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Uno stimolo infiammatorio, indotto dal trattamento sistemico con LPS, in topi giovani o adolescenti modula le successive risposte molecolari e comportamentali in modo differenziale nei maschi e nelle femmine
No full textDurante lo sviluppo di un individuo, esistono fasi di elevata sensibilità, anche dette “finestre critiche”, in cui le esperienze influiscono sulla riorganizzazione molecolare e strutturale del cervello. La plasticità sinaptica che le caratterizza permette di adattarsi all’ambiente ma può anche aumentare la vulnerabilità agli eventi stressanti, come gli insulti neuro-infiammatori, in aree cerebrali specifiche come l’ippocampo.
Il termine “programming” definisce l’effetto che gli eventi avversi lasciano sull’individuo con conseguenze anche durature, specialmente se sperimentati in una finestra di vulnerabilità. Ciò può aumentare la probabilità di insorgenza di disordini psichiatrici, come l’ansia, il disturbo bipolare, la schizofrenia e la depressione maggiore, che insorgono spesso proprio in adolescenza. Ad oggi, il peso socio-economico di queste patologie rende cruciale l’identificazione di marker precoci di insorgenza. In tale quadro, il sesso biologico sta emergendo come fattore differenziale chiave. L’obiettivo di questa tesi è stato dunque capire come uno stress neuro-infiammatorio sperimentato nel periodo pre-puberale e nell’adolescenza possa influenzare la risposta acuta del SNC, la risposta periferica e il comportamento più avanti nella vita, ad esempio nell’età adulta.
L’iniezione sistemica di LPS è il modello elettivo di studio della neuro-infiammazione nei roditori e lo abbiamo impiegato per indagare: 1) gli effetti trascrizionali acuti di uno stimolo infiammatorio indotto durante la fase giovanile (PND21) e l’adolescenza (PND35), 2) le conseguenze molecolari e comportamentali su un secondo insulto infiammatorio indotto nell’età adulta, in topi maschi e femmine. Dunque: 1) topi maschi e femmine C57BL6J sono stati iniettati con LPS (100 μg/Kg) o salina a PND21/35 e sacrificati dopo 6/24 ore, 2) i topi trattati come nel punto 1 sono stati ri-esposti a LPS (830 μg/Kg) o salina a 12 settimane e poi sacrificati 24 ore dopo. Mediante qPCR e HPLC-MS/MS sono stati valutati rispettivamente i target correlati alla risposta neuro-infiammatoria in ippocampo e i metaboliti della pathway delle chinurenine (KP) nel siero. Tramite una batteria di test comportamentali abbiamo studiato, inoltre, il comportamento esplorativo, ansioso e la memoria a breve termine in un gruppo indipendente di topi adulti. Negli animali giovani e adolescenti, gli effetti trascrizionali in ippocampo indotti da LPS su target e correlati all'attivazione microgliale erano più intensi nelle femmine che nei maschi. Inoltre, l'espressione di IDO, l’enzima limitante della KP, è stata indotta solo nelle femmine. Nell’adulto invece, sono stati i maschi a mostrare una risposta trascrizionale a LPS maggiore indipendentemente trattamento ricevuto precedentemente. Per quanto riguarda gli effetti sui metaboliti della KP, LPS ha aumentato i livelli sierici di TRP solo a PND21. L’effetto è stato tempo- e sesso- dipendente. I livelli di serotonina sono diminuiti indipendentemente da sesso ed età. Nei maschi adulti non si sono presentate variazioni di TRP, mentre le femmine esposte nuovamente a LPS si sono mostrate più sensibili rispetto ai loro controlli. A livello comportamentale, LPS ha ridotto l’esplorazione dei maschi adulti nell’OF mentre nelle femmine è stata la memoria a breve termine ad essere intaccata. Il trattamento con LPS in età precoce ha potenziato gli effetti comportamentali di uno stimolo immunitario sperimentato in età adulta, specialmente nelle femmine esposte a LPS in adolescenza. Nel complesso, i nostri dati indicano che un insulto neuro-infiammatorio sperimentato durante fasi critiche dello sviluppo ha effetti centrali, periferici e comportamentali di lunga durata che differiscono in base al sesso biologico.Critical time windows are peculiar stages of development where the brain can reorganize in response to experiences. Heightened synaptic plasticity is a double-edged blade: it enables to build up skills to fit the environment but it also increases the vulnerability to stress events, as neuroinflammatory hits of specific brain areas, like the hippocampus. The term “programming” refers to the imprinting that an adverse event leaves on the individual with consequences which may be also enduring, especially when experienced in a vulnerable window by potentially increasing sensitivity to the development of neuropsychiatric disorders, such as anxiety, bipolar disorder, schizophrenia and MDD, that emerge during adolescence. Identifying their early markers of onset is crucial given their socio-economic burden. Sex-dimorphism is emerging as a key factor for differential stress response and mental diseases development.
