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Post-traumatic epilepsy (PTE) is one of the most debilitating consequences of traumatic brain injury (TBI) and is one of the most drug-resistant forms of epilepsy. Novel therapeutic treatment options are an urgent unmet clinical need. The current focus in healthcare has been shifting to disease prevention, rather than treatment, though, not much progress has been made due to a limited understanding of the disease pathogenesis. Neuroinflammation has been implicated in the pathophysiology of traumatic brain injury and may impact neurological sequelae following TBI including functional behavior and post-traumatic epilepsy development. Inflammasome signaling is one of the major components of the neuroinflammatory response, which is increasingly being explored for its contribution to the epileptogenic mechanisms and a novel therapeutic target against epilepsy. This review discusses the role of inflammasomes as a possible connecting link between TBI and PTE with a particular focus on clinical and preclinical evidence of therapeutic inflammasome targeting and its downstream effector molecules for their contribution to epileptogenesis. Finally, we also discuss emerging evidence indicating the potential of evaluating inflammasome proteins in biofluids and the brain by non-invasive neuroimaging, as potential biomarkers for predicting PTE development.
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Lesões Encefálicas Traumáticas , Epilepsia Pós-Traumática , Inflamassomos , Humanos , Lesões Encefálicas Traumáticas/metabolismo , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/imunologia , Inflamassomos/metabolismo , Animais , Epilepsia Pós-Traumática/metabolismo , Epilepsia Pós-Traumática/etiologiaRESUMO
OBJECTIVE: More than one third of mesial temporal lobe epilepsy (MTLE) patients are resistant to current antiseizure medications (ASMs), and half experience mild-to-moderate adverse effects of ASMs. There is therefore a strong need to develop and test novel ASMs. The objective of this work is to evaluate the pharmacokinetics and neurological toxicity of E2730, a novel uncompetitive inhibitor of γ-aminobutyric acid transporter-1, and to test its seizure suppression effects in a rat model of chronic MTLE. METHODS: We first examined plasma levels and adverse neurological effects of E2730 in healthy Wistar rats. Adult male rats were implanted with osmotic pumps delivering either 10, 20, or 100 mg/kg/day of E2730 subcutaneously for 1 week. Blood sampling and behavioral assessments were performed at several timepoints. We next examined whether E2730 suppressed seizures in rats with chronic MTLE. These rats were exposed to kainic acid-induced status epilepticus, and 9 weeks later, when chronic epilepsy was established, were assigned to receive one of the three doses of E2730 or vehicle for 1 week in a randomized crossover design. Continuous video-electroencephalographic monitoring was acquired during the treatment period to evaluate epileptic seizures. RESULTS: Plasma levels following continuous infusion of E2730 showed a clear dose-related increase in concentration. The drug was well tolerated at all doses, and any sedation or neuromotor impairment was mild and transient, resolving within 48 h of treatment initiation. Remarkably, E2730 treatment in chronically epileptic rats led to seizure suppression in a dose-dependent manner, with 65% of rats becoming seizure-free at the highest dose tested. Mean seizure class did not differ between the treatment groups. SIGNIFICANCE: This study shows that continuous subcutaneous infusion of E2730 over 7 days results in a marked, dose-dependent suppression of spontaneous recurrent seizures, with minimal adverse neurological effects, in a rat model of chronic MTLE. E2730 shows strong promise as an effective new ASM to be translated into clinical trials.
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Epilepsia do Lobo Temporal , Epilepsia , Humanos , Adulto , Ratos , Masculino , Animais , Epilepsia do Lobo Temporal/induzido quimicamente , Epilepsia do Lobo Temporal/tratamento farmacológico , Ratos Wistar , Convulsões/tratamento farmacológico , Eletroencefalografia , Ácido gama-Aminobutírico , Modelos Animais de Doenças , HipocampoRESUMO
(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 (>98%) 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.
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Cobre , Flumazenil , Cobre/química , Radioisótopos de Flúor/química , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos , Ácido gama-AminobutíricoRESUMO
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.
