J. Neurochem. (2011) 118, 680–694.
Recent observations suggest that besides their role in the immune system, chemokines have important functions in the brain. There is a great line of evidence to ...suggest that chemokines are a unique class of neurotransmitters/neuromodulators, which regulate many biological aspects as diverse as neurodevelopment, neuroinflammation and synaptic transmission. In physiopathological conditions, many chemokines are synthesized in activated astrocytes and microglial cells, suggesting their involvement in brain defense mechanisms. However, when evoking chemokine functions in the nervous system, it is important to make a distinction between resting conditions and various pathological states including inflammatory diseases, autoimmune or neurodegenerative disorders in which chemokine functions have been extensively studied. We illustrate here the emergent concept of the neuromodulatory/neurotransmitter activities of neurochemokines and their potential role as a regulatory alarm system and as a group of messenger molecules for the crosstalk between neurons and cells from their surrounding microenvironment. In this deliberately challenging review, we provide novel hypotheses on the role of these subtle messenger molecules in brain functions leading to the evidence that previous dogmas concerning chemokines should be reconsidered.
Selenoprotein T (SELENOT), a PACAP-regulated thioredoxin-like protein, plays a role in catecholamine secretion and protects dopaminergic neurons. However, the role of SELENOT in the establishment of ...the catecholaminergic (CA) neuronal system is not known yet.
We analyzed by immunohistochemistry and RNAscope in situ hybridization the distribution of SELENOT and the expression of its mRNA, respectively. In addition, 3D imaging involving immunostaining in toto, clearing through the iDISCO+ method, acquisitions by light-sheet microscopy, and processing of 3D images was performed to map the CA neuronal system. A semi-automatic quantification of 3D images was carried out.
SELENOT protein and mRNA are widely distributed in the mouse brain, with important local variations. Three-dimensional mapping, through tyrosine hydroxylase (TH) labeling, and semi-automated quantification of CA neurons in brain-specific SELENOT knockout mice showed a significant decrease in the number of TH-positive neurons in the area postrema (AP-A2), the A11 cell group (A11), and the zona incerta (ZI-A13) of SELENOT-deficient females, and in the hypothalamus (Hyp-A12-A14-A15) of SELENOT-deficient females and males.
These results showed that SELENOT is diffusely expressed in the mouse brain and that its deficiency impacts CA neuron distribution in different brain areas including Hyp-A12-A14-A15, in both male and female mice.
•We explore compulsivity and social disinhibition as subcomponents of disinhibition.•An original behavioural approach in a semi-ecological situation was used.•Different neural networks are implicated ...in compulsivity and social disinhibition.
Disinhibition is a core symptom of many neurodegenerative diseases, particularly frontotemporal dementia, and is a major cause of stress for caregivers. While a distinction between behavioural and cognitive disinhibition is common, an operational definition of behavioural disinhibition is still missing. Furthermore, conventional assessment of behavioural disinhibition, based on questionnaires completed by the caregivers, often lacks ecological validity. Therefore, their neuroanatomical correlates are non-univocal.
In the present work, we used an original behavioural approach in a semi-ecological situation to assess two specific dimensions of behavioural disinhibition: compulsivity and social disinhibition. First, we investigated disinhibition profile in patients compared to controls. Then, to validate our approach, compulsivity and social disinhibition scores were correlated with classic cognitive tests measuring disinhibition (Hayling Test) and social cognition (mini-Social cognition & Emotional Assessment). Finally, we disentangled the anatomical networks underlying these two subtypes of behavioural disinhibition, taking in account the grey (voxel-based morphometry) and white matter (diffusion tensor imaging tractography). We included 17 behavioural variant frontotemporal dementia patients and 18 healthy controls.
We identified patients as more compulsive and socially disinhibited than controls. We found that behavioural metrics in the semi-ecological task were related to cognitive performance: compulsivity correlated with the Hayling test and both compulsivity and social disinhibition were associated with the emotion recognition test. Based on voxel-based morphometry and tractography, compulsivity correlated with atrophy in the bilateral orbitofrontal cortex, the right temporal region and subcortical structures, as well as with alterations of the bilateral cingulum and uncinate fasciculus, the right inferior longitudinal fasciculus and the right arcuate fasciculus. Thus, the network of regions related to compulsivity matched the “semantic appraisal” network. Social disinhibition was associated with bilateral frontal atrophy and impairments in the forceps minor, the bilateral cingulum and the left uncinate fasciculus, regions corresponding to the frontal component of the “salience” network.