Aim of this thesis is to understand how the experience of a neuroinflammatory stress during pre-puberty and adolescence may affect the acute central, peripheral and behavioural response later in life.
The systemic injection of LPS is the elective model to study neuroinflammation in rodents, so we employed this model to investigate: 1) the acute transcriptional effects of an immune challenge experienced during juvenile (PND21) and adolescence (PND35), 2) its molecular and behavioural effects on a second inflammatory hit experienced as adults, in male and female mice.
Two cohorts were studied: 1) male and female C57BL6J mice were injected i.p. with LPS (100 μg/Kg) or saline at PND21/35 and sacrificed 6 or 24 hours later; 2) mice treated as in point 1 were re-exposed to LPS (830 μg/Kg) or saline at 12wks and sacrificed after 24h. Neuroinflammation-related targets were evaluated in the hippocampus by means of qPCR and metabolites of the kynurenine pathway (KP) were measured in the serum by means of HPLC-MS/MS. An independent group of adult mice were tested for explorative and anxiety-like behaviour, and short-term memory with a battery of tests.
Juvenile and adolescent hippocampal transcriptional response to LPS with respect to inflammatory and microglia-related targets was more intense in females than in males. Consistently, the mRNA expression of the KP limiting enzyme IDO was induced in females only. In adults, this trend was reversed, males showed a stronger transcriptional effect irrespective of experiencing the immune challenge only in early life or also as adults. Serum TRP levels were increased by the immune challenge only in PND21 animals with a different timing between male and female mice, while serotonin was decreased by LPS at both ages and in both sexes. In adult male animals, the effect of LPS on TRP catabolism was not affected by a previous exposure to the immune challenge, while females re-exposed to the inflammatory hit as adults appeared to be more sensible than their saline-receiving counterparts. Behavioural impairments were highlighted: in the OF, LPS reduced exploratory behaviour of males experiencing the immune challenge only as adults whereas females showed short-term memory impairment after the Y-maze.
LPS treatment at PND21 or PND35 potentiated the behavioural effects of a subsequent exposure to the endotoxin in adulthood especially in female animals exposed to the immune challenge as adolescents. Overall, our data suggest that a neuroinflammatory insult experienced during critical time windows of development have central, peripheral and behavioural long-lasting effects and differ according to biological sex
Differences in presynaptic hippocampal GABAergic terminals at the early stage of life in female and male mice: effect of an acute early inflammatory challenge
No full textGABA dictates the efficiency of synaptic connection, influencing its developmental complexity, but its role is tuned by developmental sex differences which affect the efficiency of its innervation. We investigated the efficiency of mechanisms of GABA storage and exocytosis in hippocampal terminals of male and female mice during the juvenile period (PND21), adolescence (PND36) or adulthood (PND90). The expression of mRNA encoding for the presynaptic GABA transporter type 1, (GAT1) and the vesicular GABA transporter (VGAT1) was analysed. A significant scaling-down in the GAT1 mRNA levels (SLC6A1) was detected at PND21 in both sexes until adulthood, while the SLC32A1-VGAT mRNA level was conserved. We also analysed the density of GAT1 and VGAT proteins. Western blot analysis unveiled the presence of a monomeric and an oligomeric form of GAT1. The density of the monomeric form was conserved at the different stages of development in both sexes. Differently, the oligomeric assembly was significantly overexpressed in hippocampal synaptosomal lysates from PND21 male and female mice, but recovered at PND36. VGAT density was largely conserved in PND21 and PND36 male hippocampal synaptosomal lysates when compared to adult particles, but significantly lower in PND21 female particles. Notably, these changes are consistent and support the altered vesicular storage of newly taken-up [3H]GABA detected in PND21 male and female hippocampal synaptosomes as well as the different responsiveness of GABAergic male and female synaptosomes to increasing depolarizing stimuli (12, 20 and 30 mM KCl-enriched solutions) measured as efficiency of the [3H]GABA exocytosis. Interstingly, an acute LPS treatment affects the efficiency of GABA exocytosis at PND36 in a sex-dependent manner. These results add new knowledge on the role of GABA as effector of central inhibitory plasticity at the early stage of development and its relevance in dimorphic adaptation in physio pathological conditions
ADOLESCENCE AS A CRITICAL TIME-WINDOW FOR NEUROINFLAMMATION IN THE MOUSE: WHY SEX MATTERS
No full textGoing Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
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