1,721,059 research outputs found
Probing brain function with pharmacological MRI
Full text linkLo sviluppo di tecniche di risonanza magnetica funzionale (fMRI) ha rivoluzionato le ricerca neuroscientifica clinica, determinando la possibilità di investigare le dinamiche spazio-temporali dell’attività cerebrale in maniera non invasiva e con grande accuratezza.
Sebbene la tecnica sia stata originariamente sviluppata in ambito
clinico, essa ha il potenziale di poter essere utilizzata in ambito preclinico come efficace strumento investigativo e traslazionale. Tuttavia, l’implementazione preclinica di questi metodi è complicata da una serie di costrizioni sperimentali, in primis l’utilizzo di anestetici, che minano fortemente il potenziale traslazionale di queste tecniche.
Il recente sviluppo di tecniche di "MRI farmacologico" (phMRI) offre la possibilità di superare alcune delle limitazioni sperimentali correlate all’implementazione di approcci fMRI classici in animali da laboratorio. La tecnica si basa sull'utilizzo di metodi fMRI per mappare alterazioni di attività cerebrale prodotte dalla somministrazione di sostanze psicoattive. Studi preliminari hanno evidenziato la
capacità di generare robusti e specifici segnali phMRI anche in condizioni di anestesia,
ed ha dimostrato la possibilità di stimolare selettivamente diversi sistemi di
neurotrasmettitori.
Sfruttando la conservazione di circuiti cerebrali tra specie, tecniche phMRI offrono
quindi l’opportunità di ampliare in maniera significativa il repertorio di stimolazione
neuronale a disposizione in ambito preclinico, consentendo di indagare
selettivamente specifici aspetti della funzione cerebrale in diversi stati di precondizionamento
neuronale.
In tale contesto, le attività di ricerca di questa tesi sono state finalizzate ad ampliare il
campo di applicazione di metodi phMRI preclinici in due diversi ambiti sperimentali:
a) come modalità di indagine traslazionale, qualora applicata a modelli di malattia
clinicamente rilevanti, b) più in generale come piattaforma investigativa per
l'indagine della funzione cerebrale e della sua topologia funzionale in contesti
sperimentali diversi.
In un primo gruppo di studi, tecniche phMRI sono state impiegate per mappare i
circuiti neuronali attivati da antagonisti del recettore del glutammato NMDA nel
cervello del ratto (Sezione 4.1). Tali composti, grazie alle loro proprietà
psicotogeniche, sono ampiamente sfruttati come modelli sperimentali di schizofrenia
in animali ed in volontari allo scopo di valutare e validare nuovi trattamenti per la
malattia. I risultati di questa ricerca hanno evidenziato uno specifico circuito corticolimbo-
talamico che risulta essere attivato da antagonisti NMDAR sia nell'uomo che in
Riassunto
XII
specie precliniche, e che è risultato essere modulabile da meccanismi antipsicotici
diversi (Sezione 4.2).
Il potenziale traslazionale dei metodi phMRI è stato ulteriormente avvalorato da un
secondo gruppo di studi, in cui un approccio multi-parametrico “phMRI-based” è
stato impiegato per indagare molteplici aspetti della funzione cerebrale in un
modello murino di dipendenza da cocaina. Questa linea di investigazione ha
evidenziato multiple alterazioni della funzione cerebrale basale e reattiva nel cervello
di roditori esposti alla cocaina strettamente connesse a quelle osservate in analoghi
studi di imaging su pazienti cocaina-dipendenti (Sezione 4.2).
In una terza linea d’ investigazione, l'uso combinato di avanzate strategie di targeting
neuro-genetico (pharmaco-genetic silencing) e phMRI si è dimostrato efficace nello
stabilire correlazioni dirette tra cellule, circuito e comportamento in linee di topo
geneticamente modificate. Questi studi hanno portato all’identificazione di una
nuova e circoscritta popolazione neuroni nell'amigdala, in grado di controllare
qualitativamente la risposta comportamentale alla paura attraverso il reclutamento
di circuiti colinergici corticali (Sezione 4.3)
Infine, l'approccio phMRI si è dimostrato uno strumento potente e versatile per
l’implementazione di misure di connettività funzionale nel cervello di roditori. Questo
aspetto ha permesso l’esplorazione di nuovi approcci statistici per l’analisi della
topologia funzionale del cervello basati sulla rappresentazione di misure di
connettività in termini di reti complesse (Sezione 4.4).
Complessivamente, i risultati di questo lavoro avvalorano il potenziale traslazionale di
metodi phMRI nell’ambito di diverse aree delle neuroscienze e della psicofarmacologia.