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Comportamento Impulsivo , Inositol/metabolismo , Monoéster Fosfórico Hidrolases/genética , Córtex Pré-Frontal/metabolismo , Animais , Atenção , CDP-Diacilglicerol-Inositol 3-Fosfatidiltransferase/genética , Endofenótipos , Técnicas de Silenciamento de Genes , Liases Intramoleculares/genética , Masculino , Proteínas de Membrana/genética , Córtex Pré-Frontal/diagnóstico por imagem , Espectroscopia de Prótons por Ressonância Magnética , Ratos , Simportadores/genéticaRESUMO
Despite the prevalence of drug use within society, only a subset of individuals 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 individual'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 individuals with SUD, thereby inviting the hypothesis that certain behavioural endophenotypes may be predictive, or at least act in some way, to modify an individual'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 individual 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.
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Comportamento Aditivo/psicologia , Modelos Animais de Doenças , Comportamento de Procura de Droga , Transtornos Relacionados ao Uso de Substâncias/psicologia , Animais , Cognição , Humanos , Fenótipo , Reforço Psicológico , RoedoresRESUMO
We have previously shown that impulsivity in rats is linked to decreased dopamine D2/3 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 D2/3 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 D2/3 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 D2/3 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 D2/3 receptor availability in the dorsal and ventral striatum of HI rats through inverse relationships with baseline levels of impulsivity and D2/3 receptor availability, respectively. However, we found no relationship between the effects of MPH on impulsivity and D2/3 receptor availability in any of the striatal subregions investigated. These findings indicate that trait-like impulsivity is associated with decreased D2/3 receptor availability in the left ventral striatum, and that stimulant drugs modulate impulsivity and striatal D2/3 receptor availability through independent mechanisms.
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Estimulantes do Sistema Nervoso Central/farmacologia , Corpo Estriado/metabolismo , Inibidores da Captação de Dopamina/farmacologia , Comportamento Impulsivo/efeitos dos fármacos , Metilfenidato/farmacologia , Receptores de Dopamina D2/efeitos dos fármacos , Receptores de Dopamina D3/efeitos dos fármacos , Animais , Corpo Estriado/efeitos dos fármacos , Masculino , Metilfenidato/análogos & derivados , Tomografia por Emissão de Pósitrons , RatosRESUMO
PURPOSE: To evaluate the feasibility of spectral editing for quantification of γ-aminobutyric acid (GABA) in the rat brain and to determine whether altered GABA concentration in the ventral striatum is a neural endophenotype associated with trait-like impulsive behavior. MATERIALS AND METHODS: Spectra were acquired at 4.7T for 23 male Lister-hooded rats that had been previously screened for extremely low and high impulsivity phenotypes on an automated behavioral task (n = 11 low-impulsive; n = 12 high-impulsive). Voxels of 3 × 7 × 4 mm(3) (84 µL) centered bilaterally across the ventral striatum were used to evaluate GABA concentration ratios. RESULTS: Quantifiable GABA signals in the ventral striatum were obtained for all rats. Mean-edited GABA to n-acetyl aspartate (NAA) ratios in the ventral striatum were 0.22 (95% confidence interval [CI] [0.18, 0.25]). Mean GABA/NAA ratios in this region were significantly decreased by 28% in high-impulsive rats compared to low-impulsive rats (P = 0.02; 95% CI [-53%, -2%]). CONCLUSION: These findings demonstrate that spectral editing at 4.7T is a feasible method to assess in vivo GABA concentrations in the rat brain. The results show that diminished GABA content in the ventral striatum may be a neural endophenotype associated with impulsivity. J. Magn. Reson. Imaging 2016;43:1308-1312.
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Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Imageamento por Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética/métodos , Imagem Molecular/métodos , Ácido gama-Aminobutírico/metabolismo , Animais , Interpretação de Imagem Assistida por Computador/métodos , Masculino , Ratos , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
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.
