Validating a novel ADHD model for medication development

Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder which manifests as deficits in impulse control, excessive activity in home or school settings, and an inability to focus attention on relevant stimuli. While millions of individuals with ADHD lack this ability to effectively modulate behaviors and optimize societal, academic, or occupational performance, surprisingly little is known regarding its genetic etiology and few improvements in therapeutics have been accomplished over the past decades. This lack of progress is partly attributable to the dearth of genetic models of ADHD enabling unbiased exploration of the genetic architecture of hyperactive-impulsive behavior. The goal of my dissertation is to fill this critical need for a genetic model which may be used to meaningfully advance the field of ADHD research. Toward that end, I systemically evaluated the face, construct, and predictive validity of a genetically variable line mice selectively bred for increased home cage activity in order to determine whether it may faithfully recapitulate facets of ADHD symptomatology. In Chapter 1, the rodent models of ADHD currently used are reviewed in terms of their validity, advantages and limitations, and the extent to which these models have informed or obfuscated our understanding of ADHD. Chapter 2 summarizes promising results from our initial foray into assessing the predictive validity of the line; Generation 11 High-Active mice demonstrate home cage hyperactivity which is paradoxically ameliorated by chronic low-dose amphetamine. Furthermore in this chapter I establish a statistical procedure for estimating whether line differences are due to selection for hyperactivity versus genetic drift; results suggest the genetic underpinnings of home cage hyperactivity are unique and likely differ from those mediating other forms of increased physical activity. Chapter 3 vastly expounds on the face validity of the line by confirming the hyperactivity and motor impulsivity of the High-Active line in two different versions of the operant Go/No-go task and within adolescent males and adult females. Interestingly, the High-Active line shows little evidence of inattention as assessed by spontaneous alternation in the Y-maze, suggesting High-Active validity may be circumscribed to the Hyperactive-Impulsive subtype of ADHD. Furthermore the predictive validity of the line is reaffirmed in this chapter as the same low-dose amphetamine which reduces hyperactivity also paradoxically ameliorates motor impulsivity. Analysis of regional neural activation of High-Active versus Control mice at baseline and in response to low-dose amphetamine indicates dysregulated prefrontal cortex and cerebellum may partly modulate High-Active impulsive behavior. Chapter 4 addresses a fundamental question regarding the construct validity of the High-Active line. In this large-scale cross-fostering experiment I demonstrate that the significant deficits in the maternal competence of High-Active dams do not influence the hyperactivity of High-Active offspring; raw genetics mediate this transgenerational phenotype whose expression cannot be influenced even by the most stressful of perinatal environments. I further infer evidence of extreme dopaminergic dysregulation in the High-Active line, as only a genetic ablation of the dopamine transporter has produced dams which even somewhat approach the severity of High-Active deficits in maternal care. In Chapter 5 I propose high-yield uses of this now-validated model of ADHD, including strategies for uncovering relevant genetic etiological factors, identifying novel compounds to advance therapeutic approaches, and elucidating endophenotypes which may aid in the diagnosis of ADHD. Ultimately the efforts of this dissertation have culminated in a validated genetic model of Hyperactive-Impulsive ADHD which is poised to serve as a platform for significantly advancing our understanding of this ubiquitous, heritable behavioral disorder

Konstrukcija ženskog identiteta u pravaškim humorističko-satiričkim listovima druge polovine 19. stoljeća

Stranka prava pojavila se na političkoj sceni 1861. predvođena Antom Starčevićem i Eugenom Kvaternikom. Specifičnost stranaka osnovanih u tom razdoblju stranačko je novinarstvo, tj. političari su preko svojega tiska komunicirali s narodom. Najvažniji instrument pravaša bili su humorističko-satirički listovi. Stoga rad pokazuje na koji su način pravaši konstruirali ženski identitet u humorističko-satiričkim listovima i tako utjecali na javno mišljenje. Kvalitativna analiza šest najzastupljenijih tema u humorističko-satiričkim listovima pokazuje koje su ključne dihotomije u muško-ženskim odnosima te kako se stereotipni rodni binarizam odražavao na položaj žene u društvu. Metodom kvantitativne analize sadržaja statistički je prikazana zastupljenost pojedinih tema

Forging Money in the Kingdom of Yugoslavia in the 1930s, with Special Attention to the Sava Banovina and the Banovina of Croatia