La combinazione di phMRI e tecniche di manipolazione genetica
avanzate definisce una nuova, potente piattaforma tecnologica per lo studio delle
basi circuitali del comportamento in animali da laboratorio.The development of functional Magnetic Resonance Imaging (fMRI) has heralded a
revolution in neuroscience, providing clinicians with a method to non-invasively
investigate the spatio-temporal patterns of neuro-functional activity. Although
primarily developed for human investigations, there exists significant scope for the
application of fMRI in pre-clinical species as a translational and investigational
platform across different areas of neuroscience and psychiatry research. However,
the realization of this potential is hampered by a number of experimental constraints
which make the application of fMRI methods to animal models less than
straightforward. As a result, most fMRI research in laboratory species has been
reduced to the employment of basic somato-sensory stimulation paradigms, thus
greatly limiting the translational potential of the technique.
An interesting approach to overcome some of these limitations has been dubbed
“pharmacological MRI” (phMRI) and relies on the use of fMRI to map patterns of
brain activity induced by psychoactive drugs. The approach has demonstrated the
ability to elicit reliable fMRI signals even under anaesthesia, and to enable selective
stimulation of different neurotransmitter systems. Building upon the homology
between brain circuits in humans and laboratory animals, phMRI techniques thus
offer the opportunity of significantly expanding the stimulation repertoire available
to preclinical fMRI research, by allowing to selectively probe specific aspects of brain
function under different preconditioning states.
Within this framework, the research presented herein was aimed to broaden the
scope of application of preclinical phMRI both as a translational technique, when
applied to clinically-relevant disease models, and more generally as a versatile
platform for the pre-clinical investigation of brain activity and its functional topology
as a function of behavioural, pharmacological or genetic preconditioning.
In a first group of studies, we developed a phMRI assay to map the circuitry activated
by NMDAR antagonists in the rat brain. These psychotogenic compounds are widely
exploited to model schizophrenia symptoms and to provide experimental models
that may prove useful in the development of novel treatments for the disorder. The
results of this research highlighted a conserved cortico-limbo-thalamic circuit that is
activated by NMDAR antagonists both in humans and preclinical species, which can
be modulated by existing and novel antipsychotic drugs (Section 4.1).
The translational potential of phMRI measurements was further corroborated by a
second group of studies, where a multi-parametric phMRI-based approach was
applied to investigate multiple facets of brain function in a rodent cocaine selfSummary
X
administration model, a behavioural paradigm of established construct-validity for
research of drug addiction. This line of investigation revealed specific basal and
reactive functional alterations in the brain of cocaine-exposed rodents closely related
to those observed in analogous neuroimaging studies in humans (Section 4.2).
In a third line of investigation, the combined use of advanced neuro-genetic targeting
strategies (i.e. pharmacogenetic silencing) and phMRI has proven successful in
establishing direct correlations between cells, circuit and complex behaviours in
genetically engineered mouse lines. These studies (Section 4.3) have led to the
identification of a novel cell population in the amygdala that controls the behavioural
response to fear through the recruitment of cholinergic circuits.
Finally, the phMRI approach has proven a powerful tool to explore functional
connectivity in rodents, and to map a variety of different neurotransmitter pathways
by performing measures of correlated responses in spatially remote brain areas. This
has provided a useful playground to explore novel statistical methods of analysis of
functional connectivity represented in terms of complex networks (Section 4.4).
Collectively, the results of this work strongly corroborate the translational use of
phMRI approaches, and pave the way to the integrated implementation of phMRI
and advance genetic manipulation as a novel powerful platform for basic
neurobiological research
Community structure in networks of functional connectivity: resolving functional organization in the rat brain with pharmacological MRI
No full textFunctional connectivity in the rat brain: a complex network approach.
No full textFunctional connectivity analyses of fMRI data can provide a wealth of information on the brain functional organization and have been widely applied to the study of the human brain. More recently, these methods have been extended to preclinical species, thus providing a powerful translational tool. Here, we review methods and findings of functional connectivity studies in the rat. More specifically, we focus on correlation analysis of pharmacological MRI (phMRI) responses, an approach that has enabled mapping the patterns of connectivity underlying major neurotransmitter systems in vivo. We also review the use of novel statistical approaches based on a network representation of the functional connectivity and their application to the study of the rat brain functional architecture
Antagonism at serotonin 5-HT2A receptors modulates functional activity of frontohippocampal circuit
No full textDrug-anaesthetic interaction in phMRI: the case of the psychotomimetic agent phencyclidine.
No full text
Going 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
- …