Summarizing, this study validates our semi-ecological approach, through the identification of two subtypes of behavioural disinhibition, and highlights different neural networks underlying compulsivity and social disinhibition. Taken together, these findings are promising for clinical practice by providing a better characterisation of inhibition disorders, promoting their detection and consequently a more adapted management of patients.
Aim
The aim of this paper is to describe the clinical features of COVID‐19‐related encephalopathy and their metabolic correlates using brain 2‐desoxy‐2‐fluoro‐D‐glucose (FDG)‐positron‐emission ...tomography (PET)/computed tomography (CT) imaging.
Background and purpose
A variety of neurological manifestations have been reported in association with COVID‐19. COVID‐19‐related encephalopathy has seldom been reported and studied.
Methods
We report four cases of COVID‐19‐related encephalopathy. The diagnosis was made in patients with confirmed COVID‐19 who presented with new‐onset cognitive disturbances, central focal neurological signs, or seizures. All patients underwent cognitive screening, brain magnetic resonance imaging (MRI), lumbar puncture, and brain 2‐desoxy‐2‐fluoro‐D‐glucose (FDG)‐positron‐emission tomography (PET)/computed tomography (CT) (FDG‐PET/CT).
Results
The four patients were aged 60 years or older, and presented with various degrees of cognitive impairment, with predominant frontal lobe impairment. Two patients presented with cerebellar syndrome, one patient had myoclonus, one had psychiatric manifestations, and one had status epilepticus. The delay between first COVID‐19 symptoms and onset of neurological symptoms was between 0 and 12 days. None of the patients had MRI features of encephalitis nor significant cerebrospinal fluid (CSF) abnormalities. SARS‐CoV‐2 RT‐PCR in the CSF was negative for all patients. All patients presented with a consistent brain FDG‐PET/CT pattern of abnormalities, namely frontal hypometabolism and cerebellar hypermetabolism. All patients improved after immunotherapy.
Conclusions
Despite varied clinical presentations, all patients presented with a consistent FDG‐PET pattern, which may reflect an immune mechanism.
Arrays of liquid crystal defects—linear smectic dislocations—are used to trap semiconductor CdSe/CdS dot‐in‐rods which behave as single‐photon emitters. Measurements of the emission diagram are ...combined together with measurements of the emitted polarization of the single emitters. It is shown that the dot‐in‐rods are confined parallel to the linear defects to allow for a minimization of the disorder energy associated with the dislocation cores. It is demonstrated that the electric dipoles associated with the dot‐in‐rods, tilted with respect to the rods, remain oriented in the plane including the smectic linear defects and perpendicular to the substrate, most likely due to dipole/dipole interactions between the dipoles of the liquid crystal molecules and those of the dot‐in‐rods. Using smectic dislocations, nanorods can consequently be oriented along a unique direction for a given substrate, independently of the ligands' nature, without any induced aggregation, leading as well to a fixed azimuthal orientation for the dot‐in‐rods' dipoles. These results open the way for the fine control of nanoparticle anisotropic optical properties, in particular, fine control of single‐photon emission polarization.
The self‐alignment of CdSe/CdS dots‐in‐rods is realized through their deposition within aligned line defects of smectic liquid crystals. The measurements of numerous single‐photon emitters evidences, for a given liquid crystal film, a unique alignment of the in‐plane dipoles associated with these particles. Fine control of the polarization of single photons emitters is thus achieved.
Apathy occurs in approximately one third of people after stroke. Despite its frequency and functional consequences, the determinants of apathy have only been partially defined. The major difficulty ...lies in disentangling the reduction in activity due to apathy itself from those secondary to comorbidities, such as depression, sensorimotor deficits, and cognitive impairment. Here, we aimed to examine the prevalence of apathy, identify confounding sources of hypoactivity, and define its neuroimaging determinants using multivariate voxel lesion symptom-mapping (mVLSM) analyses.
We assessed apathy in a subgroup (n = 325, mean age: 63.8 ± 10.5 years, 91.1% ischemic stroke) of the GRECogVASC cohort using the validated Behavioral Dysexecutive Syndrome Inventory, interpreted using GREFEX criteria, as well as confounding factors (depression, anxiety, severity of the neurological deficit, and gait disorders). mVLSM analysis was used to define neuroimaging determinants and was repeated after controlling for confounding factors.
