Voditelj:
Prof.dr.sc. Mario Vukšić
Izvanredni profesor neuroznanosti & anatomije
Hrvatski institut za istraživanje mozga
Medicinski fakultet Sveučilišta u Zagrebu
Šalata 12, 10000 Zagreb
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Laboratorij za konfokalnu mikroskopiju osnovan je 2008. godine a koristite ga svi znanstvenici zaposleni na Hrvatskom institutu za istraživanje mozga. Laboratorij je opremljen laserskim konfokalnim mikroskopom tvrtke Zeiss tipa LSM 510-META. Uređaj koristi lasere: Argon 458/477/488/514nm, HeNe 543 nm, HeNe laser 633 nm te posjeduje i META detektor koji omogućava razlikovanje različitih preklapajućih emisijskih signala. Sistem je nadograđen na invertni mikroskop Axiovert 200M tvrtke Zeiss koji se također može koristiti za standardnu fluorescenciju te posjeduje slijedeće objektive: 10x i 20x zračne; te 40x i 63x uljne.
Trenutno se uređaj koristi za: snimanje pojedinačnih konfokalnih slika, trodimenzionalnu rekonstrukciju pojedinačnih živčanih stanica koristeći konfokalni mikroskop i Neurolucida sustav, dokazivanje prisutnosti i raspodjele različitih fluorescentnom bojom označenih struktura.

Istraživački interesi:
Procesi oporavka nakon moždane ozljede i prekidanja veza, plastičnost dendrita i dendritičkih trnova nakon lezije, pojava izrastanja aksonskih mladica.

Primjeri aplikacije:
Konfokalna slagalina prikazuje GFP-pozitivne zrnate stanice u girus dentatusu transgeničnog Thy-1 miša I trodimenzionalna rekonstrukcija iste stanice koristeći Neurolucida sustav.
(Vuksic i sur., Hippocampus 2008)
Entorinalna denervacija u transgeničnog Thy-1 miša uzrokuje brze i prolazne promjene gustoće dendritičkih trnova na zrnatim stanicama girus dentatusa.
(Vuksic i sur., Experimental Neurology 2011)

Head:
Mario Vukšić, MD, PhD
Associate Professor of Neuroscience & Anatomy
Croatian Institute for Brain Research
School of Medicine University of Zagreb
Šalata 12, 10000 Zagreb, Croatia
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The Laboratory of Confocal Microscopy was established in 2008. This is an open laboratory available to all scientists from Croatian Institute for Brain Research. The Lab basic equipment is a laser scanning microscope Zeiss LSM 510-META. The appliance uses Argon laser 458/477/488/514nm, HeNe laser 543 nm, HeNe laser 633 nm and the META detector which can spectrally separate overlapping emission signals. The system was coupled to inverted microscope Zeiss Axiovert 200M which is also equipped for standard epi-fluorescence imaging. The following objectives are available with the system: 10x air, 20x air, 40x oil and 63x oil.
Current applications include: single confocal images, 3D-reconstruction of single neurons using confocal microscopy and Neurolucida system, colocalization and distribution of various fluorescently-tagged proteins.

Research interests:
Reorganizational processes following brain trauma and deafferentation, lesion-induced plasticity of dendrites and dendritic spines; axonal sprouting.

Example application:
Confocal image stack showing GFP-expressing granule cell in the fascia dentata of the Thy-1 GFP transgenic mouse and 3D reconstruction of the same cell using Neurolucida system
(Vuksic et al., Hippocampus 2008)
Entorhinal denervation of the Thy-1 GFP transgenic mouse induces fast and transient changes in spine densities of granule cells in the fascia dentata.
(Vuksic et al., Experimental Neurology 2011)

