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Neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD), are severe age-related disorders with complex and multifactorial causes. Recent research suggests a critical link between neurodegeneration and the gut microbiome, via the gut–brain communication pathway. This review examines the role of trimethylamine N-oxide (TMAO), a gut microbiota-derived metabolite, in the development of AD and PD, and investigates its interaction with microRNAs (miRNAs) along this bidirectional pathway. TMAO, which is produced from dietary metabolites like choline and carnitine, has been linked to increased neuroinflammation, protein misfolding, and cognitive decline. In AD, elevated TMAO levels are associated with amyloid-beta and tau pathologies, blood–brain barrier disruption, and neuronal death. TMAO can cross the blood–brain barrier and promote the aggregation of amyloid and tau proteins. Similarly, TMAO affects alpha-synuclein conformation and aggregation, a hallmark of PD. TMAO also activates pro-inflammatory pathways such as NF-kB signaling, exacerbating neuroinflammation further. Moreover, TMAO modulates the expression of various miRNAs that are involved in neurodegenerative processes. Thus, the gut microbiome–miRNA–brain axis represents a newly discovered mechanistic link between gut dysbiosis and neurodegeneration. MiRNAs regulate the key pathways involved in neuroinflammation, oxidative stress, and neuronal death, contributing to disease progression. As a direct consequence, specific miRNA signatures may serve as potential biomarkers for the early detection and monitoring of AD and PD progression. This review aims to elucidate the complex interrelationships between the gut microbiota, trimethylamine-N-oxide (TMAO), microRNAs (miRNAs), and the central nervous system, and the implications of these connections in neurodegenerative diseases. In this context, an overview of the current neuroradiology techniques available for studying neuroinflammation and of the animal models used to investigate these intricate pathologies will also be provided. In summary, a bulk of evidence supports the concept that modulating the gut–brain communication pathway through dietary changes, the manipulation of the microbiome, and/or miRNA-based therapies may offer novel approaches for implementing the treatment of debilitating neurological disorders. [ABSTRACT FROM AUTHOR]

Quantum emitters, such as the negatively charged nitrogen-vacancy center in diamond, are attractive for quantum technologies, such as nano-sensing, quantum information processing, and as a non-classical light source. However, it is still challenging to position individual emitters in photonic structures while preserving the spin coherence properties of the defect. In this paper, we investigate single and ensemble waveguide-integrated nitrogen-vacancy centers in diamond fabricated by femtosecond laser writing followed by thermal annealing. Their spin coherence properties are systematically investigated and are shown to be comparable to native nitrogen-vacancy centers in diamond. This method paves the way for the fabrication of coherent spins integrated within photonic devices. [ABSTRACT FROM AUTHOR]

Negatively charged nitrogen-vacancy (NV−) centers in diamond have unique magneto-optical properties, such as high fluorescence, single-photon generation, millisecond-long coherence times, and the ability to initialize and read the spin state using purely optical means. This makes NV− centers a powerful sensing tool for a range of applications, including magnetometry, electrometry, and thermometry. Biocompatible NV-rich nanodiamonds find application in cellular microscopy, nanoscopy, and in vivo imaging. NV− centers can also detect electron spins, paramagnetic agents, and nuclear spins. Techniques have been developed to hyperpolarize 14N, 15N, and 13C nuclear spins, which could open up new perspectives in NMR and MRI. However, defects on the diamond surface, such as hydrogen, vacancies, and trapping states, can reduce the stability of NV− in favor of the neutral form (NV0), which lacks the same properties. Laser irradiation can also lead to charge-state switching and a reduction in the number of NV− centers. Efforts have been made to improve stability through diamond substrate doping, proper annealing and surface termination, laser irradiation, and electric or electrochemical tuning of the surface potential. This article discusses advances in the stabilization and enrichment of shallow NV− ensembles, describing strategies for improving the quality of diamond devices for sensing and spin-polarization transfer applications. Selected applications in the field of biosensing are discussed in more depth. [ABSTRACT FROM AUTHOR]

Ensembles of negatively charged nitrogen-vacancy centers (NV−) in diamond have been proposed for sensing of magnetic fields and paramagnetic agents, and as a source of spin-order for the hyperpolarization of nuclei in magnetic resonance applications. To this end, strongly fluorescent nanodiamonds (NDs) represent promising materials, with large surface areas and dense ensembles of NV−. However, surface effects tend to favor the less useful neutral form, the NV0 centers, and strategies to increase the density of shallow NV− centers have been proposed, including irradiation with strong laser power (Gorrini in ACS Appl Mater Interfaces. 13:43221–43232, 2021). Here, we study the fluorescence properties and optically detected magnetic resonance (ODMR) of NV− centers as a function of laser power in strongly fluorescent bulk diamond and in nanodiamonds obtained by nanomilling of the native material. In bulk diamond, we find that increasing laser power increases ODMR contrast, consistent with a power-dependent increase in spin-polarization. Conversely, in nanodiamonds we observe a non-monotonic behavior, with a decrease in ODMR contrast at higher laser power. We hypothesize that this phenomenon may be ascribed to more efficient NV−→NV0 photoconversion in nanodiamonds compared to bulk diamond, resulting in depletion of the NV− pool. A similar behavior is shown for NDs internalized in macrophage cells under the typical experimental conditions of imaging bioassays. Our results suggest strong laser irradiation is not an effective strategy in NDs, where the interplay between surface effects and local microenvironment determine the optimal experimental conditions. [ABSTRACT FROM AUTHOR]