Apathy was present for 120 patients (36.9%, 95% CI: 31.7–42.2). Stepwise linear regression identified three factors associated with apathy: depressive symptoms (R2 = .3, p = .0001), cognitive impairment (R2 = .015, p = .02), and neurological deficit (R2 = .110, p = .0001). Accordingly, only 9 (7.5%) patients had apathy without a confounding factor, i.e., isolated apathy. In conventional VLSM analysis, apathy was associated with a large number of subcortical lesions that were no longer considered after controlling for confounding factors. Strategic site analysis identified five regions associated with isolated apathy: the F3 orbitalis pars, left amygdala, left thalamus, left pallidum, and mesencephalon. mVLSM analysis identified four strategic sites associated with apathy: the right corticospinal tract (R2 = .11; p = .0001), left frontostriatal tract (R2 = .11; p = .0001), left thalamus (R2 = .04; p = .0001), and left amygdala (R2 = .01; p = .013). These regions remained significant after controlling for confounding factors but explained a lower amount of variance.
These findings indicate that poststroke apathy is more strongly associated with depression, neurological deficit, and cognitive impairment than with stroke lesions locations, at least using VLSM analysis.
The functional organization and related anatomy of executive functions are still largely unknown and were examined in the present study using a verbal fluency task. The objective of this study was to ...determine the cognitive architecture of a fluency task and related voxelwise anatomy in the GRECogVASC cohort and fMRI based meta-analytical data.
First, we proposed a model of verbal fluency in which two control processes, lexico-semantic strategic search process and attention process, interact with semantic and lexico-phonological output processes. This model was assessed by testing 404 patients and 775 controls for semantic and letter fluency, naming, and processing speed (Trail Making test part A). Regression (R2 = .276 and .3, P = .0001, both) and structural equation modeling (CFI: .88, RMSEA: .2, SRMR: .1) analyses supported this model.
Second, voxelwise lesion-symptom mapping and disconnectome analyses demonstrated fluency to be associated with left lesions of the pars opercularis, lenticular nucleus, insula, temporopolar region, and a large number of tracts. In addition, a single dissociation showed specific association of letter fluency with the pars triangularis of F3. Disconnectome mapping showed the additional role of disconnection of left frontal gyri and thalamus. By contrast, these analyses did not identify voxels specifically associated with lexico-phonological search processes.
Third, meta-analytic fMRI data (based on 72 studies) strikingly matched all structures identified by the lesion approach.
These results support our modeling of the functional architecture of verbal fluency based on two control processes (strategic search and attention) operating on semantic and lexico-phonologic output processes. Multivariate analysis supports the prominent role of the temporopolar area (BA 38) in semantic fluency and the F3 triangularis area (BA 45) in letter fluency. Finally, the lack of voxels specifically dedicated to strategic search processes could be due to a distributed organization of executive functions warranting further studies.
Abstract Objectives Genome-wide association studies (GWAS) have identified >100 loci independently contributing to type 2 diabetes (T2D) risk. However, translational implications for precision ...medicine and for the development of novel treatments have been disappointing, due to poor knowledge of how these loci impact T2D pathophysiology. Here, we aimed to measure the expression of genes located nearby T2D associated signals and to assess their effect on insulin secretion from pancreatic beta cells. Methods The expression of 104 candidate T2D susceptibility genes was measured in a human multi-tissue panel, through PCR-free expression assay. The effects of the knockdown of beta-cell enriched genes were next investigated on insulin secretion from the human EndoC-βH1 beta-cell line. Finally, we performed RNA-sequencing (RNA-seq) so as to assess the pathways affected by the knockdown of the new genes impacting insulin secretion from EndoC-βH1, and we analyzed the expression of the new genes in mouse models with altered pancreatic beta-cell function. Results We found that the candidate T2D susceptibility genes' expression is significantly enriched in pancreatic beta cells obtained by laser capture microdissection or sorted by flow cytometry and in EndoC-βH1 cells, but not in insulin sensitive tissues. Furthermore, the knockdown of seven T2D-susceptibility genes ( CDKN2A , GCK , HNF4A , KCNK16 , SLC30A8 , TBC1D4 , and TCF19 ) with already known expression and/or function in beta cells changed insulin secretion, supporting our functional approach. We showed first evidence for a role in insulin secretion of four candidate T2D-susceptibility genes ( PRC1 , SRR , ZFAND3 , and ZFAND6 ) with no previous knowledge of presence and function in beta cells. RNA-seq in EndoC-βH1 cells with decreased expression of PRC1 , SRR , ZFAND6 , or ZFAND3 identified specific gene networks related to T2D pathophysiology. Finally, a positive correlation between the expression of Ins2 and the expression of Prc1 , Srr , Zfand6 , and Zfand3 was found in mouse pancreatic islets with altered beta-cell function. Conclusions This study showed the ability of post-GWAS functional studies to identify new genes and pathways involved in human pancreatic beta-cell function and in T2D pathophysiology.
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