFRH/BPD/97281/2013 to J.F.O. and SFRH/BD/101298/2014 to S.G.G.); Human Frontier Science Program (Research Grant RGP0036/2014) to A.A.; FEDER funds through the Operational Program for Competitiveness Factors (COMPETE), and 'ON2 Programa Operacional Regional do Norte (ON.2 O Novo Norte)' QREN/FEDER to N.S
Genetic ablation of inositol 1,4,5-Trisphosphate receptor type 2 (IP3R2) fails to modify disease progression in a mouse model of Spinocerebellar Ataxia type 3
Spinocerebellar ataxia type 3 (SCA3) is a rare neurodegenerative disease caused by an abnormal polyglutamine expansion within the ataxin-3 protein (ATXN3). This leads to neurodegeneration of specific brain and spinal cord regions, resulting in a progressive loss of motor function. Despite neuronal death, non-neuronal cells, including astrocytes, are also involved in SCA3 pathogenesis. Astrogliosis is a common pathological feature in SCA3 patients and animal models of the disease. However, the contribution of astrocytes to SCA3 is not clearly defined. Inositol 1,4,5-trisphosphate receptor type 2 (IP3R2) is the predominant IP3R in mediating astrocyte somatic calcium signals, and genetically ablation of IP3R2 has been widely used to study astrocyte function. Here, we aimed to investigate the relevance of IP3R2 in the onset and progression of SCA3. For this, we tested whether IP3R2 depletion and the consecutive suppression of global astrocytic calcium signalling would lead to marked changes in the behavioral phenotype of a SCA3 mouse model, the CMVMJD135 transgenic line. This was achieved by crossing IP3R2 null mice with the CMVMJD135 mouse model and performing a longitudinal behavioral characterization of these mice using well-established motor-related function tests. Our results demonstrate that IP3R2 deletion in astrocytes does not modify SCA3 progression.This work has been funded by National funds, through the Foundation for Science and Technology (FCT)—project UIDB/50026/2020 and UIDP/50026/2020, PTDC/NEUNMC/3648/2014 and COMPETE-FEDER (POCI-01-0145-FEDER-016818); fellowships to DCG (2021.08121.BD), DMF (SFRH/BD/147947/2019), JSC (SFRH/BD/140624/2018), ANC (SFRH/BPD/118779/2016), AVF (UMINHO/BIL-CNCG/2022/11), SGG (SFRH/BD/101298/2014), and JFV (2020.05109.BD); FCT Scientific Employment Stimulus (CEEC)—Individual Call position to SDS (CEECIND/00685/2020); grants from the Bial Foundation (037/18) and “the la Caixa” Foundation (LCF/PR/HR21/52410024) to JFO; and by the projects NORTE-01-0145-FEDER-000013 and NORTE-01-0145-FEDER-000023, supported by the Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). It was also supported by grants from the ICVS Scientific Microscopy Platform, a member of the national infrastructure PPBI—Portuguese Platform of Bioimaging (PPBI-POCI-01-0145-FEDER-022122 and national funds through the Foundation for Science and Technology (FCT)
O impacto da sinalização de cálcio nos astrócitos na função cortico-límbica e no comportamento
Tese de doutoramento em Ciências da SaúdeOs astrócitos desempenham múltiplas funções desde a homeostasia cerebral ao controlo e
processamento da atividade sináptica. Eles integram sinais neuronais por elevações complexas de cálcio
(Ca2+) com impacto na comunicação neurónio-astrócito. As elevações de Ca2+ nos astrócitos podem ser
divididas em dois tipos: globais (presentes no soma e principais processos) e/ou focais (presentes nos
microdomínios). Apesar de estar descrito que as elevações globais de Ca2+ nos astrócitos podem modular
a comunicação sináptica, continuam por esclarecer quais os mecanismos moleculares envolvidos. Desta
forma, urge uma caracterização comportamental, estrutural e molecular detalhada para compreender
esses mecanismos. Nesta tese, utilizámos o modelo de murganho que apresenta a deleção constitutiva
do receptor 2 do inositol 1,4,5-trifosfato (IP3R2 KO), no qual as elevações globais de Ca2+ nos astrócitos
estão ausentes. Na primeira parte deste trabalho (Capítulo 2) demonstramos que os murganhos IP3R2 KO
têm um desenvolvimento somático e neurológico normal. Em seguida, a caracterização comportamental
deste modelo transgénico (Capítulo 3) revelou que os murganhos IP3R2 KO apresentam uma melhoria
do desempenho cognitivo em tarefas dependentes do hipocampo. Identificámos o factor de transcrição
Foxo1 como modulador da expressão de genes específicos de astrócitos, responsáveis pela regulação do
citoesqueleto e de espinhas dendríticas. A sobre-expressão do FOXO1 em astrócitos do hipocampo de
murganho C57BL/6J foi suficiente para mimetizar a melhoria cognitiva verificada no modelo IP3R2 KO.