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Depressores do Sistema Nervoso Central/farmacologia , Condicionamento Psicológico , Comportamento de Procura de Droga/efeitos dos fármacos , Etanol/farmacologia , Extinção Psicológica , Receptores de Orexina/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Benzoxazóis/farmacologia , Sinais (Psicologia) , Lobo Límbico/metabolismo , Masculino , Naftiridinas , Antagonistas dos Receptores de Orexina/farmacologia , Receptores de Orexina/metabolismo , Ratos , Ratos Endogâmicos , Transdução de Sinais , Ureia/análogos & derivados , Ureia/farmacologia , Área Tegmentar Ventral/metabolismoRESUMO
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.
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Transtornos Relacionados ao Uso de Cocaína/metabolismo , Privação de Alimentos/fisiologia , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Recompensa , Área Tegmentar Ventral/metabolismo , Animais , Comportamento Animal , Condicionamento Operante , Sinais (Psicologia) , Modelos Animais de Doenças , Extinção Psicológica/fisiologia , Técnicas de Silenciamento de Genes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Hormônio Liberador da Corticotropina/deficiência , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estresse PsicológicoRESUMO
Since the identification and cloning of the major cannabinoid receptor expressed in the brain almost 25 years ago research has highlighted the potential of drugs that target the endocannabinoid system for treating addiction. The endocannabinoids, anandamide and 2-arachidonoyl glycerol, are lipid-derived metabolites found in abundance in the basal ganglia and other brain areas innervated by the mesocorticolimbic dopamine systems. Cannabinoid CB1 receptor antagonists/inverse agonists reduce reinstatement of responding for cocaine, alcohol and opiates in rodents. However, compounds acting on the endocannabinoid system may have broader application in treating drug addiction by ameliorating associated traits and symptoms such as impulsivity and anxiety that perpetuate drug use and interfere with rehabilitation. As a trait, impulsivity is known to predispose to addiction and facilitate the emergence of addiction to stimulant drugs. In contrast, anxiety and elevated stress responses accompany extended drug use and may underlie the persistence of drug intake in dependent individuals. In this article we integrate and discuss recent findings in rodents showing selective pharmacological modulation of impulsivity and anxiety by cannabinoid agents. We highlight the potential of selective inhibitors of endocannabinoid metabolism, directed at fatty acid amide hydrolase and monoacylglycerol lipase, to reduce anxiety and stress responses, and discuss novel mechanisms underlying the modulation of the endocannabinoid system, including the attenuation of impulsivity, anxiety, and drug reward by selective CB2 receptor agonists.
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Comportamento Aditivo/tratamento farmacológico , Endocanabinoides/metabolismo , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico , Animais , Ansiedade/tratamento farmacológico , Ansiedade/etiologia , Comportamento Aditivo/fisiopatologia , Agonistas de Receptores de Canabinoides/farmacologia , Corpo Estriado/fisiologia , Desenho de Fármacos , Humanos , Comportamento Impulsivo/efeitos dos fármacos , Recompensa , Transtornos Relacionados ao Uso de Substâncias/fisiopatologiaRESUMO
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 diversity 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.
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Comportamento Impulsivo , Núcleo Accumbens/fisiologia , Córtex Pré-Frontal/fisiologia , Ácido gama-Aminobutírico/metabolismo , Animais , Humanos , Vias Neurais/metabolismo , Vias Neurais/fisiologia , Núcleo Accumbens/metabolismo , Córtex Pré-Frontal/metabolismo , Transmissão SinápticaRESUMO
BACKGROUND: N-methyl-d-aspartate receptor (NMDAR) dysfunction is thought to contribute to the pathophysiology of schizophrenia. Accordingly, NMDAR antagonists such as phencyclidine (PCP) are used widely in experimental animals to model cognitive impairment associated with this disorder. However, it is unclear whether PCP disrupts the structural integrity of brain areas relevant to the profile of cognitive impairment in schizophrenia. METHODS: Here we used high-resolution magnetic resonance imaging and voxel-based morphometry to investigate structural alterations associated with sub-chronic PCP treatment in rats. RESULTS: Sub-chronic exposure of rats to PCP (5mg/kg twice daily for 7 days) impaired sustained visual attention on a 5-choice serial reaction time task, notably when the attentional load was increased. In contrast, sub-chronic PCP had no significant effect on the attentional filtering of a pre-pulse auditory stimulus in an acoustic startle paradigm. Voxel-based morphometry revealed significantly reduced grey matter density bilaterally in the hippocampus, anterior cingulate cortex, ventral striatum, and amygdala. PCP-treated rats also exhibited reduced cortical thickness in the insular cortex. CONCLUSIONS: These findings demonstrate that sub-chronic NMDA receptor antagonism is sufficient to produce highly-localized morphological abnormalities in brain areas implicated in the pathogenesis of schizophrenia. Furthermore, PCP exposure resulted in dissociable impairments in attentional function.