• Slade N, Zorić A, Horvat B, Vukšić M, Kostović I, Poljak L (2015) Suppression of Smad-1 mRNA expression level by Smad-2 likely control dichotomy of NF-κB and Smads mediated activation. Immunobiology. 220(1):48-53
• Kostović I, Sedmak G, Vukšić M, Judaš M (2015) The relevance of human fetal subplate zone for developmental neuropathology of neuronal migration disorders and cortical dysplasia. CNS Neuroscience & Therapeutics 21(2):74-82.
• Kosi N, Alić I, Kolačević M, Vrsaljko N, Jovanov Milošević N, Sobol M, Philimonenko A, Hozak P, Gajović S, Pochet R, Mitrečić D. (2015): Nop2 is expressed during proliferation of neural stem cells and in adult mouse and human brain. Brain Research 1597:65-76.
• Jovanov-Milošević N, Petrović D, Sedmak G, Vukšić M, Hof PR, Šimić G (2012) Human fetal tau protein isoform: Focus on possibilities for Alzheimer’s disease treatment. The International Journal of Biochemistry & Cell Biology 44:1290-1294.
• Kapuralin K, Van Ginneken C, Curlin M, Timmermans JP, Gajovic S. (2012): Neurons and a subset of interstitial cells of Cajal in the enteric nervous system highly express Stam2 gene. Anatomical Record-Advances in integrative anatomy and evolutionary biology 295:113-20.
• Curlin M, Kapuralin K, Muro AF, Baralle FE, Chowdhury K, Gajović S. (2012): Stam2 expression pattern during embryo development. Gene Expression Patterns 12: 68-76.
• Vukšić M, Del Turco D, Vlachos A, Schuldt G, Müller CM, Schneider G, Deller T (2011) Unilateral entorhinal denervation leads to long-lasting dendritic alterations of mouse hippocampal granule cells. Experimental Neurology 230(2):176–185.
• Vukšić M, Petanjek Z, Kostović I (2011) Development of prefrontal layer III pyramids in infants with Down syndrome. Translational Neuroscience 2(3):225-232.
• Ghebremedhin E, Rosenberger A, Rüb U, Vukšić M, Berhe T, Bickeböller H, de Vos RAI, Thal DR, Deller T (2010) Inverse relationship between cerebrovascular lesions and severity of Lewy body pathology in patients with Lewy body disease. Journal of Neuropathology & Experimental Neurology 29(5):442-448.
• Banfić H, Višnjić D, Mise N, Balakrishnan S, Deplano S, Korchev YE, Domin J (2009) Epidermal growth factor stimulates translocation of the class II phosphoinositide 3-kinase PI3K-C2beta to the nucleus. Biochemical Journal 422(1):53-60.
• Vukšić M, Del Turco D, Bas-Orth C, Burbach GJ, Feng G, Müller CM, Schwarzacher SW, Deller T (2008). 3D-Reconstruction and functional properties of GFP-positive and GFP-negative granule cells in the fascia dentata of the Thy1-GFP mouse. Hippocampus 18(4):364-75.
• Schwarzacher SW*, Vukšić M*, Haas CA, Burbach GJ, Sloviter RS and Deller T (2006) Neuronal hyperactivity induces astrocytic expression of neurocan in the adult rat hippocampus. Glia 53:704-714. *equally contribution
• Ghebremedhin E, Del Tredici K, Vukšić M, Rüb U, Thal DR, Burbach GJ, Rosenberger A, Bickeböller H, Deller T, Rob VAI, Jansen Steur ENH, Braak H (2006) Relationship of ApoE and age at onset to Parkinson’s disease neuropathology. Journal of Neuropathology & Experimental Neurology 65:116-123.
• Kienzler F, Jedlicka P, Vukšić M, Deller T, Schwarzacher SW (2006) Excitotoxic hippocampal neuron loss following sustained electrical stimulation of the perforant pathway in the mouse. Brain Research 1085:195-198.
• Gierga K, Bürk K, Bauer M, Diaz Orozco G, Auburger G, Schultz C, Vukšić M, Schöls L, de Los RAI, Braak H, Deller T, Rüb U (2005) Involvement of the cranial nerves and their nuclei in spinocerebellar ataxia type 2 (SCA2). Acta Neuropathologica 109:617-631.
• Crljen V, Visnjić D, Banfić H (2004) Presence of different phospholipase C isoforms in the nucleus and their activation during compensatory liver growth. FEBS Lett 571(1-3):35-42.

Voditelj:
prof. dr. sc. Zdravko Petanjek, dr. med.
redoviti profesor anatomije i neuroznanosti

Suradnici
doc. dr. sc. Sanja Darmopil, dipl. ing. biologije
Ana Hladnik, dr. med.
Domagoj Džaja, dr. med.
Ivana Bičanić, dr. med.
Dora Mandić, dr. med.

Istraživački interesi:
U laboratoriju se istražuju organizacija i molekularna svojstva neurona i njihovih veza s naglaskom na neuralne sustave i područja posebno razvijena kroz evoluciju čovjeka: frontalni asocijativni korteks, te asocijativni projekcijski neuroni i kalretininski interneuroni. Navedena područja i neuroni zbog svoje brojnosti predstavljaju glavni biološki elementi u procesuiranju najkompleksnijih kognitivnih funkcija kod čovjeka te stoga imaju glavnu ulogu u etiopatogenezi važnih psihijatrijskih i neuroloških poremećaja.
Iako su osnovni principi organizacije neuralne mreže kore velikoga mozga zajednički svim sisavcima, neke vrste neurona, kao što su veliki kortiko-kortikalni piramidni neuroni s paralelnim projekcijama prema više kortikalnih područja, ali i izrazito bogatim intra-arealnim projekcijama, jasno su izražene tek kod majmuna i čovjeka. Drugim skupinama, kao što su kalretininski GABA-ergički interneuroni, broj se eksponencijalno povećava i vjerojatno se unutar ove skupine pojavljuju strukturno i funkcionalno nove populacije neurona.

