ORCID Profile
0000-0002-9163-9170
Current Organisations
University of Cambridge
,
Monash University
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Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2015
Publisher: Elsevier BV
Date: 10-2015
Publisher: Wiley
Date: 05-09-2014
DOI: 10.1111/BPH.12787
Publisher: Oxford University Press (OUP)
Date: 02-01-2020
Abstract: Maladaptive impulsivity manifests in a variety of disorders, including attention-deficit hyperactivity disorder (ADHD), depression, and substance use disorder. However, the etiological mechanisms of impulsivity remain poorly understood. In the present study, we used in-vivo proton magnetic resonance spectroscopy (1H-MRS) to investigate neurometabolite content in the prefrontal cortex (PFC) and striatum of rats exhibiting low- versus high-impulsive (LI, HI) behavior on a visual attentional task. We validated our 1H-MRS findings using regionally resolved ex-vivo mass spectroscopy, transcriptomics, and site-directed RNA interference in the ventromedial PFC. We report a significant reduction in myoinositol levels in the PFC but not the striatum of HI rats compared with LI rats. Reduced myoinositol content was localized to the infralimbic (IL) cortex, where significant reductions in transcript levels of key proteins involved in the synthesis and recycling of myoinositol (IMPase1) were also present. Knockdown of IMPase1in the IL cortex increased impulsivity in nonimpulsive rats when the demand on inhibitory response control was increased. We conclude that diminished myoinositol levels in ventromedial PFC causally mediate a specific form of impulsivity linked to vulnerability for stimulant addiction in rodents. Myoinositol and related signaling substrates may thus offer novel opportunities for treating neuropsychiatric disorders comorbid with impulsive symptomology.
Publisher: Elsevier BV
Date: 11-2009
Publisher: Springer Science and Business Media LLC
Date: 21-03-2016
DOI: 10.1038/MP.2016.32
Publisher: Wiley
Date: 28-08-2007
DOI: 10.1111/J.1528-1167.2007.01245.X
Abstract: The past decade has seen a surge in the utilization of small animal imaging for epilepsy research. In vivo imaging studies have the potential to provide important insights into the structural and functional correlates of the development and progression of epilepsy in these models. However, the small size of the rodent brain means that anatomic resolution is often relatively poor for many imaging modalities, particularly those providing functional information such as positron emission tomography. Coregistration of these images with those of higher structural resolution, such as MRI, provides an attractive approach to this problem, and also allows correlations between structural and functional imaging data. Image coregistration is commonly utilized in clinical research and practice. However, its application for small animal images has been, to date, relatively under utilized and largely unvalidated. The current review aims to provide an overview of image coregistration methods, particularly for MRI and PET, and their application to imaging of small animal models of epilepsy. Methodological advantages and potential traps are highlighted.
Publisher: Springer Science and Business Media LLC
Date: 10-11-2015
Publisher: Oxford University Press (OUP)
Date: 31-10-2014
DOI: 10.1093/IJNP/PYU010
Publisher: Springer Science and Business Media LLC
Date: 06-04-2019
Publisher: Springer Science and Business Media LLC
Date: 08-01-2015
DOI: 10.1038/NPP.2014.335
Publisher: Springer Science and Business Media LLC
Date: 23-08-2016
Publisher: Wiley
Date: 03-12-2015
DOI: 10.1002/JMRI.25093
Publisher: Springer Science and Business Media LLC
Date: 04-12-2019
DOI: 10.1038/S41386-019-0576-4
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2005
DOI: 10.1097/01.WNF.0000159955.87511.BC
Abstract: The mechanisms underlying carbamazepine aggravation of absence seizures are uncertain but are thought to involve enhancement of neuronal activity within the thalamocortical circuitry. We used c-Fos immunohistochemistry (cFos-ir) to examine patterns of neuronal activation and the relationship to seizure expression following administration of carbamazepine in a rat model of absence epilepsy (Genetic Absence Epilepsy Rats of Strasbourg, GAERS). Female ovariectomized GAERS implanted with extradural EEG electrodes received either 20 mg/kg carbamazepine or vehicle IP. Seizure expression was quantified by measuring the total number and duration of spike-wave discharges (SWD) and with the in idual burst discharge lengths over a 90-minute EEG. This was correlated with cFos-ir in thalamocortical slices from rats killed 180 minutes after carbamazepine administration. Carbamazepine-treated rats (n = 5) had a significantly greater total duration of SWD than vehicle-treated rats (17.9% versus 8.8%, P = 0.04). Despite this aggravation of seizures, the level of cFos-ir did not differ between the treatment groups. A positive correlation was found between cFos-ir in the reticularis thalami (Rt) and the total seizure duration (R = 0.66, P = 0.04) and mean burst length (R = 0.68, P = 0.03) but not total number of seizures. The lack of difference in cFos activation patterns between carbamazepine and vehicle-treated animals suggests that the mechanism for carbamazepine aggravation of absence seizures may not involve neuronal activation but rather enhanced neuronal synchronization. The association between increased neuronal activation in the Rt and seizure burden in GAERS provides further support for the critical role of this structure in the maintenance, but not initiation, of absence seizure activity.