Abnormal resting‐state functional connectivity, as measured by functional magnetic resonance imaging (MRI), has been reported in alcohol use disorders (AUD), but findings are so far inconsistent. Here, we exploited recent developments in graph‐theoretical analyses, enabling improved resolution and fine‐grained representation of brain networks, to investigate functional connectivity in 35 recently detoxified alcohol dependent patients versus 34 healthy controls. Specifically, we focused on the modular organization, that is, the presence of tightly connected substructures within a network, and on the identification of brain regions responsible for network integration using an unbiased approach based on a large‐scale network composed of more than 600 a priori defined nodes. We found significant reductions in global connectivity and region‐specific disruption in the network topology in patients compared with controls. Specifically, the basal brain and the insular–supramarginal cortices, which form tightly coupled modules in healthy subjects, were fragmented in patients. Further, patients showed a strong increase in the centrality of the anterior insula, which exhibited stronger connectivity to distal cortical regions and weaker connectivity to the posterior insula. Anterior insula centrality, a measure of the integrative role of a region, was significantly associated with increased risk of relapse. Exploratory analysis suggests partial recovery of modular structure and insular connectivity in patients after 2 weeks. These findings support the hypothesis that, at least during the early stages of abstinence, the anterior insula may drive exaggerated integration of interoceptive states in AUD patients with possible consequences for decision making and emotional states and that functional connectivity is dynamically changing during treatment. [ABSTRACT FROM AUTHOR]

Functional magnetic resonance imaging (fMRI) is an extensively used method for the investigation of normal and pathological brain function. In particular, fMRI has been used to characterize spatiotemporal hemodynamic response to pharmacological challenges as a non-invasive readout of neuronal activity. However, the mechanisms underlying regional signal changes are yet unclear. In this study, we use a meta-analytic approach to converge data from microdialysis experiments with relative cerebral blood volume (rCBV) changes following acute administration of neuropsychiatric drugs in adult male rats. At whole-brain level, the functional response patterns show very weak correlation with neurochemical alterations, while for numerous brain areas a strong positive correlation with noradrenaline release exists. At a local scale of individual brain regions, the rCBV response to neurotransmitters is anatomically heterogeneous and, importantly, based on a complex interplay of different neurotransmitters that often exert opposing effects, thus providing a mechanism for regulating and fine tuning hemodynamic responses in specific regions. [ABSTRACT FROM AUTHOR]

A few studies have reported aberrant functional connectivity in alcoholic patients, but the specific neural circuits involved remain unknown. Moreover, it is unclear whether these alterations can be reversed upon treatment. Here, we used functional MRI to study resting state connectivity in rats following chronic intermittent exposure to ethanol. Further, we evaluated the effects of SB-277011-a, a selective dopamine D3 receptor antagonist, known to decrease ethanol consumption. Alcohol-dependent and control rats (N = 13/14 per group), 3 weeks into abstinence, were administered SB-277011-a or vehicle before fMRI sessions. Resting state connectivity networks were extracted by independent component analysis. A dual-regression analysis was performed using independent component maps as spatial regressors, and the effects of alcohol history and treatment on connectivity were assessed. A history of alcohol dependence caused widespread reduction of the internal coherence of components. Weaker correlation was also found between the insula cortex (IC) and cingulate cortices, key constituents of the salience network. Similarly, reduced connectivity was observed between a component comprising the anterior insular cortex, together with the caudate putamen (CPu-AntIns), and the posterior part of the IC. On the other hand, postdependent rats showed strengthened connectivity between salience and reward networks. In particular, higher connectivity was observed between insula and nucleus accumbens, between the ventral tegmental area and the cingulate cortex and between the VTA and CPu-AntIns. Interestingly, aberrant connectivity in postdependent rats was partially restored by acute administration of SB-277011-a, which, conversely, had no significant effects in naïve rats. [ABSTRACT FROM AUTHOR]

The general misconception that γ-lactones are not thermodynamically polymerizable has limited the development of all γ-lactone-based copolymers. A few studies have reported copolymerization of these five-membered cyclic esters with more reactive monomers, yet a systematic investigation of kinetics and thermodynamics is still lacking. To explore the feasibility of the reaction, we combined equilibrium and non-isothermal syntheses for the copolymerization of γ-valerolactone with ϵ-caprolactone, initiated with methoxy polyethyleneglycol and catalyzed by Tin(II) 2-ethylhexanoate. Here, we present the polymerization kinetic and thermodynamic parameters for different monomer ratios in the reaction feed. We observed the dependency of enthalpy and entropy of polymerization upon monomer ratio changes, and estimated a linear increase in the activation energy by increasing the γ-valerolactone fraction in the starting monomer mixture. Our data demonstrate that γ-valerolactone can copolymerize with ϵ-caprolactone, but only under specific conditions. The reaction parameters determined in this study will enable preparation of additional γ-valerolactone-based copolymers and development of a family of degradable materials with improved properties in respect to commonly used polyesters. [ABSTRACT FROM AUTHOR]

Neuroimaging data can be represented as networks of nodes and edges that capture the topological organization of the brain connectivity. Graph theory provides a general and powerful framework to study these networks and their structure at various scales. By way of example, community detection methods have been widely applied to investigate the modular structure of many natural networks, including brain functional connectivity networks. Sparsification procedures are often applied to remove the weakest edges, which are the most affected by experimental noise, and to reduce the density of the graph, thus making it theoretically and computationally more tractable. However, weak links may also contain significant structural information, and procedures to identify the optimal tradeoff are the subject of active research. Here, we explore the use of percolation analysis, a method grounded in statistical physics, to identify the optimal sparsification threshold for community detection in brain connectivity networks. By using synthetic networks endowed with a ground-truth modular structure and realistic topological features typical of human brain functional connectivity networks, we show that percolation analysis can be applied to identify the optimal sparsification threshold that maximizes information on the networks' community structure. We validate this approach using three different community detection methods widely applied to the analysis of brain connectivity networks: Newman's modularity, InfoMap and Asymptotical Surprise. Importantly, we test the effects of noise and data variability, which are critical factors to determine the optimal threshold. This data-drivenmethod should prove particularly useful in the analysis of the community structure of brain networks in populations characterized by different connectivity strengths, such as patients and controls. [ABSTRACT FROM AUTHOR]

