60 research outputs found

    Experience-dependent plasticity in cortical and cerebellar regions of early- and late-trained musicians

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    A body of current evidence suggests that there is a sensitive period for musical training: people who begin training before the age of seven show better performance on tests of musical skill, and also show differences in brain structure – especially in motor cortical and cerebellar regions – compared with those who start later. In two studies, we investigated distributed patterns of structural differences between early-trained (ET) and late-trained (LT) musicians. First, we examined structural covariation between cerebellar volume and cortical thickness (CT) in sensorimotor regions in ET and LT musicians and non-musicians (NMs). We found that early musical training had a specific effect on structural covariance between the cerebellum and cortex: NMs showed negative correlations between left lobule VI and right pre-supplementary motor area (preSMA) and premotor cortex (PMC), but this relationship was reduced in ET musicians. ETs instead showed a significant negative correlation between vermal IV and right pre-SMA and dPMC. In the second study, we used support vector machine models – a subtype of supervised machine learning – to investigate cortico-cerebellar structural covariation and to better understand the age boundaries of the sensitive period for early musicianship. Our model identified a combination of 17 regions, including 9 cerebellar and 8 sensorimotor regions, that accurately identified ET and LT musicians with high sensitivity and specificity. Critically, this model – which defined ET musicians as those who began their training before the age of 7 – outperformed all other models in which age of start was earlier or later (between ages 5-10). Our model’s ability to accurately classify ET and LT musicians provides additional evidence that musical training before age 7 affects cortico-cerebellar structure in adulthood, and is consistent with the hypothesis that connected brain regions interact during development to reciprocally influence brain and behavioural maturation. Together, these results suggest that early musical training has differential impacts on the maturation of cortico-cerebellar networks important for optimizing sensorimotor performance. This work enriches our understanding of how experience-dependent plasticity is affected by early musical training, providing a more nuanced understanding of the interrelated nature of brain development

    Pathophysiology of Spinal Cord Injury (SCI)

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    Spinal cord injury (SCI) leads to paralysis, sensory, and autonomic nervous system dysfunctions. However, the pathophysiology of SCI is complex, and not limited to the nervous system. Indeed, several other organs and tissue are also affected by the injury, directly or not, acutely or chronically, which induces numerous health complications. Although a lot of research has been performed to repair motor and sensory functions, SCI-induced health issues are less studied, although they represent a major concern among patients. There is a gap of knowledge in pre-clinical models studying these SCI-induced health complications that limits translational applications in humans. This reprint describes several aspects of the pathophysiology of spinal cord injuries. This includes, but is not limited to, the impact of SCI on cardiovascular and respiratory functions, bladder and bowel function, autonomic dysreflexia, liver pathology, metabolic syndrome, bones and muscles loss, and cognitive functions

    Development and optimisation of tools for preclinical studies on Parkinson's disease