Glavne teme istraživanja:

1. Kvantitativna (utvrđivanje broja i distribucije) i kvalitativna (utvrđivanje morfoloških i molekularnih obilježja) analiza piramidnih neurona sloja III i GABA-ergičkih interneurona te regionalna komparativna analiza navedenih obilježja između multimodalnih, unimodalnih i primarnih kortikalnih područja. Također se provodi i komparativna analiza navedenih obilježja između čovjeka, majmuna i štakora.
2. Usporedba parametara stanične organizacije normalnog mozga čovjeka i makaki majmuna s mozgovima osoba oboljelih od psihijatrijskih i neuroloških poremećaja (npr. tkivo dobiveno prilikom operacija pacijenata s teškim oblicima epilepsije), kao i s podacima iz eksperimentalnih modela (model epilepsije frontalnog režnja majmuna). Ovaj dio istraživanja provodi se u suradnji s laboratorijem dr. Monique Esclapez u Marseilleu (Brain Dynamic Institute Marseille (BDI: http://ins.medecine.univmed.fr/).
3. Istraživanje genetički modificiranog (“humaniziranog”) FoxP2 miša u svrhu utvrđivanja kako promjene u strukturi gena (koje su bile selekcionirane tijekom evolucije čovjeka i smatraju se jednom on najvažnijih promjena u razvoju govora) utječu na organizaciju kortikalnih veza. Ovaj dio istraživanja provodi se u suradnji s laboratorijem prof. Svante Paabo u Leipzigu (Max Planck Institute for Evolutionary Anthropology Leipzig; MPI-EVA: http://www.eva.mpg.de/).
4. Razvojne studije u majmuna i čovjeka usmjerene na istraživanja za primate specifičnih razvojnih događanja, kao što su obrazac rasta dendritičkog stabla asocijativnih piramidnih neurona, mjesto stvaranja kalretininskih neurona i specifični putovi migracije neurona.

METODOLOGIJA:
KVANTITATIVNA ANALIZA HISTOLOŠKIH PREPARATA; morfometrija i stereologija
U laboratoriju se koriste općeprihvaćene i dobro definirane kvantitativne metode analize obojenih histoloških preparata:

• stereologija (optički frakcionator)
• rekonstrukcija serijskih rezova i 3D mapiranje mozga
• rekonstrukcija neurona, anatomsko mapiranje
• morfometrija (rekonstrukcija i analiza grananja dendritičkog stabla i aksona te utvrđivanje broja i položaja dendritičkih trnova)

Kvantitativna analiza histoloških preparata provodi se uz korištenje Neurolucida i Stereoinvestigator programskih paketa (MicroBrightField, Williston, USA) na dva video-računarsko-mikroskopska sustava s 3D motoriziranim stolićem kontroliranih elektroničkim upravljačem. Stariji sustav sastoji se od Hitachi 3CCD video kamere u boji HV-C20M, Lucivid mikromonitora spojenog na Olympus BX50 mikroskop s 3D motoriziranim stolićem kontroliranim s elektroničkim upravljačem MAC 2000 (Ludl Electronic Products Ltd.). Noviji sistem (2010) sastoji se od MBF-DV-46 digitalne kamere koja se nalazi na Olympus BX61 mikroskopu motoriziranom za kretanje u dubinu, te motoriziranog stolića za pokretanje u x-y smjeru i koji je kontroliran MAC 5000 elektroničkim upravljačem (Ludl Electronic Products Ltd.).

HISTOLOŠKE TEHNIKE

• Golgi metode: Golgi-Cox, Rapid Golgi
• Histokemija: AchE, PAS-Alcian, NADPH
• Imunohistokemija za identifikaciju interneurona (GAD, kalretinin, somatostatin, parvalbumin, kalbindin), mapiramidnih neurona (SMI32, MAP2) te neurotransmitera i aksonskih završetaka (GABA, GAD; 65 i 67, VGAT, VGLUT1, VGLUT2). Imunohistokemijska bojenja provode se kao jednostruka bojenja korištenjem biotiniliranih protutijela i metode označavanja bazirane na DAB-u, te kao višestruka obilježavanja korištenjem fluorescentnih protutijela.
• Identifikacija i morfološka analiza neurona obilježenih tehnikama praćenja aksonskih projekcija te neurona obilježenih tijekom elektrofiziološkog eksperimenta: analiza neurona obilježenih tehnikama aksonskog transporta (biotin-dekstran-amin; pšenična klica konjugirana s aglutininom u koloidnom zlatu), uključujući i metode retrogradnog trans-sinaptičkog prijenosa biljega (rabies virus) te analiza morfologije neurona koji su po završetku elektrofiziološkog eksperimenta injicirani biocitinom.