Self-similarity across length scales is pervasively observed in natural systems. Here, we investigate topological self-similarity in complex networks representing diverse forms of connectivity in the brain and some related dynamical systems, by considering the correlation between edges directly connecting any two nodes in a network and indirect connection between the same via all triangles spanning the rest of the network. We note that this aspect of self-similarity, which is distinct from hierarchically nested connectivity (coarse-grain similarity), is closely related to idempotence of the matrix representing the graph. We introduce two measures, ι(1)ι(1) and ι(∞)ι(∞), which represent the element-wise correlation coefficients between the initial matrix and the ones obtained after squaring it once or infinitely many times, and term the matrices which yield large values of these parameters "quasi-idempotent". These measures delineate qualitatively different forms of "shallow" and "deep" quasi-idempotence, which are influenced by nodal strength heterogeneity. A high degree of quasi-idempotence was observed for partially synchronized mean-field Kuramoto oscillators with noise, electronic chaotic oscillators, and cultures of dissociated neurons, wherein the expression of quasi-idempotence correlated strongly with network maturity. Quasi-idempotence was also detected for macro-scale brain networks representing axonal connectivity, synchronization of slow activity fluctuations during idleness, and co-activation across experimental tasks, and preliminary data indicated that quasi-idempotence of structural connectivity may decrease with ageing. This initial study highlights that the form of network self-similarity indexed by quasi-idempotence is detectable in diverse dynamical systems, and draws attention to it as a possible basis for measures representing network "collectivity" and pattern formation. [ABSTRACT FROM AUTHOR]

Different measures of brain connectivity can be defined based on neuroimaging read-outs, including structural and functional connectivity. Neurological and psychiatric conditions are often associated with abnormal connectivity, but comparing the effects of the disease on different types of connectivity remains a challenge. In this paper, we address the problem of quantifying the relative effects of brain disease on structural and functional connectivity at a group level. Within the framework of a graph representation of connectivity, we introduce a kernel two-sample test as an effective method to assess the difference between the patients and control group. Moreover, we propose a common representation space for structural and functional connectivity networks, and a novel test statistics to quantitatively assess differential effects of the disease on different types of connectivity. We apply this approach to a dataset from BTBR mice, a murine model of Agenesis of the Corpus Callosum (ACC), a congenital disorder characterized by the absence of the main bundle of fibers connecting the two hemispheres. We used normo-callosal mice (B6) as a comparator. The application of the proposed methods to this data-set shows that the two types of connectivity can be successfully used to discriminate between BTBR and B6, meaning that both types of connectivity are affected by ACC. However, our novel test statistics shows that structural connectivity is significantly more affected than functional connectivity, consistent with the idea that functional connectivity has a robust topology that can tolerate substantial alterations in its structural connectivity substrate. [ABSTRACT FROM AUTHOR]

The combined use of mice that have genetic mutations (transgenic mouse models) of human pathology and advanced neuroimaging methods (such as magnetic resonance imaging) has the potential to radically change how we approach disease understanding, diagnosis and treatment. Morphological changes occurring in the brain of transgenic animals as a result of the interaction between environment and genotype can be assessed using advanced image analysis methods, an effort described as ‘mouse brain phenotyping’. However, the computational methods involved in the analysis of high-resolution brain images are demanding. While running such analysis on local clusters is possible, not all users have access to such infrastructure and even for those that do, having additional computational capacity can be beneficial (e.g. to meet sudden high throughput demands). In this paper we use a commercial cloud platform for brain neuroimaging and analysis. We achieve a registration-based multi-atlas, multi-template anatomical segmentation, normally a lengthy-in-time effort, within a few hours. Naturally, performing such analyses on the cloud entails a monetary cost, and it is worthwhile identifying strategies that can allocate resources intelligently. In our context a critical aspect is the identification of how long each job will take. We propose a method that estimates the complexity of an image-processing task, a registration, using statistical moments and shape descriptors of the image content. We use this information to learn and predict the completion time of a registration. The proposed approach is easy to deploy, and could serve as an alternative for laboratories that may require instant access to large high-performance-computing infrastructures. To facilitate adoption from the community we publicly release the source code. [ABSTRACT FROM AUTHOR]

Mapping of structural and functional connectivity may provide deeper understanding of brain function and disfunction. Diffusion Magnetic Resonance Imaging (DMRI) is a powerful technique to non-invasively delineate white matter (WM) tracts and to obtain a three-dimensional description of the structural architecture of the brain. However, DMRI tractography methods produce highly multi-dimensional datasets whose interpretation requires advanced analytical tools. Indeed, manual identification of specific neuroanatomical tracts based on prior anatomical knowledge is time-consuming and prone to operator-induced bias. Here we propose an automatic multi-subject fiber clustering method that enables retrieval of group-wise WM fiber bundles. In order to account for variance across subjects, we developed a multi-subject approach based on a method known as Dominant Sets algorithm, via an intra- and cross-subject clustering. The intra-subject step allows us to reduce the complexity of the raw tractography data, thus obtaining homogeneous neuroanatomically-plausible bundles in each diffusion space. The cross-subject step, characterized by a proper space-invariant metric in the original diffusion space, enables the identification of the same WM bundles across multiple subjects without any prior neuroanatomical knowledge. Quantitative analysis was conducted comparing our algorithm with spectral clustering and affinity propagation methods on synthetic dataset. We also performed qualitative analysis on mouse brain tractography retrieving significant WM structures. The approach serves the final goal of detecting WM bundles at a population level, thus paving the way to the study of the WM organization across groups. [ABSTRACT FROM AUTHOR]

