Biology subjects

Veronese, M.

Publications and source records attributed to Veronese, M..

28 records · Page 2Linked to original sources

bioRxiv2021

Less is more: a dose-response mechanistic account of intranasal oxytocin pharmacodynamics in the human brain

Intranasal oxytocin is receiving increasing research attention as a potential treatment for several brain disorders due to promising preclinical results. However, translating these findings to humans has been hampered by remaining uncertainties about its pharmacodynamics and the methods used to probe its effects in the human brain. Using a dose-response design (9, 18 and 36 IU) and a novel administration device, we demonstrate that oxytocin-induced physiological changes in the amygdala at rest, a key-hub of the brain oxytocin system, follow a dose-response curve with maximal effects for lower doses. Yet, the effects of oxytocin vary by amygdala subdivision, highlighting the need to qualify dose-response curves within subregion. We further link physiological changes with the density of the oxytocin receptor gene mRNA across brain regions, strengthening our confidence in intranasal oxytocin as a valid approach to engage central targets. Finally, we demonstrate that intranasal oxytocin does not disrupt cerebrovascular reactivity; the absence of major vascular confounds corroborates the validity of haemodynamic neuroimaging to probe the effects of intranasal oxytocin in the human brain.

neuroscience↗

bioRxiv2020

Unravelling the effects of methylphenidate on the dopaminergic and noradrenergic functional circuits

Functional magnetic resonance imaging (fMRI) can be combined with drugs to investigate the system-level functional responses in the brain to such challenges. However, most psychoactive agents act on multiple neurotransmitters, limiting the ability of fMRI to identify functional effects related to actions on discrete pharmacological targets. We recently introduced a multimodal approach, REACT (Receptor-Enriched Analysis of functional Connectivity by Targets), which offers the opportunity to disentangle effects of drugs on different neurotransmitters and clarify the biological mechanisms driving clinical efficacy and side effects of a compound. Here, we focus on methylphenidate (MPH), which binds to the dopamine transporter (DAT) and the norepinephrine transporter (NET), to unravel its effects on dopaminergic and noradrenergic functional circuits in the healthy brain at rest. We then explored the relationship between these target-enriched resting state functional connectivity (FC) maps and inter-individual variability in behavioural responses to a reinforcement-learning task encompassing a novelty manipulation to disentangle the molecular systems underlying specific cognitive/behavioural effects. Results showed a significant MPH-induced FC increase in sensorimotor areas in the functional circuit associated with DAT. We also found that MPH-induced variations in DAT-and NET-enriched FC were significantly correlated with inter-individual differences in effects of MPH on key behavioural responses associated with the reinforcement-learning task. Our findings show that MPH-related FC changes are specifically associated with DAT and provide evidence that when compounds have mixed pharmacological profiles, REACT may be able to capture regional functional effects that are underpinned by the same cognitive mechanism but are related to distinct molecular targets.

neuroscience↗

bioRxiv2019

The Innate Immune Toll-Like Receptor-2 modulates the Depressogenic and Anorexiolytic Neuroinflammatory Response in Obstructive Sleep Apnoea

BackgroundThe neurological mechanisms of the disease process of obstructive sleep apnea, the second most frequent sleep disorder, remain unclear whilst its links with several major neuropsychiatric disorders, such as depression, anxiety and even Alzheimers disorder, are increasingly recognised. A radical theory, that inflammation in the brain may underlie certain phenotypes of many of these disorders, has been proposed, and the microglial TLR2 system may serve as an important crossroad at the borderlands of several pathogenesis. This study undertook to investigate whether a neuroinflammatory response occurs under conditions of OSA, and whether it might be related to a modulated response due to TLR2 functionality in an established rodent model of OSA. MethodsThe effects of three weeks exposure to chronic intermittent hypoxia were monitored in mice with or without functional TLR2 (C57BL/6-Tyrc-Brd-Tg(Tlr2-luc/gfp)Kri/Gaj; TLR2-/-, C57BL/6-Tlr2tm1Kir), that were investigated by multimodal in vivo and ex vivo imaging, combining magnetic resonance and bioluminescence imaging and a variety of functional tests. ResultsAn acute neuroinflammatory response was demonstrated following the three days in the basal forebrain of mice, and more chronically in other parts of the frontal cortex. Adaptive changes in specific neurocircuitry were demonstrated, with significant links to agitated (mal)adaptive behaviour under episodes of stress, and an increased ability to gain weight. ConclusionsOur results suggest that microglial activation and an innate immune response might be the missing link underlying the pathogenesis of well known structural, psychologic and metabolic changes experienced by some patients with OSA.