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Atenção , Encéfalo/patologia , Esquizofrenia/patologia , Psicologia do Esquizofrênico , Percepção Visual , Animais , Percepção Auditiva , Modelos Animais de Doenças , Substância Cinzenta/patologia , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Tamanho do Órgão , Fenciclidina , Inibição Pré-Pulso , Ratos , Reflexo de SobressaltoRESUMO
ABSTRACT: Understanding the mechanisms that underpin the transition from acute to chronic pain is critical for the development of more effective and targeted treatments. There is growing interest in the contribution of glial cells to this process, with cross-sectional preclinical studies demonstrating specific changes in these cell types capturing targeted timepoints from the acute phase and the chronic phase. In vivo longitudinal assessment of the development and evolution of these changes in experimental animals and humans has presented a significant challenge. Recent technological advances in preclinical and clinical positron emission tomography, including the development of specific radiotracers for gliosis, offer great promise for the field. These advances now permit tracking of glial changes over time and provide the ability to relate these changes to pain-relevant symptomology, comorbid psychiatric conditions, and treatment outcomes at both a group and an individual level. In this article, we summarize evidence for gliosis in the transition from acute to chronic pain and provide an overview of the specific radiotracers available to measure this process, highlighting their potential, particularly when combined with ex vivo/in vitro techniques, to understand the pathophysiology of chronic neuropathic pain. These complementary investigations can be used to bridge the existing gap in the field concerning the contribution of gliosis to neuropathic pain and identify potential targets for interventions.
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Purpose To develop an approach for in vivo detection of interstitial cardiac fibrosis using PET with a peptide tracer targeting proteolyzed collagen IV (T-peptide). Materials and Methods T-peptide was conjugated to the copper chelator MeCOSar (chemical name, 5-(8-methyl-3,6,10,13,16,19-hexaaza-bicyclo[6.6.6]icosan-1-ylamino)-5-oxopentanoic acid) and radiolabeled with copper 64 (64Cu). PET/CT scans were acquired following intravenous delivery of 64Cu-T-peptide-MeCOSar (0.25 mg/kg; 18 MBq ± 2.7 [SD]) to male transgenic mice overexpressing ß2-adrenergic receptors with intermediate (7 months of age; n = 4 per group) to severe (10 months of age; n = 11 per group) cardiac fibrosis and their wild-type controls. PET scans were also performed following coadministration of the radiolabeled probe with nonlabeled T-peptide in excess to confirm binding specificity. PET data were analyzed by t tests for static scans and analysis of variance tests (one- or two-way) for dynamic scans. Results PET/CT scans revealed significantly elevated (2.24-4.26-fold; P < .05) 64Cu-T-peptide-MeCOSar binding in the fibrotic hearts of aged transgenic ß2-adrenergic receptor mice across the entire 45-minute acquisition period compared with healthy controls. The cardiac tracer accumulation and presence of diffuse cardiac fibrosis in older animals were confirmed by gamma counting (P < .05) and histologic evaluation, respectively. Coadministration of a nonradiolabeled probe in excess abolished the elevated radiotracer binding in the aged transgenic hearts. Importantly, PET tracer accumulation was also detected in younger (7 months of age) transgenic mice with intermediate cardiac fibrosis, although this was only apparent from 20 minutes following injection (1.6-2.2-fold binding increase; P < .05). Conclusion The T-peptide PET tracer targeting proteolyzed collagen IV provided a sensitive and specific approach of detecting diffuse cardiac fibrosis at varying degrees of severity in a transgenic mouse model. Keywords: Diffuse Cardiac Fibrosis, Molecular Peptide Probe, Molecular Imaging, PET/CT © RSNA, 2024.