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    Successful drug development requires numerous tests to deem a drug safe and efficacious. Before clinical trials, preclinical testing is needed to ensure that the drug can be safely tried out in humans. In preclinical testing, efficacy is also assessed to minimise the risk of a drug failing in clinical trials. Parkinson’s disease (PD) is a common age-associated neurodegenerative disease characterised by distinct debilitating motor symptoms caused by the dysfunction of the dopaminergic nigrostriatal pathway. For PD, a plethora of cellular and animal models have been developed to study the pathophysiology of the disease and to test potential new therapeutic interventions for treating the disease. New models are constantly created. However, methods to study outcomes also need to be developed and refined for reliable and reproducible results, which is pivotal to demonstrating the efficacy of drugs. This dissertation work developed new tools and refined current methods to study PD in preclinical models and studied the characteristics of the cytomegalovirus (CMV) promoter and a primary culture of postnatal dopamine neurons used to model PD. First, we used infrared analysis of optical densities to assess the striatal innervation of tyrosine hydroxylase-positive (TH+) fibres in rat brain sections, a useful alternative to colourimetric optical density analyses. We also developed a novel method based on convolutional neural network algorithms to count dopaminergic neurons from rodent brain sections. The number of neurons counted had a high degree of correlation with results obtained using other counting methods, and counting was substantially faster with the algorithm. Additionally, we developed reporter assays, both reporter plasmids, and cell lines, to measure the activity of a PD-associated drug target, Dicer. These assays, using either exogenous or endogenous fluorescent and bioluminescent indicators, were validated and produced comparable results to previously published similar assays in more physiologically relevant conditions. We also found out that a commonly used promoter in gene therapy, the CMV promoter, could be activated by neurotransmission. We showed in vivo that methamphetamine – a potent dopamine-releasing drug – activated the CMV promoter in the rat brain. Moreover, we observed differences in the distribution of the endoplasmic reticulum between different compartments of cultured mouse TH+ neurons. In summary, the methods and refined tools obtained in these studies expand the toolbox of researchers engaged in studying PD preclinically and may be applicable to other disease areas and human clinical studies as well. Furthermore, our findings on the activation of the CMV promoter are important to consider when designing gene expression systems, reporter assays, or gene therapies for preclinical PD studies utilising amphetamines. And finally, we gained novel insight into the ultrastructural characteristics of cultured postnatal dopamine neurons and provided a valuable resource for the research community.Onnistunut lääkekehitys vaatii useita tutkimuksia, jolla lääkeaine voidaan osoittaa turvalliseksi ja tehokkaaksi. Ennen kliiniisiä kokeita, prekliinissisä kokeissa lääkeaineen turvallisuudesta tulee varmistua voidakseen sitä tutkia potilailla. Prekliinisissä kokeissa myös lääkeaineen tehoa tarkastellaan minimoidakseen riski epäonnistua kliinisissä tutkimuksissa. Parkinsonin tauti on yleinen hermostoa rappeuttava sairaus, joka aiheuttaa haitallisia ja tunnusomaisia liikehäiriöitä, jotka johtuvat keskiaivojen dopamiinijärjestelmän toimintahäiriöstä. Parkinsonin tautiin on kehitetty valtava määrä solu- ja eläinmalleja taudin patofysiologian tutkimiseksi ja uusien lääkkeiden tehon osoittamiseksi. Uusia malleja kehitetään jatkuvasti lisää, mutta myös lopputuloksia määrittäviä menetelmiä tulisi kehittää ja parantaa luotettavien ja toistettavien tulosten aikaansaamiseksi. Tämä on erityisen tärkeää, kun aikeena on osoittaa lääkeaine tehokkaaksi. Tässä väitöskirjatyössä kehitettiin uusia työkaluja ja paranneltiin aiempia menetelmiä Parkinsonin taudin tutkimiseksi prekliinisissä malleissa, ja tutkittiin cytomegalovirus (CMV) promoottorin sekä Parkinsonin taudin mallintamiseen soveltuvan dopaamiinihermosoluviljelmän ominaisuuksia. Ensiksi hyödynsimme rotan striatumin tyrosiinihydroksylaasi positiivisten (TH+) hermosoluyhteyksien optisten tiheyksien mittaamisessa infrapuna-analyysiä, tavallisen väriaineanalyysin sijaan, tarjoten vaihtoehtoisen menetelmän optisten tiheyksien mittaamiseksi. Lisäksi kehitimme uuden hermoverkkoalgoritmeihin perustuvan menetelmän solujen laskemiseksi jyrsijöiden aivoleikkeistä. Solulaskelmat korreloivat voimakkaasti muilla laskentamenetelmillä saatujen tulosten kanssa ja algoritmilla saadut laskelmat olivat huomattavasti nopeampia. Kehitimme myös, sekä plasmidi- että solupohjaisia, reportterikokeita Parkinsonin tautiin liitetyn entsyymin, Dicerin, aktivaation mittaamiseksi. Nämä reportterikokeet, jotka hyödynsivät ekso- ja endogeenisiä fluoresenssi- sekä luminesenssi-indikaattoreita, validoitiin ja tulokset olivat verrattavissa aiempiin julkaistuihin reporttereihin, paranneltujen fysiologisesti suotuisien olosuhteiden myötä. Näiden lisäksi huomasimme, että CMV promoottori, jota käytetään geeniterapioissa, voi aktivoitua neurotransmission myötä. Osoitimme in vivo, että metamfetamiinin – voimakas dopamiinia vapautta aine – annostelun myötä CMV promoottori aktivoitui rottien aivoissa. Viimeiseksi huomasimme eroja solulimakalvoston rakenteissa viljeltyjen hiiren TH+ hermosolujen eri osissa. Yhteenvetona, tässä työssä kehitetyt ja parannellut työkalut laajentavat Parkinsonin taudin prekliinisten tutkijoiden työkalurepertuaaria, mutta ne ovat myös mahdollisesti sovellettavissa muiden tautien, sekä kliinisten tutkimusten, tutkimiseen. Lisäksi löydöksemme CMV-promoottorin aktivaatiosta, on tärkeä tieto ottaa huomioon suunnitellessa ekspressiovektoreita, reportterikokeita, ja geeniterapioita käytettäväksi prekliiniisissä Parkinsonin taudin kokeissa, joissa käytetään amfetamiineja. Ja lopuksi, saimme uusia havaintoja viljeltyjen dopamiinihermosolujen ultrarakenteellisista ominaisuuksista ja tuotimme hyödyllisen resurssin tutkijoiden käytettäväksi