Publisher: Wiley
Date: 12-06-2012
DOI: 10.1111/J.1528-1167.2012.03525.X
Abstract: Temporal hypometabolism on fluorodeoxyglucose positron emission tomography (FDG-PET) is a common finding in patients with drug-resistant temporal lobe epilepsy (TLE). The pathophysiology underlying the hypometabolism, including whether it reflects a primary epileptogenic process, or whether it occurs later as result of limbic atrophy or as a result of chronic seizures, remains unknown. This study aimed to investigate the ontologic relationship among limbic atrophy, histological changes, and hypometabolism in rats. Serial in vivo imaging with FDG-PET and volumetric magnetic resonance imaging (MRI) was acquired before and during the process of limbic epileptogenesis resulting from kainic acid-induced status epilepticus in the rat. The imaging data were correlated with histologic measures of cell loss, and markers of astrogliosis (glial fibrillary acid protein [GFAP]), synaptogenesis (synaptophysin), glucose transporter 1 (Glut1) and energy metabolism (cytochrome oxidase C), on brains of the animals following the final imaging point. Hippoc al hypometabolism on FDG-PET was found to be present 24 h following status epilepticus, tending to lessen by 1 week and then become more marked again following the onset of spontaneous seizures. Atrophy of limbic structures was evident from 7 days post-SE, becoming progressively more marked on serial MRI over subsequent weeks. No relationship was observed between the severity of MRI-detected atrophy or CA1 pyramidal cell loss and the degree of the hypometabolism on FDG-PET. However, an inverse relationship was observed between hypometabolism and increased expression of the Glut1 and synaptophysin in the hippoc us. These findings demonstrate that hypometabolism occurs early in the processes of limbic epileptogenesis and is not merely a consequence of pyramidal cell loss or the progressive atrophy of limbic brain structures that follow. The hypometabolism may reflect cellular mechanisms occurring early during epileptogenesis in addition to any effects of the subsequent recurrent spontaneous seizures.
Publisher: Springer Science and Business Media LLC
Date: 15-11-2018
Publisher: Wiley
Date: 20-04-2015
DOI: 10.1111/ADB.12251
Abstract: Orexins (hypocretins) are hypothalamic neuropeptides that innervate the entire neuraxis, including the prelimbic cortex and ventral tegmental area and have been implicated in ethanol-seeking behaviour. The present study aimed to use the orexin-1 (OX1 ) receptor antagonist SB-334867 to examine the role of prelimbic cortex and ventral tegmental area OX1 receptors in cue-induced reinstatement of ethanol-seeking. Ethanol-preferring rats (iP) rats were trained to self-administer ethanol (10 percent v/v, FR3) or sucrose (0.2-1 percent w/v, FR3) in the presence of reward-associated cues before being implanted with indwelling guide cannulae. Rats then underwent extinction training for 11 days. On test days, rats were given a microinjection of vehicle or SB-334867 (3 μg/side) and presented with reward-associated cues to precipitate reinstatement. Results show SB-334867 infused into the prelimbic cortex attenuated cue-induced reinstatement of ethanol-seeking, but not sucrose-seeking. OX1 antagonism in the ventral tegmental area also attenuated cue-induced reinstatement of ethanol-seeking. These findings suggest that OX1 receptors located in the prelimbic cortex and ventral tegmental area are part of a circuit driving cue-mediated ethanol-seeking behaviour.