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Cobre , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Masculino , Animais , Camundongos , Sondas Moleculares , Tomografia por Emissão de Pósitrons , Imagem Molecular , Camundongos Transgênicos , Colágeno Tipo IV , Fibrose , PeptídeosRESUMO
Disagreements about language use are common both between and within fields. Where interests require multidisciplinary collaboration or the field of research has the potential to impact society at large, it becomes critical to minimize these disagreements where possible. The development of diverse intelligent systems, regardless of the substrate (e.g., silicon vs. biology), is a case where both conditions are met. Significant advancements have occurred in the development of technology progressing toward these diverse intelligence systems. Whether progress is silicon based, such as the use of large language models, or through synthetic biology methods, such as the development of organoids, a clear need for a community-based approach to seeking consensus on nomenclature is now vital. Here, we welcome collaboration from the wider scientific community, proposing a pathway forward to achieving this intention, highlighting key terms and fields of relevance, and suggesting potential consensus-making methods to be applied.
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Background: Only some individuals who use drugs recreationally eventually develop a substance use disorder, characterized in part by the rigid engagement in drug foraging behavior (drug seeking), which is often maintained in the face of adverse consequences (i.e., is compulsive). The neurobehavioral determinants of this individual vulnerability have not been fully elucidated. Methods: Using a prospective longitudinal study involving 39 male rats, we combined multidimensional characterization of behavioral traits of vulnerability to stimulant use disorder (impulsivity and stickiness) and resilience (sign tracking and sensation seeking/locomotor reactivity to novelty) with magnetic resonance imaging to identify the structural and functional brain correlates of the later emergence of compulsive drug seeking in drug-naïve subjects. We developed a novel behavioral procedure to investigate the individual tendency to persist in drug-seeking behavior in the face of punishment in a drug-free state in subjects with a prolonged history of cocaine seeking under the control of the conditioned reinforcing properties of a drug-paired Pavlovian conditioned stimulus. Results: In drug-naïve rats, the tendency to develop compulsive cocaine seeking was characterized by behavioral stickiness-related functional hypoconnectivity between the prefrontal cortex and posterior dorsomedial striatum in combination with impulsivity-related structural alterations in the infralimbic cortex, anterior insula, and nucleus accumbens. Conclusions: These findings show that the vulnerability to developing compulsive cocaine-seeking behavior stems from preexisting structural or functional changes in two distinct corticostriatal systems that underlie deficits in impulse control and goal-directed behavior.
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Accumulating evidence indicates that impulsivity, in its multiple forms, involves cortical and subcortical mechanisms and abnormal dopamine (DA) transmission. Although decreased DA D2/D3 receptor availability in the nucleus accumbens (NAcb) predicts trait-like impulsivity in rats it is unclear whether this neurochemical marker extends to both the NAcb core (NAcbC) and shell (NAcbS) and whether markers for other neurotransmitter systems implicated in impulsivity such as serotonin (5-HT), endogenous opioids and γ-amino-butyric acid (GABA) are likewise altered in impulsive rats. We therefore used autoradiography to investigate DA transporter (DAT), 5-HT transporter (5-HTT) and D1, D2/D3, µ-opioid and GABA(A) receptor binding in selected regions of the prefrontal cortex and striatum in rats expressing low and high impulsive behaviour on the five-choice serial reaction-time task. High-impulsive (HI) rats exhibited significantly lower binding for DAT and D2/D3 receptors in the NAcbS and for D1 receptors in the NAcbC compared with low-impulsive (LI) rats. HI rats also showed significantly lower GABA(A) receptor binding in the anterior cingulate cortex. For all regions where receptor binding was altered in HI rats, binding was inversely correlated with impulsive responding on task. There were no significant differences in binding for 5-HTT or µ-opioid receptors in any of the regions investigated. These results indicate that altered D2/D3 receptor binding is localised to the NAcbS of trait-like impulsive rats and is accompanied by reduced binding for DAT. Alterations in binding for D1 receptors in the NAcbC and GABA(A) receptors in the anterior cingulate cortex demonstrate additional markers and putative mechanisms underlying the expression of behavioural impulsivity.