Ponajviše na osnovi arhivske građe, ali i onodobnoga tiska, prikazuje se složenost fenomena krivotvorenja novca na području Kraljevine Jugoslavije tridesetih godina 20. stoljeća. Obuhvaćeni su uglavnom slučajevi krivotvorenja iz Savske Banovine i Banovine Hrvatske. Pokušali smo obraditi politički, društveni i geografski aspekt krivotvorenja. Osobito se osvrće na odnos vlasti prema krivotvorenju, na sociodemografske karakteristike krivotvoritelja i krivotvoriteljskih organizacija te na geografske tokove novca. Analizom smo nastojali prikazati neke karakteristike krivotvoriteljske prakse.The author gives a complex picture of forging money on the territory of the Kingdom of Yugoslavia in the 1930s, primarily based on archive material, but also on the contemporary press. He mostly covers cases of forging in the Sava Banovina and the Banovina of Croatia, analysing the political, social and geographical aspects. He pays special attention to how the authorities reacted to the forging, the socio-demographic characteristics of the forgers and forging organisations, and to the territorial flow of the money. His analysis is aimed at showing some characteristics of the practice of forging

Striatal transcriptome of a mouse model of ADHD reveals a pattern of synaptic remodeling

Despite the prevalence and high heritability of Attention-Deficit/Hyperactivity Disorder (ADHD), genetic etiology remains elusive. Clinical evidence points in part to reduced function of the striatum, but which specific genes are differentially expressed and how they sculpt striatal physiology to predispose ADHD are not well understood. As an exploratory tool, a polygenic mouse model of ADHD was recently developed through selective breeding for high home cage activity. Relative to the Control line, the High-Active line displays hyperactivity and motor impulsivity which are ameliorated with amphetamine. This study compared gene expression in the striatum between Control and High-Active mice to develop a coherent hypothesis for how genes might affect striatal physiology and predispose ADHD-like symptoms. To this end, striatal transcriptomes of High-Active and Control mice were analyzed after mice were treated with saline or amphetamines. The pseudogene Gm6180 for n-cofilin (Cfl1) displayed 20-fold higher expression in High-Active mice corresponding with reduced Cfl1 expression suggesting synaptic actin dysregulation. Latrophilin 3 (Lphn3), which is associated with ADHD in human populations and is involved in synapse structure, and its ligand fibronectin leucine rich transmembrane protein 3 (Flrt3), were downregulated in High-Active mice. Multiple genes were altered in High-Active mice in a manner predicted to downregulate the canonical Wnt pathway. A smaller and different set of genes including glyoxalase (Glo1) were differentially regulated in High-Active as compared to Control in response to amphetamine. Together, results suggest genes involved in excitatory synapse regulation and maintenance are downregulated in ADHD-like mice. Consistent with the molecular prediction, stereological analysis of the striatum from a separate set of mice processed for imunohistochemical detection of synaptophysin revealed approximately a 46% reduction in synaptophysin immunoreactivity in High-Active relative to Control. Results provide a new set of molecular targets related to synapse maintenance for the next generation of ADHD medicines

Striatal transcriptome of a mouse model of ADHD reveals a pattern of synaptic remodeling.

Despite the prevalence and high heritability of Attention-Deficit/Hyperactivity Disorder (ADHD), genetic etiology remains elusive. Clinical evidence points in part to reduced function of the striatum, but which specific genes are differentially expressed and how they sculpt striatal physiology to predispose ADHD are not well understood. As an exploratory tool, a polygenic mouse model of ADHD was recently developed through selective breeding for high home cage activity. Relative to the Control line, the High-Active line displays hyperactivity and motor impulsivity which are ameliorated with amphetamine. This study compared gene expression in the striatum between Control and High-Active mice to develop a coherent hypothesis for how genes might affect striatal physiology and predispose ADHD-like symptoms. To this end, striatal transcriptomes of High-Active and Control mice were analyzed after mice were treated with saline or amphetamines. The pseudogene Gm6180 for n-cofilin (Cfl1) displayed 20-fold higher expression in High-Active mice corresponding with reduced Cfl1 expression suggesting synaptic actin dysregulation. Latrophilin 3 (Lphn3), which is associated with ADHD in human populations and is involved in synapse structure, and its ligand fibronectin leucine rich transmembrane protein 3 (Flrt3), were downregulated in High-Active mice. Multiple genes were altered in High-Active mice in a manner predicted to downregulate the canonical Wnt pathway. A smaller and different set of genes including glyoxalase (Glo1) were differentially regulated in High-Active as compared to Control in response to amphetamine. Together, results suggest genes involved in excitatory synapse regulation and maintenance are downregulated in ADHD-like mice. Consistent with the molecular prediction, stereological analysis of the striatum from a separate set of mice processed for imunohistochemical detection of synaptophysin revealed approximately a 46% reduction in synaptophysin immunoreactivity in High-Active relative to Control. Results provide a new set of molecular targets related to synapse maintenance for the next generation of ADHD medicines