Nanolithography techniques enable the fabrication of complex nanodevices that can be used for biosensing purposes. However, these devices are normally supported by a substrate and their use is limited to in vitro applications. Following a top-down procedure, we designed and fabricated composite inductance-capacitance (LC) nanoresonators that can be detached from their substrate and dispersed in water. The multimaterial composition of these resonators makes it possible to differentially functionalize different parts of the device to obtain stable aqueous suspensions and multi-sensing capabilities. For the first time, we demonstrate detection of these devices in an aqueous environment, and we show that they can be sensitized to their local environment and to chemical binding of specific molecular moieties. The possibility to optically probe the nanoresonator resonance in liquid dispersions paves the way to a variety of new applications, including injection into living organisms for in vivo sensing and imaging. [ABSTRACT FROM AUTHOR]

Microglia are phagocytic cells that infiltrate the brain during development and have a role in the elimination of synapses during brain maturation. Changes in microglial morphology and gene expression have been associated with neurodevelopmental disorders. However, it remains unknown whether these changes are a primary cause or a secondary consequence of neuronal deficits. Here we tested whether a primary deficit in microglia was sufficient to induce some autism-related behavioral and functional connectivity deficits. Mice lacking the chemokine receptor Cx3cr1 exhibit a transient reduction of microglia during the early postnatal period and a consequent deficit in synaptic pruning. We show that deficient synaptic pruning is associated with weak synaptic transmission, decreased functional brain connectivity, deficits in social interaction and increased repetitive-behavior phenotypes that have been previously associated with autism and other neurodevelopmental and neuropsychiatric disorders. These findings open the possibility that disruptions in microglia-mediated synaptic pruning could contribute to neurodevelopmental and neuropsychiatric disorders. [ABSTRACT FROM AUTHOR]

Dendrimers are branched polymers with spherical morphology. Their tuneable chemistry and surface modification make them valuable nanomaterials for biomedical applications. In view of possible dendrimer uses as brain-aimed nanocarriers, the authors studied amine- and lipid-functionalised (G4) polyamidoamine (PAMAM) biocompatibility with cell population forming the blood-brain barrier (BBB). Both amine-PAMAM and lipid-PAMAM dendrimers were able to enter endothelial and primary neural cells. However, only amine-PAMAM damaged cell membranes in a dose-dependent manner. Transmission electron microscopy evidenced the ability of dendrimers to precipitate salts and serum components present in culture medium that slightly increased toxicity of the amine-PAMAM. Amine- and lipid-PAMAM were both able to cross the BBB and differently induced CD11b and CCR2 overexpression on primary CX3CR1-GFP murine microglia in vitro. These data emphasise the role of dendrimer surface functionalisation in toxicity and neural immune cell activation, raising concerns about possible neuroinflammatory reactions. [ABSTRACT FROM AUTHOR]

Translational approaches to study the neural substrates of stress and assess the mechanistic efficacy of novel anti-anxiety agents necessitate the use of stressors with a similar degree of saliency across species. The alpha-2 adrenoreceptor antagonist yohimbine represents an attractive experimental tool owing to its well-documented stress-inducing properties in humans and laboratory species. We investigated the neural substrates engaged by yohimbine in the rat brain by using functional magnetic resonance imaging and mapped their modulation by neurotransmitter systems involved in stress responses. Yohimbine elicited a composite pattern of brain activation, highlighting the recruitment of cortico-striato-thalamic regions and extra-hypothalamic stress neurocircuits. This effect was strongly attenuated by the α-2-adrenoceptor agonist medetomidine and by the dopamine (DA) D1 receptor antagonist SCH23390, thus revealing a primary contribution of both norepinephrine and DA on the neurofunctional cascade elicited by the drug. Pretreatment with the corticotrophin-releasing factor type-1 receptor (CRF1R) antagonist CP154,526 produced a region-dependent inhibition of yohimbine-induced activation in the amygdala, striatum, and cingulate cortex, while the orexin type-1 receptor (OX1R) antagonists GSK1059865 robustly inhibited the response in fronto-hippocampal regions as well as in several key components of the extended amygdala. CP154,526 and GSK1059865 did not prevent yohimbine-induced plasma corticosterone release, a finding that corroborates a central origin of the effects mapped. Our findings provide novel insight into the brain substrates and neurochemical mediators engaged by the stress-inducing agent yohimbine. The differential pattern of inhibition produced by CRF1R and OX1R antagonists suggests that these two neuropeptide systems can modulate the functional response to stress via distinct central neural pathways. [ABSTRACT FROM AUTHOR]

BTBR T+tf/J (BTBR) mice display prominent behavioural deficits analogous to the defining symptoms of autism, a feature that has prompted a widespread use of the model in preclinical autism research. Because neuro-behavioural traits are described with respect to reference populations, multiple investigators have examined and described the behaviour of BTBR mice against that exhibited by C57BL/6J (B6), a mouse line characterised by high sociability and low self-grooming. In an attempt to probe the translational relevance of this comparison for autism research, we used Magnetic Resonance Imaging (MRI) to map in both strain multiple morpho-anatomical and functional neuroimaging readouts that have been extensively used in patient populations. Diffusion tensor tractography confirmed previous reports of callosal agenesis and lack of hippocampal commissure in BTBR mice, and revealed a concomitant rostro-caudal reorganisation of major cortical white matter bundles. Intact inter-hemispheric tracts were found in the anterior commissure, ventro-medial thalamus, and in a strain-specific white matter formation located above the third ventricle. BTBR also exhibited decreased fronto-cortical, occipital and thalamic gray matter volume and widespread reductions in cortical thickness with respect to control B6 mice. Foci of increased gray matter volume and thickness were observed in the medial prefrontal and insular cortex. Mapping of resting-state brain activity using cerebral blood volume weighted fMRI revealed reduced cortico-thalamic function together with foci of increased activity in the hypothalamus and dorsal hippocampus of BTBR mice. Collectively, our results show pronounced functional and structural abnormalities in the brain of BTBR mice with respect to control B6 mice. The large and widespread white and gray matter abnormalities observed do not appear to be representative of the neuroanatomical alterations typically observed in autistic patients. The presence of reduced fronto-cortical metabolism is of potential translational relevance, as this feature recapitulates previously-reported clinical observations. [ABSTRACT FROM AUTHOR]