Publisher: Springer New York
Date: 2016
Publisher: Society for Neuroscience
Date: 27-08-2014
DOI: 10.1523/JNEUROSCI.4763-12.2014
Abstract: Corticotrophin-releasing factor (CRF) modulates the influence of stress on cocaine reward and reward seeking acting at multiple sites, including the ventral tegmental area (VTA). There is controversy, however, concerning the contribution of CRF receptor type 1 (CRFR1) to this effect and whether CRF within the VTA is involved in other aspects of reward seeking independent of acute stress. Here we examine the role of CRFR1 within the VTA in relation to cocaine and natural reward using viral delivery of short hairpin RNAs (lenti-shCRFR1) and investigate the effect on operant self-administration and motivation to self-administer, as well as stress- and cue-induced reward seeking in mice. While knockdown of CRFR1 in the VTA had no effect on self-administration behavior for either cocaine or sucrose, it effectively blocked acute food deprivation stress-induced reinstatement of cocaine seeking. We also observed reduced cue-induced cocaine seeking assessed in a single extinction session after extended abstinence, but cue-induced sucrose seeking was unaffected, suggesting dissociation between the contribution of CRFR1 in the VTA in cocaine reward and sucrose and cocaine seeking. Further, our data indicate a role for VTA CRFR1 signaling in cocaine seeking associated with, and independent of, stress potentially involving conditioning and/or salience attribution of cocaine reward-related cues. CRFR1 signaling in the VTA therefore presents a target for convergent effects of both cue- and stress-induced cocaine-seeking pathways.
Publisher: Springer International Publishing
Date: 2019
DOI: 10.1007/164_2019_300
Abstract: Despite the prevalence of drug use within society, only a subset of in iduals actively taking addictive drugs lose control over their intake and develop compulsive drug-seeking and intake that typifies substance use disorder (SUD). Although research in this field continues to be an important and dynamic discipline, the specific neuroadaptations that drive compulsive behaviour in humans addicted to drugs and the neurobiological mechanisms that underlie an in idual's innate susceptibility to SUD remain surprisingly poorly understood. Nonetheless, it is clear from research within the clinical domain that some behavioural traits are recurrently co-expressed in in iduals with SUD, thereby inviting the hypothesis that certain behavioural endophenotypes may be predictive, or at least act in some way, to modify an in idual's probability for developing this disorder. The analysis of such endophenotypes and their catalytic relationship to the expression of addiction-related behaviours has been greatly augmented by experimental approaches in rodents that attempt to capture diagnostically relevant aspects of this progressive brain disorder. This work has evolved from an early focus on aberrant drug reinforcement mechanisms to a now much richer account of the putatively impaired cognitive control processes that ultimately determine in idual trajectories to compulsive drug-related behaviours. In this chapter we discuss the utility of experimental approaches in rodents designed to elucidate the neurobiological and genetic underpinnings of so-called risk traits and how these innate vulnerabilities collectively contribute to the pathogenesis of SUD.
Publisher: Elsevier BV
Date: 2010
DOI: 10.1016/J.PHARMTHERA.2009.11.002
Abstract: Alcohol, tobacco and illicit drug dependence represents a serious health and social issue within the community. As drug dependence has become more widely recognized as a clinical disorder and the severity of the problem been fully realized, options available for treatment have grown along with our understanding of the neurobiological mechanisms underlying the development and persistence of addiction. Treatment has progressed from purely social and behavioral approaches to now encompass pharmacotherapy to attempt to disrupt the mechanisms underlying these disorders. Despite these advances, many forms of addiction lack effective therapeutics and the prevalence of this disorder remains unacceptably high. As a result, a significant effort within the research community has been dedicated to the identification of novel targets for the development of therapeutics based upon our understanding of the pathological processes underlying addiction. The current review aims to provide an overview of existing and clinically trialed pharmacotherapies for alcohol, opiate, psychostimulant, nicotine, cannabis and inhalant addictions. Further, we discuss some of the potential targets that have been recently indentified from basic studies that may hold promise for the development of novel treatments.