Suor Angelica et autres sœurs (komorni ansambl i solisti Muzičke akademije Sveučilišta u Zagrebu, 11. 2. 2021.)

Snimka izvedbe održane na Muzičkoj akademiji u Koncertnoj dvorani "Blagoje Bersa" 11. 2. 2021. Na projektu postavljanja opere sudjelovale su četiri sastavnice Sveučilišta u Zagrebu: Muzička akademija, Akademija dramske umjetnosti, Akademija likovnih umjetnosti i Fakultet strojarstva i brodogradnje. Izvođači: studenti solo pjevanja (Marija Salečić, Marko Antolković, Ines Grubišić, Lucija Klarić, Maja Sremec, Neža Vasle, Vlatka Kladarić, Lucija Ercegovac, Stefani Pijetlović, Patricija Žudetić, Tea Zec, Ana Majdak, Petra Cik, Barbara Pijetlović), komorni ansambl (Barbara Tomić (flauta, piccolo), Andrea Pedron (udaraljke), Petra Barišić (harfa), Ellen Široka (harfa), Dubravko Ćepulić Polgar (orgulje), Ivana Hrkać (pozitiv), Marko Glogović (violina), Edita Kolovrat (violina), Filip Kojundžić (viola), Lana-Lucija Horvatić (violončelo)). Umjetničko vodstvo: red. prof. art. Mladen Tarbuk. Dirigent: Mateo Narančić. Redatelj: Matthias Behrends. Program: Suor Angelica et autres sœurs, pasticcio-opera sastavljena od glazbe skladatelja različitih stilskih razdoblja (Puccini, Poulenc, Mozart, Barber, Klose, Hindemith, Hildegard von Bingen, Caplet, Tarbuk, Ravel) prema romanu Veronike Peters "Što sve stane u dva kofera"

Suor Angelica et autres sœurs (komorni ansambl i solisti Muzičke akademije u Zagrebu, 11.2.2021.)

Snimka izvedbe održane na Muzičkoj akademiji u Koncertnoj dvorani "Blagoje Bersa" 11.2.2021. Na projektu postavljanja opere sudjelovale su četiri sastavnice Sveučilišta u Zagrebu: Muzička akademija, Akademija dramske umjetnosti, Akademija likovnih umjetnosti i Fakultet strojarstva i brodogradnje. Izvođači: studenti solo pjevanja: Marija Salečić, Marko Antolković, Ines Grubišić, Lucija Klarić, Maja Sremec, Neža Vasle, Vlatka Kladarić, Lucija Ercegovac, Stefani Pijetlović, Patricija Žudetić, Tea Zec, Ana Majdak, Petra Cik, Barbara Pijetlović; komorni ansambl: Barbara Tomić (flauta, piccolo), Andrea Pedron (udaraljke), Petra Barišić (harfa), Ellen Široka (harfa), Dubravko Ćepulić Polgar (orgulje), Ivana Hrkać (pozitiv), Marko Glogović (violina), Edita Kolovrat (violina), Filip Kojundžić (viola), Lana-Lucija Horvatić (violončelo); umjetničko vodstvo: Mladen Tarbuk; dirigent: Mateo Narančić; redatelj: Matthias Behrends. Program: Suor Angelica et autres sœurs, pasticcio-opera sastavljena od glazbe skladatelja različitih stilskih razdoblja (Puccini, Poulenc, Mozart, Barber, Klose, Hindemith, Hildegard von Bingen, Caplet, Tarbuk, Ravel) prema romanu Veronike Peters "Što sve stane u dva kofera"