2,389 research outputs found
Functional networks and network perturbations in rodents
Synchronous low-frequency oscillation in the resting human brain has been found to form networks of functionally associated areas and hence has been widely used to map the functional connectivity of the brain using techniques such as resting-state functional MRI (rsfMRI). Interestingly, similar resting-state networks can also be detected in the anesthetized rodent brain, including the default mode-like network. This opens up opportunities for understanding the neurophysiological basis of the rsfMRI signal, the behavioral relevance of the network characteristics, connectomic deficits in diseases and treatment effects on brain connectivity using rodents, particularly transgenic mouse models. In this review, we will provide an overview on the resting-state networks in the rat and mouse brains, the effects of pharmacological agents, brain stimulation, structural connectivity, genetics on these networks, neuroplasticity after behavioral training and applications in models of neurological disease and psychiatric disorders. The influence of anesthesia, strain difference, and physiological variation on the rsfMRI-based connectivity measure will be discussed
The (un)conscious mouse as a model for human brain functions: key principles of anesthesia and their impact on translational neuroimaging
In recent years, technical and procedural advances have brought functional magnetic resonance imaging (fMRI) to the field of murine neuroscience. Due to its unique capacity to measure functional activity non-invasively, across the entire brain, fMRI allows for the direct comparison of large-scale murine and human brain functions. This opens an avenue for bidirectional translational strategies to address fundamental questions ranging from neurological disorders to the nature of consciousness. The key challenges of murine fMRI are: (1) to generate and maintain functional brain states that approximate those of calm and relaxed human volunteers, while (2) preserving neurovascular coupling and physiological baseline conditions. Low-dose anesthetic protocols are commonly applied in murine functional brain studies to prevent stress and facilitate a calm and relaxed condition among animals. Yet, current mono-anesthesia has been shown to impair neural transmission and hemodynamic integrity. By linking the current state of murine electrophysiology, Ca(2+) imaging and fMRI of anesthetic effects to findings from human studies, this systematic review proposes general principles to design, apply and monitor anesthetic protocols in a more sophisticated way. The further development of balanced multimodal anesthesia, combining two or more drugs with complementary modes of action helps to shape and maintain specific brain states and relevant aspects of murine physiology. Functional connectivity and its dynamic repertoire as assessed by fMRI can be used to make inferences about cortical states and provide additional information about whole-brain functional dynamics. Based on this, a simple and comprehensive functional neurosignature pattern can be determined for use in defining brain states and anesthetic depth in rest and in response to stimuli. Such a signature can be evaluated and shared between labs to indicate the brain state of a mouse during experiments, an important step toward translating findings across species
Neuroplastic Changes Following Brain Ischemia and their Contribution to Stroke Recovery: Novel Approaches in Neurorehabilitation
Ischemic damage to the brain triggers substantial reorganization of spared areas and pathways, which is associated with limited, spontaneous restoration of function. A better understanding of this plastic remodeling is crucial to develop more effective strategies for stroke rehabilitation. In this review article, we discuss advances in the comprehension of post-stroke network reorganization in patients and animal models. We first focus on rodent studies that have shed light on the mechanisms underlying neuronal remodeling in the perilesional area and contralesional hemisphere after motor cortex infarcts. Analysis of electrophysiological data has demonstrated brain-wide alterations in functional connectivity in both hemispheres, well beyond the infarcted area. We then illustrate the potential use of non-invasive brain stimulation (NIBS) techniques to boost recovery. We finally discuss rehabilitative protocols based on robotic devices as a tool to promote endogenous plasticity and functional restoration
Donepezil Impairs Memory in Healthy Older Subjects: Behavioural, EEG and Simultaneous EEG/fMRI Biomarkers
Rising life expectancies coupled with an increasing awareness of age-related cognitive decline have led to the unwarranted use of psychopharmaceuticals, including acetylcholinesterase inhibitors (AChEIs), by significant numbers of healthy older individuals. This trend has developed despite very limited data regarding the effectiveness of such drugs on non-clinical groups and recent work indicates that AChEIs can have negative cognitive effects in healthy populations. For the first time, we use a combination of EEG and simultaneous EEG/fMRI to examine the effects of a commonly prescribed AChEI (donepezil) on cognition in healthy older participants. The short- and long-term impact of donepezil was assessed using two double-blind, placebo-controlled trials. In both cases, we utilised cognitive (paired associates learning (CPAL)) and electrophysiological measures (resting EEG power) that have demonstrated high-sensitivity to age-related cognitive decline. Experiment 1 tested the effects of 5 mg/per day dosage on cognitive and EEG markers at 6-hour, 2-week and 4-week follow-ups. In experiment 2, the same markers were further scrutinised using simultaneous EEG/fMRI after a single 5 mg dose. Experiment 1 found significant negative effects of donepezil on CPAL and resting Alpha and Beta band power. Experiment 2 replicated these results and found additional drug-related increases in the Delta band. EEG/fMRI analyses revealed that these oscillatory differences were associated with activity differences in the left hippocampus (Delta), right frontal-parietal network (Alpha), and default-mode network (Beta). We demonstrate the utility of simple cognitive and EEG measures in evaluating drug responses after acute and chronic donepezil administration. The presentation of previously established markers of age-related cognitive decline indicates that AChEIs can impair cognitive function in healthy older individuals. To our knowledge this is the first study to identify the precise neuroanatomical origins of EEG drug markers using simultaneous EEG/fMRI. The results of this study may be useful for evaluating novel drugs for cognitive enhancement
Probing brain function with pharmacological MRI
Lo sviluppo di tecniche di risonanza magnetica funzionale (fMRI) ha rivoluzionato le ricerca neuroscientifica clinica, determinando la possibilit\ue0 di investigare le dinamiche spazio-temporali dell\u2019attivit\ue0 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\u2019implementazione preclinica di questi metodi \ue8 complicata da una serie di costrizioni sperimentali, in primis l\u2019utilizzo di anestetici, che minano fortemente il potenziale traslazionale di queste tecniche.