    Drug development progress in duchenne muscular dystrophy

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    Duchenne muscular dystrophy (DMD) is a severe, progressive, and incurable X-linked disorder caused by mutations in the dystrophin gene. Patients with DMD have an absence of functional dystrophin protein, which results in chronic damage of muscle fibers during contraction, thus leading to deterioration of muscle quality and loss of muscle mass over time. Although there is currently no cure for DMD, improvements in treatment care and management could delay disease progression and improve quality of life, thereby prolonging life expectancy for these patients. Furthermore, active research efforts are ongoing to develop therapeutic strategies that target dystrophin deficiency, such as gene replacement therapies, exon skipping, and readthrough therapy, as well as strategies that target secondary pathology of DMD, such as novel anti-inflammatory compounds, myostatin inhibitors, and cardioprotective compounds. Furthermore, longitudinal modeling approaches have been used to characterize the progression of MRI and functional endpoints for predictive purposes to inform Go/No Go decisions in drug development. This review showcases approved drugs or drug candidates along their development paths and also provides information on primary endpoints and enrollment size of Ph2/3 and Ph3 trials in the DMD space

    Biochemical Biomarkers and Neurodegenerative Diseases

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    In this book, we collected scientific articles, including reviews and research articles, showcasing the lastest literature on the importance of biochemical biomarkers in the management of neurodegenerative diseases, from screening to diagnosis, prognosis, and treatment

    Cell-Specific Spinophilin Function Underlying Striatal Motor Adaptations Associated with Amphetamine-Induced Behavioral Sensitization