neuroscience↗

bioRxiv2019

Mesocorticolimbic circuit mechanisms underlying the effects of ketamine on dopamine: a translational imaging study

Patients with schizophrenia show increased striatal dopamine synthesis capacity in imaging studies. However, the mechanism underlying this is unclear but may be due to N-methyl-D-aspartate receptor (NMDAR) hypofunction and parvalbumin (PV) neuronal dysfunction leading to disinhibition of mesostriatal dopamine neurons. Here, we test this in a translational mouse imaging study using a ketamine model. Mice were treated with sub-chronic ketamine (30mg/kg) or saline followed by in-vivo positron emission tomography of striatal dopamine synthesis capacity, analogous to measures used in patients. Locomotor activity was measured using the open field test. In-vivo cell-type-specific chemogenetic approaches and pharmacological interventions were used to manipulate neuronal excitability. Immunohistochemistry and RNA sequencing were used to investigate molecular mechanisms. Sub-chronic ketamine increased striatal dopamine synthesis capacity (Cohens d=2.5, P<0.001) and locomotor activity. These effects were countered by inhibition of midbrain dopamine neurons, and by activation of cortical and ventral subiculum PV interneurons. Sub-chronic ketamine reduced PV expression in these neurons. Pharmacological intervention with SEP-363856, a novel psychotropic agent with agonism at trace amine receptor 1 (TAAR1), significantly reduced the ketamine-induced increase in dopamine synthesis capacity. These results show that sub-chronic ketamine treatment in mice mimics the dopaminergic alterations in patients with psychosis, and suggest an underlying neurocircuit involving PV interneuron hypofunction in frontal cortex and hippocampus as well as activation of midbrain dopamine neurons. A novel TAAR1 agonist reversed the dopaminergic alterations suggesting a therapeutic mechanism for targeting presynaptic dopamine dysfunction in patients.

neuroscience↗

bioRxiv2019

Links between central CB1-receptor availability and peripheral endocannabinoids in patients with first episode psychosis

There is an established, albeit poorly-understood link between psychosis and metabolic abnormalities such as altered glucose metabolism and dyslipidemia, which often precede the initiation of antipsychotic treatment. It is known that obesity-associated metabolic disorders are promoted by peripheral activation of the endocannabinoid system (ECS). Our recent data suggest that ECS dysregulation may also play a role in psychosis. With the aim of characterizing the involvement of the central and peripheral ECSs and their mutual associations, here we performed a combined neuroimaging and metabolomic study in patients with first-episode psychosis (FEP) and healthy controls (HC). Regional brain cannabinoid receptor type 1 (CB1R) availability was quantified in two, independent samples of patients with FEP (n=20 and n=8) and HC (n=20 and n=10), by applying 3D positron emission tomography (PET), using two radiotracers, [11C]MePPEP and [18F]FMPEP-d2. Ten endogenous endocannabinoids or related metabolites were quantified in serum, drawn from these individuals during the same imaging session. Circulating levels of arachidonic acid and oleyl ethanolamide were reduced in FEP individuals, but not in those who were predominantly medication-free. In HC, there was an inverse association between levels of circulating arachidonoyl glycerol, anandamide, oleyl ethanolamide and palmitoyl ethanolamide, and CB1R availability in the posterior cingulate cortex. This phenomenon was, however, not observed in FEP patients. Our data thus provide evidence of cross-talk and dysregulation between peripheral endocannabinoids and central CB1R availability in FEP.

neuroscience↗

bioRxiv2018

Dynamic 11C-PiB PET shows cerebrospinal fluid flow alterations in Alzheimer’s disease and multiple sclerosis