Pharmacological stimulation of N-methyl- D-aspartate receptors ( NMDAr) could enhance the outcome of cue-exposure therapy for smoking cessation. NMDAr stimulation can be achieved by increasing pharmacologically the synaptic levels of glycine, a necessary co-agonist. Here, we evaluate the effects of SSR504734, a selective inhibitor of glycine type I transporter ( GlyT1) in an extinction-reinstatement procedure inducing robust and lasting nicotine-seeking behavior in rats. Male Wistar rats were trained to associate discriminative stimuli ( S D s) with the availability of nicotine (0.03 mg/kg/65 μL/2 second/infusion) or sucrose (45-mg pellet) versus non-reward in two-lever operant cages. Reinforced response was followed by cue signaling 20-second time-out ( CSs). Once the training criterion was met, rats underwent extinction of lever presses, in the absence of reinforcers, S D s and CSs. Re-exposure to nicotine or sucrose S D+/ CS+, but not non-reward S D−/ CS−, revived responding at the previously reinforced lever. Acute pre-treatment with SSR504734 (10 mg/kg i.p.) reduced nicotine-seeking but not sucrose-seeking behavior without influencing rats' locomotor activity. Sub-chronic treatment (10 mg/kg i.p. for 5 days) during daily exposure to S D+/ CS+ reduced nicotine-seeking; however, this effect was transient, with return to S D+/ CS+ responding at 72 hours. Full recovery to S D+/ CS+ responding was observed after 1 month suggesting that SSR504734 sub-acute treatment did not engage the long-term plasticity mechanisms probably involved in nicotine-seeking. In conclusion, GlyT1-inhibitors might offer a therapeutic opportunity for acute cue-controlled nicotine-seeking, but the lack of persistent effects of the sub-chronic treatment associated with nicotine cues exposure suggests that short-term administration of GlyT1-inhibitor SSR504734 is not sufficient to promote extinction of nicotine-cue conditioned responding. [ABSTRACT FROM AUTHOR]

Antimicrobial peptides (AMPs) are an abundant and wide class of molecules produced by many tissues and cell types in a variety of mammals, plant and animal species. Linear alpha-helical antimicrobial peptides are among the most widespread membrane-disruptive AMPs in nature, representing a particularly successful structural arrangement in innate defense. Recently, AMPs have received increasing attention as potential therapeutic agents, owing to their broad activity spectrum and their reduced tendency to induce resistance. The introduction of non-natural amino acids will be a key requisite in order to contrast host resistance and increase compound's life. In this work, the possibility to design novel AMP sequences with non-natural amino acids was achieved through a flexible computational approach, based on chemophysical profiles of peptide sequences. Quantitative structure-activity relationship (QSAR) descriptors were employed to code each peptide and train two statistical models in order to account for structural and functional properties of alpha-helical amphipathic AMPs. These models were then used as fitness functions for a multi-objective evolutional algorithm, together with a set of constraints for the design of a series of candidate AMPs. Two ab-initio natural peptides were synthesized and experimentally validated for antimicrobial activity, together with a series of control peptides. Furthermore, a well-known Cecropin-Mellitin alpha helical antimicrobial hybrid (CM18) was optimized by shortening its amino acid sequence while maintaining its activity and a peptide with non-natural amino acids was designed and tested, demonstrating the higher activity achievable with artificial residues. [ABSTRACT FROM AUTHOR]

The octopus sucker represents a fascinating natural system performing adhesion on different terrains and substrates. Octopuses use suckers to anchor the body to the substrate or to grasp, investigate and manipulate objects, just to mention a few of their functions. Our study focuses on the morphology and adhesion mechanism of suckers in Octopus vulgaris. We use three different techniques (MRI, ultrasonography, and histology) and a 3D reconstruction approach to contribute knowledge on both morphology and functionality of the sucker structure in O. vulgaris. The results of our investigation are two-fold. First, we observe some morphological differences with respect to the octopus species previously studied (i.e., Octopus joubini, Octopus maya, Octopus bimaculoides/bimaculatus and Eledone cirrosa). In particular, in O. vulgaris the acetabular chamber, that is a hollow spherical cavity in other octopuses, shows an ellipsoidal cavity which roof has an important protuberance with surface roughness. Second, based on our findings, we propose a hypothesis on the sucker adhesion mechanism in O. vulgaris. We hypothesize that the process of continuous adhesion is achieved by sealing the orifice between acetabulum and infundibulum portions via the acetabular protuberance. We suggest this to take place while the infundibular part achieves a completely flat shape; and, by sustaining adhesion through preservation of sucker configuration. In vivo ultrasonographic recordings support our proposed adhesion model by showing the sucker in action. Such an underlying physical mechanism offers innovative potential cues for developing bioinspired artificial adhesion systems. Furthermore, we think that it could possibly represent a useful approach in order to investigate any potential difference in the ecology and in the performance of adhesion by different species. [ABSTRACT FROM AUTHOR]