Publisher: Wiley
Date: 02-2013
DOI: 10.1111/EJN.12146
Publisher: Springer Science and Business Media LLC
Date: 02-03-2017
Publisher: Wiley
Date: 21-01-2011
Publisher: Wiley
Date: 27-01-2014
DOI: 10.1111/EJN.12485
Abstract: The investigation of impulsivity as a core marker of several major neuropsychiatric disorders has been greatly influenced by the therapeutic efficacy of drugs that block the reuptake of dopamine and noradrenaline in the brain. As a result, research into the neural mechanisms of impulsivity has focused on the catecholamine systems as the loci responsible for the expression of impulsive behaviour and the primary mechanism of action of clinically effective drugs for attention-deficit hyperactivity disorder (ADHD). However, abnormalities in the catecholamine systems alone are unlikely to account for the full ersity and complexity of impulsivity subtypes, nor can they fully explain co-morbid brain disorders such as drug addiction. Here we review the lesser-studied role of γ-aminobutyric acid (GABA) in impulsivity, a major target of the dopaminergic and noradrenergic systems in the prefrontal cortex and striatum, and consider how abnormalities in this inhibitory neurotransmitter might contribute to several forms of impulsive behaviour in humans and experimental animals. Our analysis reveals several promising leads for future research that may help inform the development of new therapies for disorders of impulse control.
Publisher: Elsevier BV
Date: 02-2005
DOI: 10.1016/J.BRAINRES.2004.11.022
Abstract: Evidence from studies in rodents and humans support an anti-seizure action of neuropeptide Y (NPY) in focal, acquired epilepsy. However, the effects of NPY in generalized genetic epilepsy remain unexplored. In this study, adult male Genetic Absence Epilepsy Rats of Strasbourg (GAERS) were implanted with extradural electrodes and an intracerebroventricular (icv) cannula. Six and 12 nmol NPY or vehicle was administered icv in a random order (n=6), and the effect of NPY on seizure activity quantitated from a 90-min EEG recording. A rapid onset and sustained seizure suppression was observed following NPY treatment compared to vehicle, with both 6 and 12 nmol NPY having a significantly decreased mean percentage time in seizure (5.7 +/- 1.4% and 5.0 +/- 1.7% vs. 15.8 +/- 3.4%) and mean number of seizures per minute (0.5 +/- 0.1 and 0.4 +/- 0.1 vs. 1.1 +/- 0.1). There was no significant difference between the degree of seizure suppression after 6 and 12 nmol NPY. The results of this study demonstrate that NPY suppresses absence seizures in GAERS. This suggests that NPY modulates pathological oscillatory thalamocortical activity and may represent a new therapeutic approach for the treatment of generalized epilepsies.
Publisher: Elsevier BV
Date: 2014
DOI: 10.1016/J.NEUROPHARM.2013.05.041
Abstract: This article reviews recent advances in the elucidation of neurobehavioral endophenotypes associated with drug addiction made possible by the translational neuroimaging techniques magnetic resonance imaging (MRI) and positron emission tomography (PET). Increasingly, these non-invasive imaging approaches have been the catalyst for advancing our understanding of the etiology of drug addiction as a brain disorder involving complex interactions between pre-disposing behavioral traits, environmental influences and neural perturbations arising from the chronic abuse of licit and illicit drugs. In this article we discuss the causal role of trait markers associated with impulsivity and novelty-/sensation-seeking in speeding the development of compulsive drug administration and in facilitating relapse. We also discuss the striking convergence of imaging findings from these behavioural traits and addiction in rats, monkeys and humans with a focus on biomarkers of dopamine neurotransmission, and highlight areas where further research is needed to disambiguate underlying causal mechanisms. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.