Cerebrospinal fluid (CSF) plays an important role in the clearance of solutes and maintenance of brain homeostasis. 11C-PiB PET was recently proposed as a tool for detection of CSF clearance alterations in Alzheimers disease. The current study seeks to investigate the magnitude of 11C-PiB PET signal in the lateral ventricles of an independent group of Alzheimers and mild cognitive impairment subjects. We have also evaluated multiple sclerosis as a model of disease with CSF clearance alterations without amyloid-beta tissue accumulation.\n\nMethodsA set of Alzheimers and mild cognitive impairment subjects and a set of multiple sclerosis subjects with matched healthy controls underwent MRI and dynamic 11C-PiB PET. Manual lateral ventricle regions of interest were generated from MRI data. PET data was analysed using a simplified reference tissue model with cerebellum or a supervised reference region, for the Alzheimers and multiple sclerosis datasets, respectively. Magnitude of 11C-PiB signal in the lateral ventricles was calculated as area under curve from 35 to 80 minutes and standard uptake value ratio (SUVR) from 50 to 70 minutes. Compartmental modelling analysis was performed on a separate dataset containing Alzheimers and matched healthy control data with an arterial input function to further understand the kinetics of the lateral ventricular 11C-PiB signal.\n\nResultsAnalysis of variance revealed significant group differences in lateral ventricular SUVR across the Alzheimers, mild cognitive impairment, and healthy control groups (p=0.004). Additional pairwise comparisons revealed significantly lower lateral ventricular SUVR in Alzheimers compared to healthy controls (p<0.001) and mild cognitive impairment (p=0.029). Lateral ventricular SUVR was also significantly lower in multiple sclerosis compared to healthy controls (p=0.008). Compartmental modelling analysis revealed significantly lower uptake rates of 11C-PiB signal from blood (p=0.005) and brain tissue (p=0.004) to the lateral ventricles in Alzheimers compared to healthy controls. This analysis also revealed significantly lower clearance of 11C-PiB signal out of the lateral ventricles in Alzheimers compared to healthy controls (p=0.002).\n\nConclusionOverall, these results indicate that dynamic 11C-PiB PET can be used to observe pathological changes in cerebrospinal fluid dynamics and that cerebrospinal fluid-mediated clearance is reduced in Alzheimers disease and multiple sclerosis compared to healthy controls.

neuroscience↗

bioRxiv2018

Topological gene-expression networks recapitulate brain anatomy and function

Understanding how gene expression translates to and affects human behaviour is one of the ultimate aims of neuroscience. In this paper, we present a pipeline based on Mapper, a topological simplification tool, to produce and analyze genes co-expression data. We first validate the method by reproducing key results from the literature on the Allen Human Brain Atlas, and the correlations between resting-state fMRI and gene co-expression maps. We then analyze a dopamine-related gene-set and find that co-expression networks produced by Mapper returned a structure that matches the well-known anatomy of the dopaminergic pathway. Our results suggest that topological network descriptions can be a powerful tool to explore the relationships between genetic pathways and their association with brain function and its perturbation due to illness and/or pharmacological challenge.

neuroscience↗

bioRxiv2018

Increased Cerebral Blood Flow after single dose of antipsychotics in healthy volunteers depends on dopamine D2 receptor density profiles.

As a result of neuro-vascular coupling, the functional effects of antipsychotics in human brain have been investigated in both healthy and clinical populations using haemodynamic markers such as regional Cerebral Blood Flow (rCBF). However, the relationship between observed haemodynamic effects and the pharmacological action of these drugs has not been fully established. Here, we analysed MRI-based rCBF data from a placebo-controlled study in healthy volunteers, who received a single dose of three different D2 receptor antagonists and tested the association of the main effects of the drugs on rCBF against normative population maps of D2R protein density and gene-expression data. In particular, we correlated CBF changes after antipsychotic administration with non-displaceable binding potential (BPND) template maps of the high affinity D2-antagonist Positron Emission Tomography (PET) ligand [18F]Fallypride and brain post-mortem microarray mRNA expression data for the DRD2 gene. For all antipsychotics, rCBF changes were directly proportional to brain D2R densities and DRD2 mRNA expression measures, although PET BPND spatial profiles explained more variance as compared with mRNA profiles (PET R2 range= 0.20-0.60, mRNA PET R2 range 0.04-0.20, pairwise-comparisons all p<0.05). In addition, the spatial coupling between {Delta}CBF and D2R profiles varied between the different antipsychotics tested, possibly reflecting differential affinities. Overall, these results indicate that the functional effects of antipsychotics as measured with rCBF are tightly correlated with the distribution of their target receptors in striatal and extra-striatal regions. Our results further demonstrate the link between neurotransmitter targets and haemodynamic changes reinforcing rCBF as a robust in-vivo marker of drug effects. This work is important in bridging the gap between pharmacokinetic and pharmacodynamics of novel and existing compounds.