ABSTRACT Ghrelin (GHR) is an orexigenic gut peptide that interacts with brain ghrelin receptors (GHR-Rs) to promote food intake. Recent research suggests that GHR acts as a modulator of motivated behavior, suggesting a direct influence of GHR on brain reinforcement circuits. In the present studies, we investigated the role of GHR and GHR-Rs in brain reinforcement function. Pharmacological magnetic resonance imaging was used to spatially resolve the functional activation produced by systemic administration of an orexigenic GHR dose. The imaging data revealed a focal activation of a network of subcortical structures that comprise brain reinforcement circuits-ventral tegmental area, lateral hypothalamus and nucleus accumbens. We next analyzed whether brain reinforcement circuits require functional GHR-Rs. To this purpose, wild-type (WT) or mutant rats sustaining N-ethyl-N-nitrosourea-induced knockout of GHR-Rs (GHR-R null rats) were implanted with stimulating electrodes aimed at the lateral hypothalamus, shaped to respond for intracranial self-stimulation (ICSS) and then tested using a rate-frequency procedure to examine ICSS response patterns. WT rats were readily shaped using stimulation intensities of 75 µA, whereas GHR-R null rats required 300 µA for ICSS shaping. No differences in rate-frequency curves were noted for WT rats at 75 µA and GHR-R null rats at 300 µA. When current intensity was lowered to 100 µA, GHR-R null rats did not respond for ICSS. Taken collectively, these data suggest that systemic GHR can activate mesolimbic dopaminergic areas, and highlight a facilitative role of GHR-Rs on the activity of brain reinforcement systems. [ABSTRACT FROM AUTHOR]

Modafinil (MOD) is a wake-promoting drug with pro-cognitive properties. Despite its increasing use, the neuronal substrates of MOD action remain elusive. In particular, animal studies have highlighted a putative role of diencephalic areas as primary neuronal substrate of MOD action, with inconsistent evidence of recruitment of fronto-cortical areas despite the established pro-cognitive effects of the drug. Moreover, most animal studies have employed doses of MOD of limited clinical relevance. We used pharmacological magnetic resonance imaging (phMRI) in the anesthetized rat to map the circuitry activated by a MOD dose producing clinically relevant plasma exposure, as here ascertained by pharmacokinetic measurements. We observed prominent and sustained activation of the prefrontal and cingulate cortex, together with weaker but significant activation of the somatosensory cortex, medial thalamic domains, hippocampus, ventral striatum and dorsal raphe. Correlation analysis of phMRI data highlighted enhanced connectivity within a neural network including dopamine projections from the ventral tegmental area to the nucleus accumbens. The pro-arousing effect of MOD was assessed using electroencephalographic recording under anesthetic conditions comparable to those used for phMRI, together with the corresponding Fos immunoreactivity distribution. MOD produced electroencephalogram desynchronization, resulting in reduced delta and increased theta frequency bands, and a pattern of Fos induction largely consistent with the phMRI study. Altogether, these findings show that clinically relevant MOD doses can robustly activate fronto-cortical areas involved in higher cognitive functions and a network of pro-arousing areas, which provide a plausible substrate for the wake-promoting and pro-cognitive effects of the drug. [ABSTRACT FROM AUTHOR]

Cocaine addiction is often modeled in experimental paradigms where rodents learn to self-administer (SA) the drug. However, the extent to which these models replicate the functional alterations observed in clinical neuroimaging studies of cocaine addiction remains unknown. We used magnetic resonance imaging (MRI) to assess basal and evoked brain function in rats subjected to a prolonged, extended-access cocaine SA scheme. Specifically, we measured basal cerebral blood volume (bCBV), an established correlate of basal metabolism, and assessed the reactivity of the dopaminergic system by mapping the pharmacological MRI (phMRI) response evoked by the dopamine-releaser amphetamine. Cocaine-exposed subjects exhibited reduced bCBV in fronto-cortical areas, nucleus accumbens, ventral hippocampus, and thalamus. The cocaine group also showed an attenuated functional response to amphetamine in ventrostriatal areas, an effect that was significantly correlated with total cocaine intake. An inverse relationship between bCBV in the reticular thalamus and the frontal response elicited by amphetamine was found in control subjects but not in the cocaine group, suggesting that the inhibitory interplay within this attentional circuit may be compromised by the drug. Importantly, histopathological analysis did not reveal significant alterations of the microvascular bed in the brain of cocaine-exposed subjects, suggesting that the imaging findings cannot be merely ascribed to cocaine-induced vascular damage. These results document that chronic, extended-access cocaine SA in the rat produces focal fronto-cortical and striatal alterations that serve as plausible neurobiological substrate for the behavioral expression of compulsive drug intake in laboratory animals. [ABSTRACT FROM AUTHOR]

Orexins are neuro-modulatory peptides involved in the control of diverse physiological functions through interaction with two receptors, orexin-1 (OX1R) and orexin-2 (OX2R). Recent evidence in pre-clinical models points toward a putative dichotomic role of the two receptors, with OX2R predominantly involved in the regulation of the sleep/wake cycle and arousal, and the OX1R being more specifically involved in reward processing and motivated behaviour. However, the specific neural substrates underlying these distinct processes in the rat brain remain to be elucidated. Here we used functional magnetic resonance imaging (fMRI) in the rat to map the modulatory effect of selective OXR blockade on the functional response produced by D-amphetamine, a psychostimulant and arousing drug that stimulates orexigenic activity. OXR blockade was produced by GSK1059865 and JNJ1037049, two novel OX1R and OX2R antagonists with unprecedented selectivity at the counter receptor type. Both drugs inhibited the functional response to D-amphetamine albeit with distinct neuroanatomical patterns: GSK1059865 focally modulated functional responses in striatal terminals, whereas JNJ1037049 induced a widespread pattern of attenuation characterised by a prominent cortical involvement. At the same doses tested in the fMRI study, JNJ1037049 exhibited robust hypnotic properties, while GSK1059865 failed to display significant sleep-promoting effects, but significantly reduced drug-seeking behaviour in cocaine-induced conditioned place preference. Collectively, these findings highlight an essential contribution of the OX2R in modulating cortical activity and arousal, an effect that is consistent with the robust hypnotic effect exhibited by JNJ1037049. The subcortical and striatal pattern observed with GSK1059865 represent a possible neurofunctional correlate for the modulatory role of OX1R in controlling reward-processing and goal-oriented behaviours in the rat. [ABSTRACT FROM AUTHOR]