Publisher: MDPI AG
Date: 13-09-2009
DOI: 10.3390/MOLECULES27185931
Abstract: (1) Background: [18F]Flumazenil 1 ([18F]FMZ) is an established positron emission tomography (PET) radiotracer for the imaging of the gamma-aminobutyric acid (GABA) receptor subtype, GABAA in the brain. The production of [18F]FMZ 1 for its clinical use has proven to be challenging, requiring harsh radiochemical conditions, while affording low radiochemical yields. Fully characterized, new methods for the improved production of [18F]FMZ 1 are needed. (2) Methods: We investigate the use of late-stage copper-mediated radiofluorination of aryl stannanes to improve the production of [18F]FMZ 1 that is suitable for clinical use. Mass spectrometry was used to identify the chemical by-products that were produced under the reaction conditions. (3) Results: The radiosynthesis of [18F]FMZ 1 was fully automated using the iPhase FlexLab radiochemistry module, affording a 22.2 ± 2.7% (n = 5) decay-corrected yield after 80 min. [18F]FMZ 1 was obtained with a high radiochemical purity ( %) and molar activity (247.9 ± 25.9 GBq/µmol). (4) Conclusions: The copper-mediated radiofluorination of the stannyl precursor is an effective strategy for the production of clinically suitable [18F]FMZ 1.
Publisher: The Company of Biologists
Date: 2013
DOI: 10.1242/DMM.010934
Abstract: Impulsivity describes the tendency of an in idual to act prematurely without foresight and is associated with a number of neuropsychiatric co-morbidities, including drug addiction. As such, there is increasing interest in the neurobiological mechanisms of impulsivity, as well as the genetic and environmental influences that govern the expression of this behaviour. Tests used on rodent models of impulsivity share strong parallels with tasks used to assess this trait in humans, and studies in both suggest a crucial role of monoaminergic corticostriatal systems in the expression of this behavioural trait. Furthermore, rodent models have enabled investigation of the causal relationship between drug abuse and impulsivity. Here, we review the use of rodent models of impulsivity for investigating the mechanisms involved in this trait, and how these mechanisms could contribute to the pathogenesis of addiction.
Publisher: Proceedings of the National Academy of Sciences
Date: 06-03-2007
Abstract: Huntington's disease is characterized by death of striatal projection neurons. We used a Cre/Lox transgenic approach to generate an animal model in which D1 dopamine receptor ( Drd1a )+ cells are progressively ablated in the postnatal brain. Striatal Drd1a, substance P , and dynorphin expression is progressively lost, whereas D2 dopamine receptor ( Drd2 ) and enkephalin expression is up-regulated. Magnetic resonance spectroscopic analysis demonstrated early elevation of the striatal choline/creatine ratio, a finding associated with extensive reactive striatal astrogliosis. Sequential MRI demonstrated a progressive reduction in striatal volume and secondary ventricular enlargement confirmed to be due to loss of striatal cells. Mutant mice had normal gait and rotarod performance but displayed hindlimb dystonia, locomotor hyperactivity, and handling-induced electrographically verified spontaneous seizures. Ethological assessment identified an increase in rearing and impairments in the oral behaviors of sifting and chewing. In line with the limbic seizure profile, cell loss, astrogliosis, microgliosis, and down-regulated dynorphin expression were seen in the hippoc al dentate gyrus. This study specifically implicates Drd1a + cell loss with tail suspension hindlimb dystonia, hyperactivity, and abnormal oral function. The latter may relate to the speech and swallowing disturbances and the classic sign of tongue-protrusion motor impersistence observed in Huntington's disease. In addition, the findings of this study support the notion that Drd1a and Drd2 are segregated on striatal projection neurons.
