Browsing by Author "Portugal, Camila Cabral"
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- Astrocyte-derived TNF and glutamate critically modulate microglia activation by methamphetaminePublication . Canedo, Teresa; Portugal, Camila Cabral; Socodato, Renato; Almeida, Tiago Oliveira; Terceiro, Ana Filipa; Bravo, Joana; Silva, Ana Isabel; Magalhães, João Duarte; Guerra-Gomes, Sónia; Oliveira, João Filipe; Sousa, Nuno; Magalhães, Ana; Relvas, João Bettencourt; Summavielle, TeresaMethamphetamine (Meth) is a powerful illicit psychostimulant, widely used for recreational purposes. Besides disrupting the monoaminergic system and promoting oxidative brain damage, Meth also causes neuroinflammation, contributing to synaptic dysfunction and behavioral deficits. Aberrant activation of microglia, the largest myeloid cell population in the brain, is a common feature in neurological disorders triggered by neuroinflammation. In this study, we investigated the mechanisms underlying the aberrant activation of microglia elicited by Meth in the adult mouse brain. We found that binge Meth exposure caused microgliosis and disrupted risk assessment behavior (a feature that usually occurs in individuals who abuse Meth), both of which required astrocyte-to-microglia crosstalk. Mechanistically, Meth triggered a detrimental increase of glutamate exocytosis from astrocytes (in a process dependent on TNF production and calcium mobilization), promoting microglial expansion and reactivity. Ablating TNF production, or suppressing astrocytic calcium mobilization, prevented Meth-elicited microglia reactivity and re-established risk assessment behavior as tested by elevated plus maze (EPM). Overall, our data indicate that glial crosstalk is critical to relay alterations caused by acute Meth exposure.
- Maternal separation effects on mother rodents’ behaviour: A systematic reviewPublication . Alves, Renata L.; Portugal, Camila Cabral; Summavielle, Teresa; Barbosa, Fernando; Magalhães, AnaMaternal separation (MS) is a widely-used paradigm to study the effect of early-life adversity on brain development and resilience to psychopathology. Most of the related literature focuses on MS impact on offspring, however, it should ideally also consider the impact of altered maternal behaviour caused by MS itself. This systematic review aimed at providing a comprehensive compilation of the effects of MS on key maternal behaviour aspects. We performed a keyword literature search using Boolean operators. Databases were searched between 2000-2018. Additional studies were included from manual search. Twenty-nine articles addressing the impact of MS on maternal behaviour and/or mothers’ anxiety, depression-like behaviour, memory and consequences on underlying mechanisms. The methodological aspects and main conclusions were extracted from each study. This review shows that MS induces changes in dams. Results are particularly robust for increased anxiety and depressive-like symptoms, and altered maternal behaviours, predominantly for longer periods of MS. Finally, research in the field could strongly benefit from the establishment of guidelines to reduce the methodological inconsistencies here identified.
- A mouse model reproducing the pathophysiology of neonatal group B streptococcal infectionPublication . Bonifácio Andrade, Elva; Magalhães, Ana; Puga, Ana; Costa, Madalena; Bravo, Joana; Portugal, Camila Cabral; Ribeiro, Adília; Correia-Neves, Margarida; Faustino, Augusto; Firon, Arnaud; Trieu-Cuot, Patrick; Summavielle, Teresa; Ferreira, PaulaGroup B streptococcal (GBS) meningitis remains a devastating disease. The absence of an animal model reproducing the natural infectious process has limited our understanding of the disease and, consequently, delayed the development of effective treatments. We describe here a mouse model in which bacteria are transmitted to the offspring from vaginally colonised pregnant females, the natural route of infection. We show that GBS strain BM110, belonging to the CC17 clonal complex, is more virulent in this vertical transmission model than the isogenic mutant BM110∆cylE, which is deprived of hemolysin/cytolysin. Pups exposed to the more virulent strain exhibit higher mortality rates and lung inflammation than those exposed to the attenuated strain. Moreover, pups that survive to BM110 infection present neurological developmental disability, revealed by impaired learning performance and memory in adulthood. The use of this new mouse model, that reproduces key steps of GBS infection in newborns, will promote a better understanding of the physiopathology of GBS-induced meningitis.
- Neuron–microglia contact-dependent mechanisms attenuate methamphetamine-induced microglia reactivity and enhance neuronal plasticityPublication . Bravo, Joana; Ribeiro, Inês; Terceiro, Ana Filipa; Andrade, Elva B.; Portugal, Camila Cabral; Lopes, Igor M.; Azevedo, Maria M.; Sousa, Mafalda; Lopes, Cátia D. F.; Lobo, Andrea C.; Canedo, Teresa; Relvas, João Bettencourt; Summavielle, TeresaExposure to methamphetamine (Meth) has been classically associated with damage to neuronal terminals. However, it is now becoming clear that addiction may also result from the interplay between glial cells and neurons. Recently, we demonstrated that binge Meth administration promotes microgliosis and microglia pro-inflammation via astrocytic glutamate release in a TNF/IP3R2-Ca2+-dependent manner. Here, we investigated the contribution of neuronal cells to this process. As the crosstalk between microglia and neurons may occur by contact-dependent and/or contact-independent mechanisms, we developed co-cultures of primary neurons and microglia in microfluidic devices to investigate how their interaction affects Meth-induced microglia activation. Our results show that neurons exposed to Meth do not activate microglia in a cell-autonomous way but require astrocyte mediation. Importantly, we found that neurons can partially prevent Meth-induced microglia activation via astrocytes, which seems to be achieved by increasing arginase 1 expression and strengthening the CD200/CD200r pathway. We also observed an increase in synaptic individual area, as determined by co-localization of pre- and post-synaptic markers. The present study provides evidence that contact-dependent mechanisms between neurons and microglia can attenuate pro-inflammatory events such as Meth-induced microglia activation.
- Profiling microglia in a mouse model of Machado–Joseph diseasePublication . Campos, Ana Bela; Silva, Sara Duarte; Fernandes, Bruno; Neves, Sofia Pereira das; Marques, Fernanda; Castro, Andreia Teixeira; Carvalho, Andreia Neves; Fernandes, Daniela Monteiro; Portugal, Camila Cabral; Socodato, Renato; Summavielle, Teresa; Ambrósio, António Francisco; Relvas, João Bettencourt; Maciel, PatríciaMicroglia have been increasingly implicated in neurodegenerative diseases (NDs), and specific disease associated microglia (DAM) profiles have been defined for several of these NDs. Yet, the microglial profile in Machado–Joseph disease (MJD) remains unexplored. Here, we characterized the profile of microglia in the CMVMJD135 mouse model of MJD. This characterization was performed using primary microglial cultures and microglial cells obtained from disease-relevant brain regions of neonatal and adult CMVMJD135 mice, respectively. Machine learning models were implemented to identify potential clusters of microglia based on their morphological features, and an RNA-sequencing analysis was performed to identify molecular perturbations and potential therapeutic targets. Our findings reveal morphological alterations that point to an increased activation state of microglia in CMVMJD135 mice and a disease-specific transcriptional profile of MJD microglia, encompassing a total of 101 differentially expressed genes, with enrichment in molecular pathways related to oxidative stress, immune response, cell proliferation, cell death, and lipid metabolism. Overall, these results allowed us to define the cellular and molecular profile of MJD-associated microglia and to identify genes and pathways that might represent potential therapeutic targets for this disorder.