Several second-generation antipsychotics are characterised by a significant antagonistic effect at serotonin 5-HT2A receptors (5-HT2AR), a feature that has been associated with lower incidence of extra-pyramidal symptoms and a putative amelioration of positive and negative symptoms experienced by schizophrenic patients. However, the neurofunctional substrate of 5-HT2A antagonism and its exact contribution to the complex pharmacological profile of these drugs remain to be elucidated. Here, we used pharmacological magnetic resonance imaging to map the modulatory effects of the selective 5-HT2AR antagonist Ml00907 on the spatiotemporal patterns of brain activity elicited by acute phencyclidine (PCP) challenge in the rat. PCP is a non-competitive NMDA receptor antagonist that induces dysregulation of corticolimbic glutamatergic neurotransmission and produces cognitive impairment and psychotic-like symptoms reminiscent of those observed in schizophrenia. Pre-administration of M100907 produced focal and region-dependent attenuation of PCP-induced response in frontoseptohippocampal areas. As early studies highlighted a permissive role of 5-HT2AR on frontal dopamine release, the role of post-synaptic dopamine D1 receptors on PCP-induced response was examined by using the potent antagonist SCH23390. Interestingly, SCH23390 did not affect PCP’s response in any of the regions examined. This finding rules out a significant contribution of dopamine in the functional changes mapped and, indirectly, the inhibitory effect of M100907, in favour of a glutamatergic origin. Our data expand recent evidence suggesting a key role of 5-HT2AR in modulating glutamate-mediated cognitive performance in the prefrontal cortex and highlight the whole frontoseptohippocampal circuit as a key functional substrate of 5-HT2AR antagonism in normal and disease states. [ABSTRACT FROM AUTHOR]

Increasing experimental evidence suggests that impaired N-methyl- d-aspartic acid (NMDA) receptor (NMDAr) function could be a key pathophysiological determinant of schizophrenia. Agonists at the allosteric glycine (Gly) binding site of the NMDA complex can promote NMDAr activity, a strategy that could provide therapeutic efficacy for the disorder. NMDAr antagonists like phencyclidine (PCP) can induce psychotic and dissociative symptoms similar to those observed in schizophrenia and are therefore widely used experimentally to impair NMDA neurotransmission in vivo. In the present study, we used pharmacological magnetic resonance imaging (phMRI) to investigate the modulatory effects of endogenous and exogenous agonists at the NMDAr Gly site on the spatiotemporal patterns of brain activation induced by acute PCP challenge in the rat. The drugs investigated were d-serine, an endogenous agonist of the NMDAr Gly site, and SSR504734, a potent Gly transporter type 1 (GlyT-1) inhibitor that can potentiate NMDAr function by increasing synaptic levels of Gly. Acute administration of PCP induced robust and sustained activation of discrete cortico-limbo-thalamic circuits. Pretreatment with d-serine (1 g/kg) or SSR504734 (10 mg/kg) completely inhibited PCP-induced functional activation. This effect was accompanied by weak but sustained deactivation particularly in cortical areas. These findings suggest that agents that stimulate NMDAr via Gly co-agonist site can potentiate NMDAr activity in the living brain and corroborate the potential for this class of drugs to provide selective enhancement of NMDAr neurotransmission in schizophrenia. [ABSTRACT FROM AUTHOR]

Acute administration of NMDA receptor (NMDAR) antagonists such as phencyclidine (PCP) or ketamine induces symptoms that closely resemble those of schizophrenia in humans, a finding that has led to the hypothesis that a decreased NMDAR function may be a predisposing or even causative factor in schizophrenia. However, the precise neuropharmacological mechanisms underlying these effects remain to be fully elucidated. Here, we applied pharmacological MRI (phMRI) to examine the brain circuitry underlying the psychotomimetic action of PCP in the anesthetized rat, and investigated how these functional changes are modulated by drugs that possess distinct pharmacological mechanisms. Acute administration of PCP (0.5 mg/kg i.v.) produced robust and sustained positive relative cerebral blood volume (rCBV) changes in discrete cortico-limbo-thalamic regions. Pretreatment with the selective D2 dopamine antagonist raclopride (0.3 mg/kg i.p.) did not significantly affect the rCBV response to PCP, while the atypical antipsychotic clozapine (5 mg/kg i.p.) produced region-dependent effects, with complete suppression of the rCBV response in the thalamus, and weaker attenuation of the response in cortical and hippocampal structures. The response to PCP was strongly suppressed in all regions by pretreatment with two drugs that can inhibit aberrant glutamatergic activity: the anticonvulsant lamotrigine (10 mg/kg i.p.) and the mGluR2/3 agonist LY354740 (10 mg/kg i.p.). Taken together, our findings corroborate the pivotal role of dysfunctional glutamatergic neurotransmission in the functional response elicited by PCP, while the lack of effect of raclopride argues against a primary role of dopamine D2 receptor activation in this process. Finally, the thalamic effect of clozapine could be key to elucidating the functional basis of its pharmacological action.Neuropsychopharmacology (2008) 33, 1690–1703; doi:10.1038/sj.npp.1301547; published online 5 September 2007 [ABSTRACT FROM AUTHOR]