Publisher: Springer Science and Business Media LLC
Date: 11-02-2013
DOI: 10.1038/NPP.2013.44
Publisher: Society for Neuroscience
Date: 04-03-2015
DOI: 10.1523/JNEUROSCI.3890-14.2015
Abstract: We have previously shown that impulsivity in rats is linked to decreased dopamine D 2/3 receptor availability in the ventral striatum. In the present study, we investigated, using longitudinal positron emission tomography (PET), the effects of orally administered methylphenidate (MPH), a first-line treatment for attention deficit hyperactivity disorder, on D 2/3 receptor availability in the dorsal and ventral striatum and related these changes to impulsivity. Rats were screened for impulsive behavior on a five-choice serial reaction time task. After a baseline PET scan with the D 2/3 ligand [ 18 F]fallypride, rats received 6 mg/kg MPH, orally, twice each day for 28 d. Rats were then reassessed for impulsivity and underwent a second [ 18 F]fallypride PET scan. Before MPH treatment, we found that D 2/3 receptor availability was significantly decreased in the left but not the right ventral striatum of high-impulse (HI) rats compared with low-impulse (LI) rats. MPH treatment increased impulsivity in LI rats, and modulated impulsivity and D 2/3 receptor availability in the dorsal and ventral striatum of HI rats through inverse relationships with baseline levels of impulsivity and D 2/3 receptor availability, respectively. However, we found no relationship between the effects of MPH on impulsivity and D 2/3 receptor availability in any of the striatal subregions investigated. These findings indicate that trait-like impulsivity is associated with decreased D 2/3 receptor availability in the left ventral striatum, and that stimulant drugs modulate impulsivity and striatal D 2/3 receptor availability through independent mechanisms.
Publisher: Elsevier BV
Date: 05-2011
DOI: 10.1016/J.BRAINRES.2011.03.045
Abstract: A role for orexin A in mediating the primary and conditioned reinforcing effects of alcohol has been established. It is unclear however whether the contribution of orexins to alcohol reward occurs independently of effects on appetite and feeding, and whether orexins regulate the motivation to consume alcohol compared to other rewards. To examine this further here we investigate the effect of the orexin(1) receptor antagonist, SB-334867, on self-administration of alcohol (10% v/v) under both fixed (FR) and progressive ratio (PR) schedules of reinforcement, and whether this differs from the motivation to administer a natural food reward, sucrose (0.2-0.7% w/v) in alcohol preferring (iP) rats. SB-334867 treatment significantly reduced responding for both alcohol and sucrose under a FR3 schedule however, at the same dose, reduced responding and break point for ethanol, but not sucrose, under a PR schedule. These findings for the first time implicate a role for orexins in the motivation to self-administer alcohol and suggest that this may occur independent of any generalized effect on appetitive drive.
Publisher: Elsevier BV
Date: 04-2012
DOI: 10.1016/J.NEUBIOREV.2012.01.009
Abstract: Positron emission tomography (PET) provides dynamic images of the biodistribution of radioactive tracers in the brain. Through application of the principles of compartmental analysis, tracer uptake can be quantified in terms of specific physiological processes such as cerebral blood flow, cerebral metabolic rate, and the availability of receptors in brain. Whereas early PET studies in animal models of brain diseases were h ered by the limited spatial resolution of PET instruments, dedicated small-animal instruments now provide molecular images of rodent brain with resolution approaching 1mm, the theoretic limit of the method. Major applications of PET for brain research have consisted of studies of animal models of neurological disorders, notably Parkinson's disease (PD), Alzheimer's disease (AD), and Huntington's disease (HD), stroke, epilepsy and traumatic brain injury these studies have particularly benefited from selective neurochemical lesion models (PD), and also transgenic rodent models (AD, HD). Due to their complex and uncertain pathophysiologies, corresponding models of neuropsychiatric disorders have proven more difficult to establish. Historically, there has been an emphasis on PET studies of dopamine transmission, as assessed with a range of tracers targeting dopamine synthesis, plasma membrane transporters, and receptor binding sites. However, notable recent breakthroughs in molecular imaging include the development of greatly improved tracers for subtypes of serotonin, cannabinoid, and metabotropic glutamate receptors, as well as noradrenaline transporters, amyloid-β and neuroinflammatory changes. This article reviews the considerable recent progress in preclinical PET and discusses applications relevant to a number of neurological and neuropsychiatric disorders in humans.