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Corpo Estriado/fisiologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Comportamento Impulsivo/metabolismo , Córtex Pré-Frontal/fisiologia , Receptores Dopaminérgicos/metabolismo , Receptores de GABA-A/metabolismo , Animais , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/metabolismo , Ligantes , Masculino , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/metabolismo , Ligação Proteica , Cintilografia , Ratos , Tempo de Reação , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismoRESUMO
PURPOSE: 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. METHODS: 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. KEY FINDINGS: Hippocampal 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 hippocampus. SIGNIFICANCE: 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.
Assuntos
Epilepsia do Lobo Temporal/complicações , Epilepsia do Lobo Temporal/patologia , Transtornos do Metabolismo de Glucose/etiologia , Sistema Límbico/patologia , Análise de Variância , Animais , Atrofia/diagnóstico por imagem , Atrofia/patologia , Mapeamento Encefálico , Região CA1 Hipocampal/diagnóstico por imagem , Região CA1 Hipocampal/patologia , Modelos Animais de Doenças , Progressão da Doença , Eletroencefalografia , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Epilepsia do Lobo Temporal/induzido quimicamente , Epilepsia do Lobo Temporal/diagnóstico por imagem , Agonistas de Aminoácidos Excitatórios/toxicidade , Fluordesoxiglucose F18 , Proteína Glial Fibrilar Ácida/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Ácido Caínico/toxicidade , Sistema Límbico/diagnóstico por imagem , Imageamento por Ressonância Magnética , Masculino , Tomografia por Emissão de Pósitrons , Células Piramidais/patologia , Ratos , Ratos Wistar , Sinaptofisina/metabolismo , Fatores de TempoRESUMO
INTRODUCTION: Western diets, including those consisting of saturated fats, simple sugars and processed foods, is rising at an unprecedented rate. These lead to obesity and metabolic diseases, and possibly cognitive deficits. Exploring this, recent studies demonstrate marked impairment in spatial learning in rodents exposed to high-sugar diets. We utilised advanced touchscreen technology to assess several spatial and non-spatial components of cognition in rats chronically exposed to a high sucrose diet. METHODS: Male Wistar rats received 70 ml of 10% sucrose solution each day, or control tap water, persisting for the experiment duration (total n = 32). After 5 weeks of diet, rats performed Pairwise Discrimination, Location Discrimination, or Progressive Ratio tasks on automated touchscreens, and performance compared between groups. RESULTS: Sucrose rats consumed all the sugar solution provided to them, and had significantly increased caloric intake, compared to controls (p < 0.0001). However, in all tests, we found no significant difference in cognitive performance between Sucrose and Control treated rats. This included the number of trials for acquisition, and reversal, in Pairwise Discrimination, and number of trials required to complete Location Discrimination (p > 0.05 for all outcomes). No differences were observed in perseverative behaviour, motivation levels, or processing speed. CONCLUSION: Our study found no evidence to suggest that chronic consumption of sucrose impairs cognition, including both spatial and non-spatial learning tasks. These findings suggest that not all aspects of spatial cognition are negatively impacted by high sugar diet in rodents, and that particular use of touchscreen technology may probe different aspects of cognition than traditional tasks.
Assuntos
Cognição/fisiologia , Dieta , Sacarose Alimentar/administração & dosagem , Ingestão de Energia/fisiologia , Aprendizagem Espacial/fisiologia , Tecnologia , Animais , Masculino , Ratos , Ratos Wistar , Memória EspacialRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.