Este resultado levou-nos a avaliar o papel da sinalização global de Ca2+ no contexto da depressão, uma
doença que afeta comportamento dependente das regiões cortico-límbicas (Capítulo 4). Os murganhos
IP3R2 KO apresentam uma surpreendente resiliência ao efeito ansiogénico do stress crónico. Por fim,
explorámos o papel da sinalização de Ca2+ nos astrócitos no envelhecimento cognitivo (Capítulo 5). Os
nossos resultados demonstram uma preservação do desempenho cognitivo em murganhos IP3R2 KO
envelhecidos, caracterizado por alteração do rácio neurónio/astrócito e por refinamento dendrítico dos
neurónios da camada V do córtex pré-frontal. Em suma, este trabalho contribuiu para uma melhor
compreensão do papel da sinalização global de Ca2+ nos astrócitos desde o desenvolvimento até ao
envelhecimento, num contexto de saúde e doença. Os resultados revelaram um alvo terapêutico
específico em astrócitos com potencial aplicação em contextos de depressão e envelhecimento cognitivo.Astrocytes are responsible for distinct functions ranging from brain homeostasis to the modulation of
synaptic functioning. They integrate neuronal signals by complex calcium (Ca2+) elevations that control
intracellular mechanisms that in turn drive the neuron-astrocyte dialogue, modulating the activity of cells
and networks. It is now recognized that Ca2+ elevations in astrocytes appear spatially distributed in global
(soma and main processes) and/or focal regions (microdomains). Although it is observed that global
astrocytic Ca2+ signaling contributes to synaptic communication, its role in circuit computation and
behavioral performance is still poorly understood. A detailed behavioral, structural and molecular
characterization should provide us with putative mechanisms underlying the roles of astrocytic Ca2+.
In this thesis, we took advantage of the inositol 1,4,5-trisphosphate receptor type 2 knockout (IP3R2 KO)
mouse model, which lacks global Ca2+ signaling in astrocytes. In the first part of this work (Chapter 2), we
demonstrate that IP3R2 KO mice retain a normal developmental maturation, as compared with WT
littermates. Next, a detailed behavioral characterization of this mouse model (Chapter 3) showed that
IP3R2 KO mice display enhanced cognitive performance in hippocampal-dependent tasks. We found Foxo1
as the most active transcription factor controlling the increased expression of astrocyte-specific genes
related with fine cytoskeleton modulation and spinogenesis, which could underlie the cognitive
enhancement observed. Moreover, specific overexpression of FOXO1 in hippocampal astrocytes of
C57BL/6J mice was enough to recapitulate the enhanced fear memory observed in IP3R2 KO mice. This
striking observation prompted us to test the role of global Ca2+ signaling in the context of depression,
which affects cortico-limbic regions (Chapter 4). IP3R2 KO mice present an unexpected resilience to the
installation of stress effects, namely translated into an increased self-care and a reduced anxious-like
phenotype. Finally, we explored the role of astrocytic Ca2+ signaling in cortico-limbic performance in aged
mice that display cognitive decline (Chapter 5). We observed a preserved cognitive performance in aged
IP3R2 KO mice, an altered neuron/astrocyte ratio and a dendritic refinement of mPFC neurons. Overall,
this work contributed to a better understanding on the role of global astrocytic Ca2+ signaling from
development to aging, both in a health and disease context. We found a putative astrocyte-specific
therapeutic target that could be used to prevent depression- and aging-related deficits.The work presented in this thesis was performed in the Life and Health Sciences Research Institute (ICVS),
at the School of Medicine, University of Minho. Financial support was provided by a PhD grant
(SFRH/BD/101298/2014 to SGG), FCT Investigator grants (IF/00328/2015 to JO, IF/01079/2014 to
LP) and PTDC/MED-NEU/31417/2017 from the FCT – Foundation for Science and Technology, by BIAL
Foundation grants (207/14 to JO and 427/14 to LP), by Northern Portugal Regional Operational
Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European
Regional Development Fund (FEDER) (NORTE-01-0145-FEDER-000013); FEDER Funds, through the
Competitiveness Factors Operational Programme (COMPETE), and The National Fund, through the FCT
(POCI-01-0145-FEDER-007038)
Characterisation of microbial attack on archaeological bone
As part of an EU funded project to investigate the factors influencing bone preservation in the archaeological record, more than 250 bones from 41 archaeological sites in five countries spanning four climatic regions were studied for diagenetic alteration. Sites were selected to cover a range of environmental conditions and archaeological contexts. Microscopic and physical (mercury intrusion porosimetry) analyses of these bones revealed that the majority (68%) had suffered microbial attack. Furthermore, significant differences were found between animal and human bone in both the state of preservation and the type of microbial attack present. These differences in preservation might result from differences in early taphonomy of the bones. © 2003 Elsevier Science Ltd. All rights reserved