We investigated the functional connectivity structure underlying the widespread relative cerebral blood volume (rCBV) response to d-amphetamine in the rat brain by systematically analyzing the intersubject correlations between the response amplitudes in 48 atlas-defined brain structures. A cluster analysis resolved three distinct networks of brain regions that exhibited closely coupled responses: one corresponding to primary dopamine projections from the midbrain to the striatum, a second consisting predominantly of forebrain cortical and basal ganglia regions that share a widespread correlation pattern resembling the univariate group response, and a third including structures in the periventricular dopamine system. These results suggest that different functional networks underlie the brain's response to d-amphetamine. This approach may provide important new insights regarding the central systems that underlie pharmacological action. Magn Reson Med 57:704-713, 2007. © 2007 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

We have applied pharmacological magnetic resonance imaging (phMRI) methods to map the functional response to nicotine in drug-naïve rats. Nicotine (0.35 mg/kg intravenous (i.v.)) increased relative cerebral blood volume (rCBV) in cortical (including medial prefrontal, cingulate orbitofrontal, insular) and subcortical (including amygdala and dorsomedial hippocampus) structures. The pharmacological specificity of the effect was demonstrated by acute pretreatment with the nicotinic acetylcholine receptor (nAChR) ion-channel-blocking agent mecamylamine, which suppressed the rCBV response to nicotine. Control experiments with norepinephrine, a potent non-brain-penetrant vasopressor, at a dose that mimics the cardiovascular response induced by nicotine were performed to assess the potential confounding effects of peripheral blood pressure changes induced by nicotine. In an attempt to highlight the relative contribution of different nAChR subtypes to the observed activation pattern of nicotine, we also investigated the central phMRI response to an acute challenge with (R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-(2-pyridyl)thiophene-2-carboxamide) (cpdA, at 5, 10, 20, and 30 mg/kg i.v.) and 5-iodo-A-85380 (5IA, 5 mg/kg i.v.). CpdA is a selective agonist at homomeric α7 nAChRs, while 5IA features high in vivo affinity for the α4β2* and other less-abundant β2-containing nicotinic receptors. CpdA did not produce significant rCBV changes at any of the doses tested, whereas 5IA induced a pattern of activation very similar to that induced by nicotine. The lack of phMRI response to cpdA together with the high spatial overlap between the activation profile of nicotine and 5IA, suggest that the acute functional response to nicotine in drug-naïve rats is mediated by β2-containing nAChR isoforms, presumably belonging to the α4β2* subtype.Neuropsychopharmacology (2006) 31, 1690–1703. doi:10.1038/sj.npp.1300955; published online 16 November 2005 [ABSTRACT FROM AUTHOR]

Dopamine (DA) receptors are a major target for drugs employed in the treatment of neuropsychiatric disorders such as schizophrenia and drug dependence. The D3 subtype of the D2 DA receptor family presents a particularly focal distribution in limbic brain areas known to be associated with cognitive and emotional functions. This study examined the modulation of brain activation induced by acute administration of amphetamine in the rat by the highly selective DA D3 receptor antagonist SB-277011-A using relative cerebral blood volume (rCBV) pharmacological MRI (phMRI). The acute administration of D-amphetamine (1 mg/kg i.v.) produced a widespread rCBV response that was strongest in cortical regions. SB-277011-A (20 mg/kg i.p.) itself did not produce significant changes in rCBV, but potentiated the phMRI response to 1 mg/kg i.v. D-amphetamine in a regionally specific manner, involving a number of structures outside the focal distribution of the D3 receptor. Potentiated regions included the accumbens, dorsal caudate putamen, islands of Calleja, thalamus, cingulate cortex, ventral tegmental area, dorsal Raphe nucleus, and ventral subiculum. The increased response following D3 receptor antagonism is consistent with this receptor mediating an inhibitory action on brain activity following a dopaminergic stimulus. Synapse 54:1-10, 2004. © 2004 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

We have computed the electronic structure and the imaginary part of the dielectric function of the Au55 cluster using a tight-binding model which takes into account size and boundary effects. Besides the Drude behavior, we obtain anomalous absorption peaks in the infrared region due to the breakdown of the selection rule Δ k=0. Taking into account surface coating effects, the onset of the interband absorption above 2.5 eV results to be red shifted, in agreement with the experimental data. As a consequence, we obtain a dramatic increase of the width of the plasmonic absorption peak, which accounts for the experimental optical spectra observed by Kreibig. [ABSTRACT FROM AUTHOR]

Due to the large number of possible applications in quantum technology fields—especially regarding quantum sensing—of nitrogen-vacancy (NV) centers in nanodiamonds (NDs), research on a cheap, scalable and effective NDs synthesis technique has acquired an increasing interest. Standard production methods, such as detonation and grinding, require multistep post-synthesis processes and do not allow precise control in the size and fluorescence intensity of NDs. For this reason, a different approach consisting of pulsed laser ablation of carbon precursors has recently been proposed. In this work, we demonstrate the synthesis of NV-fluorescent NDs through pulsed laser ablation of an N-doped graphite target. The obtained NDs are fully characterized in the morphological and optical properties, in particular with optically detected magnetic resonance spectroscopy to unequivocally prove the NV origin of the NDs photoluminescence. Moreover, to compare the different fluorescent NDs laser-ablation-based synthesis techniques recently developed, we report an analysis of the effect of the medium in which laser ablation of graphite is performed. Along with it, thermodynamic aspects of the physical processes occurring during laser irradiation are analyzed. Finally, we show that the use of properly N-doped graphite as a target for laser ablation can lead to precise control in the number of NV centers in the produced NDs. [ABSTRACT FROM AUTHOR]