pharmacology and toxicology↗

bioRxiv2017

PET studies of the glial cell marker TSPO in psychosis patients - a meta-analysis using individual participant data

BackgroundAccumulating evidence suggests that the immune system may be an important target for new treatment approaches in schizophrenia. Positron emission tomography (PET) and radioligands binding to the translocator protein (TSPO), which is expressed in glial cells in brain including immune cells, represents a potential method for patient stratification and treatment monitoring. This study examined if patients with first episode psychosis and schizophrenia had altered TSPO levels as compared to healthy control subjects.\n\nMethodsPubMed was searched for studies comparing patients with psychosis to healthy controls using second-generation TSPO radioligands. The outcome measure was distribution volume (VT), an index of TSPO levels, in frontal cortex (FC), temporal cortex (TC) and hippocampus (HIP). Bayes factors (BF) were applied to examine the relative support for higher, lower or no-change of TSPO levels in patients as compared to healthy controls.\n\nResultsFive studies, with 75 patients with first-episode psychosis or schizophrenia and 77 healthy control subjects were included. BF showed strong support for lower patient VT relative to no-change (all BF>32) or relative to an increase (all BF>422) in all brain regions. From the posterior distributions, mean patient-control differences in standardized VT values were -0.48 for FC (95% credible interval (CredInt)=-0.88 to -0.09), -0.47 for TC (CredInt=-0.87 to -0.07) and -0.63 for HIP (CredInt=-1.00 to -0.25).\n\nDiscussionThe observed reduction of TPSO in compared to control subjects in patients may correspond to altered function or lower density of brain immune cells. Future studies should focus on investigating the underlying biological mechanisms and their relevance for treatment.

immunology↗

bioRxiv2017

The Effect Of Perinatal Brain Injury On Dopaminergic Function And Hippocampal Volume In Adult Life

BackgroundVery preterm birth (<32 weeks of gestation) is associated with long-lasting brain alterations and an increased risk of psychiatric disorders associated with dopaminergic abnormalities. Preclinical studies have shown perinatal brain injuries, including hippocampal lesions, cause lasting changes in dopamine function, but it is not known if this occurs in humans. The purpose of this study was to determine whether very preterm birth and perinatal brain injury were associated with altered dopamine synthesis and reduced hippocampal volume in humans in adulthood.\n\nMethodsWe compared adults who were born very preterm with associated perinatal brain injury to adults born very preterm without perinatal brain injury, and age-matched controls born at full term using [18F]-DOPA PET and structural MRI imaging.\n\nResultsDopamine synthesis capacity was significantly reduced in the perinatal brain injury group relative to both the group born very preterm without brain injury (Cohens d=1.36, p=0.02) and the control group (Cohens d=1.07, p=0.01). Hippocampal volume was reduced in the perinatal brain injury group relative to controls (Cohens d = 1.17, p = 0.01). There was a significant correlation between hippocampal volume and striatal dopamine synthesis capacity (r = 0.344, p= 0.03).\n\nConclusionsPerinatal brain injury, but not very preterm birth without macroscopic brain injury, is associated with persistent alterations in dopaminergic function and reductions in hippocampal volume. This is the first evidence in humans linking neonatal hippocampal injury to adult dopamine dysfunction, and has implications for understanding the mechanism underlying cognitive impairments and neuropsychiatric disorders following very preterm birth.

neuroscience↗