Publisher: Springer Science and Business Media LLC
Date: 07-07-2017
Publisher: Wiley
Date: 28-08-2007
DOI: 10.1111/J.1528-1167.2007.01242.X
Abstract: The neurobiological processes that result in epilepsy, known as epileptogenesis, are incompletely understood. Moreover, there is currently no therapy that effectively halts or impedes the development or progression of the condition. Positron Emission Tomography (PET) provides valuable information about the function of the brain in vivo, and is playing a central role in both clinical practice and research. This technique reliably reveals functional abnormalities in many epilepsy syndromes, particularly temporal lobe epilepsy. Unfortunately, epileptogenesis is extremely difficult to study in human patients who usually present with established epilepsy, rather than at the early stages of the process. Animal models offer the advantage of permitting the assessment of the pre-, developing, and chronic epileptic states. However, traditional techniques (e.g., histology) are only able to examine the brain at one time point during epileptogenesis in any one in idual. Recent advances in dedicated small animal PET (saPET) allow researchers for the first time to study in vivo biomolecular changes in the brain during epileptogenesis by means of serial acquisitions in the same animal. Repeated application of in vivo imaging modalities in the same animal also decreases the effect of biological inter-in idual variability and the number of animals to be used. The availability of novel PET tracers permits the investigation of a broad range of biochemical and physiological processes in the brain. Besides research on epileptogenesis, saPET can also be applied to investigate in vivo the biological effect of novel treatment strategies. saPET is widely used in many fields of pathophysiological investigation and is likely to significantly enhance epilepsy research.
Publisher: Wiley
Date: 22-04-2009
DOI: 10.1002/JMRI.21766
Abstract: To report the detection of structural and functional biological changes in living animals using small animal in vivo MRI that complements traditional ex vivo histological techniques. We report the development and validation of the application of large deformation high dimensional mapping (HDM-LD) segmentation for the hippoc us in the rat. High resolution volumetric T2 weighted MRI images were acquired at 4.7 Tesla from six male in-breed nonepileptic Wistar rats. Two HDM-LD segmentations of the hippoc us (automated 1 and automated 2) were compared with the manual segmentations of two investigators who independently segmented the hippoc i (manual 1 and manual 2). The mean overlap for the hippoc i between automated 1 and automated 2 for the right hippoc i was 94.4% (SD 1.0) and for the left hippoc i was 94.3% (SD 2.5), while the mean overlap between automated 1 and manual 1 for the right hippoc i was 91.4% (SD 1.3) and for the left hippoc i was 91.9% (SD 1.4). Mean values for absolute differences for comparisons of all the segmentations were the following: automated 1 versus automated 2, 3.2% (SD 1.0) manual 1 versus manual 2 6.82% (SD 5.22) automated 1 versus manual 1 13.0% (SD 1.8). HDM-LD can be applied to obtain accurate and reproducible three-dimensional segmentations of the hippoc us from rat MR images. HDM-LD will be a useful tool for investigations of hippoc al structural changes in vivo in rat models of human disease.
Publisher: Elsevier BV
Date: 2014
Publisher: Springer Science and Business Media LLC
Date: 15-09-2015
DOI: 10.1038/MP.2015.140
Abstract: Impulsivity is an endophenotype of vulnerability for compulsive behaviors. However, the neural mechanisms whereby impulsivity facilitates the development of compulsive disorders, such as addiction or obsessive compulsive disorder, remain unknown. We first investigated, in rats, anatomical and functional correlates of impulsivity in the anterior insular (AI) cortex by measuring both the thickness of, and cellular plasticity markers in, the AI with magnetic resonance imaging and in situ hybridization of the immediate early gene zif268, respectively. We then investigated the influence of bilateral AI cortex lesions on the high impulsivity trait, as measured in the five-choice serial reaction time task (5-CSRTT), and the associated propensity to develop compulsivity as measured by high drinking levels in a schedule-induced polydipsia procedure (SIP). We demonstrate that the AI cortex causally contributes to in idual vulnerability to impulsive-compulsive behavior in rats. Motor impulsivity, as measured by premature responses in the 5-CSRTT, was shown to correlate with the thinness of the anterior region of the insular cortex, in which highly impulsive (HI) rats expressed lower zif268 mRNA levels. Lesions of AI reduced impulsive behavior in HI rats, which were also highly susceptible to develop compulsive behavior as measured in a SIP procedure. AI lesions also attenuated both the development and the expression of SIP. This study thus identifies the AI as a novel neural substrate of maladaptive impulse control mechanisms that may facilitate the development of compulsive disorders.
Location: Australia
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Bianca Jupp.