Il recente sviluppo di tecniche di "MRI farmacologico" (phMRI) offre la possibilit\ue0 di superare alcune delle limitazioni sperimentali correlate all\u2019implementazione di approcci fMRI classici in animali da laboratorio. La tecnica si basa sull'utilizzo di metodi fMRI per mappare alterazioni di attivit\ue0 cerebrale prodotte dalla somministrazione di sostanze psicoattive. Studi preliminari hanno evidenziato la
capacit\ue0 di generare robusti e specifici segnali phMRI anche in condizioni di anestesia,
ed ha dimostrato la possibilit\ue0 di stimolare selettivamente diversi sistemi di
neurotrasmettitori.
Sfruttando la conservazione di circuiti cerebrali tra specie, tecniche phMRI offrono
quindi l\u2019opportunit\ue0 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 attivit\ue0 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 modalit\ue0 di indagine traslazionale, qualora applicata a modelli di malattia
clinicamente rilevanti, b) pi\uf9 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 propriet\ue0
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
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specie precliniche, e che \ue8 risultato essere modulabile da meccanismi antipsicotici
diversi (Sezione 4.2).
Il potenziale traslazionale dei metodi phMRI \ue8 stato ulteriormente avvalorato da un
secondo gruppo di studi, in cui un approccio multi-parametrico \u201cphMRI-based\u201d \ue8
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\u2019 investigazione, l'uso combinato di avanzate strategie di targeting
neuro-genetico (pharmaco-genetic silencing) e phMRI si \ue8 dimostrato efficace nello
stabilire correlazioni dirette tra cellule, circuito e comportamento in linee di topo
geneticamente modificate. Questi studi hanno portato all\u2019identificazione 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 \ue8 dimostrato uno strumento potente e versatile per
l\u2019implementazione di misure di connettivit\ue0 funzionale nel cervello di roditori. Questo
aspetto ha permesso l\u2019esplorazione di nuovi approcci statistici per l\u2019analisi della
topologia funzionale del cervello basati sulla rappresentazione di misure di
connettivit\ue0 in termini di reti complesse (Sezione 4.4).
Complessivamente, i risultati di questo lavoro avvalorano il potenziale traslazionale di
metodi phMRI nell\u2019ambito 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
\u201cpharmacological MRI\u201d (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
The thalamic reticular nucleus: a functional hub for thalamocortical network dysfunction in schizophrenia and a target for drug discovery
The thalamus (comprising many distinct nuclei) plays a key role in facilitating sensory discrimination and cognitive processes through connections with the cortex. Impaired thalamocortical processing has long been considered to be involved in schizophrenia. In this review we focus on the thalamic reticular nucleus (TRN) providing evidence for it being an important communication hub between the thalamus and cortex and how it may play a key role in the pathophysiology of schizophrenia. We first highlight the functional neuroanatomy, neurotransmitter localisation and physiology of the TRN. We then present evidence of the physiological roles of the TRN in relation to oscillatory activity, cognition and behaviour. Next we discuss the role of the TRN in rodent models of risk factors for schizophrenia (genetic and pharmacological) and provide evidence for TRN deficits in schizophrenia. Finally we discuss new drug targets for schizophrenia in relation to restoring TRN circuitry dysfunction
Multimodal connectivity of the human basal forebrain
The cholinergic innervation of the cortex originates from neurons in the basal forebrain (BF) and plays a crucial role in cognitive processing. However, it is unclear how the organization of BF cholinergic neurons in the human brain is related to their functional and structural integration with the cortex. To address this, we have used high-resolution 7 Tesla diffusion and resting-state functional MRI to examine multimodal forebrain cholinergic connectivity with the neocortex in humans. Discrete parcellation analyses revealed that structural and functional parcellation broadly differentiated the anteromedial from posterolateral nuclei of BF. Next, we used gradient estimation to capture more fine-grained connectivity profile of the BF-cortical projectome and found moving from anteromedial to posterolateral BF, structural and functional gradients became progressively detethered, with the most pronounced dissimilarity localized in the nucleus basalis of Meynert (NbM). Additionally, functional but not structural connectivity with the BF grew stronger at shorter geodesic distances, with weakly myelinated transmodal cortical areas most strongly expressing this divergence. Moreover, [18F] FEOBV PET imaging was used to demonstrate that these transmodal cortical areas are also among the most densely innervated regions. This intrinsic BF cholinergic connectivity map of cortex was compared with meta-analytic connectivity map of cholinergic modulation on attention, demonstrating that patterns of brain activity evoked by directed attention are altered by pharmacological activation of acetylcholine (ACh) compared to placebo and these patterns spatially overlap with the intrinsic BF cholinergic connectivity map. Altogether, our findings provide new insights into how cholinergic signaling is organized in the human brain
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