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    Indiana University-Purdue University Indianapolis (IUPUI)Striatal-mediated pathological disease-states such as Obsessive-Compulsive Disorder (OCD), Parkinson’s Disease (PD), and psychostimulant drug addiction/abuse are coupled with distinct motor movement abnormalities. In addition, these disorders are associated with perturbed synaptic transmission. Proper synaptic transmission is critical for maintaining neuronal communication. Furthermore, in many striatal-dependent disease-states, the principle striatal neurons, medium spiny neurons (MSNs), exhibit differential perturbations in downstream signaling. Signal transduction pathways that are localized to the glutamatergic post-synaptic density (PSD) of GABAergic MSNs regulate protein phosphorylation in a tightly controlled manner. Alterations in the control of this phosphorylation in striatal MSNs are observed in myriad striatal pathological diseasestates and can give rise to perturbations in synaptic transmission. While serine/threonine kinases obtain substrate specificity, in part, by phosphorylating specific consensus sites, serine/threonine phosphatases such as protein phosphatase 1 (PP1) are much more promiscuous. To obtain substrate selectivity, PP1 associates with targeting proteins. The major targeting protein for PP1 in the PSD of striatal dendritic spines is spinophilin. Spinophilin not only binds PP1, but also concurrently interacts with myriad synaptic proteins. Interestingly, dopamine depletion, an animal model of PD, modulates spinophilin protein-protein interactions in the striatum. However, spinophilin function on basal striatal-mediated motor behaviors such as the rotarod or under hyperdopaminergic states such as those observed following psychostimulant-induced behavioral sensitization are less well characterized. To elucidate spinophilin function more specifically, we have generated multiple transgenic animals that allow for cell type-specific loss of spinophilin as well as cell-specific interrogation of spinophilin protein interactions. Here, I report the functional role of spinophilin in regulating striatal mediated motor behaviors and functional changes associated with amphetamine-induced locomotor sensitization. In addition, we define changes in spinophilin protein-protein interactions that may mediate these behavioral changes. Furthermore, global loss of spinophilin abrogates amphetamine-induced sensitization and plays a critical role in striatal motor learning and performance. The data suggest that the striatal spinophilin protein interactome is upregulated in MSNs following psychostimulant administration. In addition, loss of spinophilin changes protein expression in myriad psychostimulant-mediated striatal adaptations. Taken together the data suggests that spinophilin’s protein-protein interactions in the striatum are obligate for appropriate striatal mediated motor function

    Anatomy, structure and function: Understanding extremes in fear and anxiety by in vivo imaging techniques

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    Development of Translational Imaging Biomarkers in Mouse Models of Huntington's Disease

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    Huntington’s disease (HD) is a genetic neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin (HTT) gene that results in movement disorders and cognitive and psychiatric decline. To better track disease onset and progression, biomarkers that precede irreversible structural changes are needed. Alterations in metabolic processes detectable using magnetic resonance imaging (MRI) and other MR approaches may provide such biomarkers but need characterisation in HD mouse models to improve their clinical translatability. The aim of this thesis was to develop imaging biomarkers in transgenic R6/2 and knock-in zQ175 mice, two commonly used HD mouse models. To undertake the most comprehensive time-course analyses of metabolite concentrations in these models so far, proton magnetic resonance spectroscopy (1H-MRS) was acquired in selected brain regions throughout disease progression. Significant metabolic alterations were observed in zQ175 and R6/2 mice, with fluctuations at early disease stages. These changes suggested diminished neuronal integrity and reactive gliosis, which were confirmed using histology. Brain regions also exhibited specific metabolic profiles, many of said profiles being observed across both mouse models (albeit with some discrepancies). Chemical Exchange Saturation Transfer (CEST), which ought to overcome the limited sensitivity of 1H-MRS, was also acquired. However, we show CEST is not sensitive to HD pathology and do not recommend it for biomarker development in HD. Lastly, we acquired diffusion-weighted MRS (DW-MRS) in zQ175 mice to assess the diffusion of metabolites confined to cell-specific compartments. We found no changes in metabolite diffusion properties, but given the experimental nature of the protocol we used, DW-MRS needs further investigation in the context of HD. Overall, we have moved the field of HD forward by evaluating in detail the metabolic consequences of the disease in two mouse models that are widely used to investigate HD pathogenesis and evaluate therapeutic targets

    Recent Advances in Drug Addiction Research and Clinical Applications

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    Although it is well-accepted that drug addiction is a major public health concern, how we address it as a society continues to evolve as recent advances in the lab and clinic clarify the nature of the problem and influence our views. This unique collection of eight chapters reviews key findings on the neurobiology and therapeutics of addiction while capturing the diversity of perspectives that shape these concepts, which range from evolutionary biology to psychiatry to the legal system. This book discusses in depth how technological advances have led to important discoveries and how these discoveries, in turn, are increasingly being translated into clinical practice. It also presents avenues for future study that hold promise for the many affected by addiction
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