Head:
Zdravko Petanjek, MD, PhD
Professor of Gross Anatomy and Neuroscience

Members:
Sanja Darmopil, PhD, MSc, Assistant Professor of Neuroscience
Ana Hladnik, MD, PhD student
Domagoj Džaja, MD, PhD student
Ivana Bičanić, MD, PhD student
Dora Mandić, MD, PhD student

The goal of our laboratory is to study organization and molecular properties of microcircuitry with an emphasis on neuronal elements that became particularly expressed during evolution of the human neocortex. Therefore, we specifically focus on the human associative frontal cortex as well as on the associative layer III of projecting neurons and calretinin expressing GABA-interneurons. Due to their expansion and unique features they are considered to be a main biological substrate of the most complex cognitive functions and involved in pathophysiology of various psychiatric and neurological disorders.
Despite common principles in connectivity, some neuron types are specific for monkey and human cerebral cortex, such as large cortico-cortical projecting neurons with parallel projection to several cortical areas and extremely reach local intra-areal connections. Also, a certain class of GABA-interneurons, calretinin expressing, shows a supralinear increase in number suggesting an appearance of new neuron types inside this group. These neurons are the key elements of human microcircuitry which molecular specificity and neuronal interaction need to be determined in order to assess how human cortex processes information.

RESEARCH TOPICS:

1. Quantitative (number and distribution) and qualitative (morphological and chemical properties) analysis of human specific neuron subclasses (layer IIIC pyramidal neurons, calretinin expressing GABA-interneurons) with comparative analysis of regional differences comparing multimodal, unimodal and primary cortical areas, as well as analysis of species differences (human, monkey and rat).
2. Comparison of cellular organization parameters in the normal human and monkey brain with morphology and chemical properties of specific neuron subclasses in various psychiatric and neurological disorders (analysis of cortical resections obtained after surgery of patients with severe epilepsy), including experimental models (model of frontal lobe epilepsy in monkey). This part of the research is performed in collaboration with dr.Monique Esclapez at the Brain Dynamic Institute Marseille (BDI: http://ins.medecine.univmed.fr/).
3. Examination of genetically modified mice model (“humanized” Foxp2 mice) in order to show how changes in the structure of a gene (that was positively selected during human evolution and related to the appearance of language) will affect the organization of cortical circuitry (this research is performed in collaboration with prof. Svante Paabo at the Max Planck Institute for Evolutionary Anthropology Leipzig; MPI-EVA: http://www.eva.mpg.de/).
4. Developmental studies in monkey and human with an emphasis on studying primate specific developmental events, as well as a pattern of dendritic growth in associative pyramidal neurons, place of origin of calretinin neurons and specific neuronal migratory routes.

TOOLS:

QUANTITATIVE ANALYSIS OF HISTOLOGICAL SECTIONS; morphometry and stereology
In our laboratory we are using well established qualitative methods for analysis of stained brain tissue:

• stereology (optical fractionator method),
• serial section reconstruction with three-dimensional brain mapping,
• neuron tracing, anatomical mapping and
• morphometry (reconstruction and analysis of branching pattern of the axon and dendrites together with spine counting).

These analyses are performed using Neurolucida and Stereoinvestigator software (MicroBrightField, Williston, USA) on two computer based automatic measuring microscope-video system connected to three-dimensional motorized stages controllers. An older system consists of Hitachi 3CCD color video camera HV-C20M placed on the Olympus BX50 microscope and connected to the MAC 2000 stage controller, (Ludl Electronic Products Ltd). A newer system (2010) is equipped with MBF digital camera placed on the Olympus BX61 microscope and connected to the MAC 5000 stage controller (Ludl Electronic Products Ltd).

TISSUE STAINING TECHINQUES

• Golgi methods: Golgi-Cox, Rapid Golgi method
• Histochemistry: AchE, PAS-Alcian, NADPH etc.
• Immunohistochemistry for identification of local circuit neuron markers (GAD, calretinin, somatostatin, parvalbumin, calbindin), pyramidal neuron markers (SMI32, MAP2) and markers of neurotransmitters and neurotransmitter terminals (GABA, GAD 65 and 67, VGAT, VGLUT1, VGLUT2). Immunohistochemistry is performed as a single labeling; using mostly byotinilated antibodies proceeded by DAB protocol, and as multiple labeling using mostly fluorescent labels.
• Identification and morphological analysis of neurons label by tracing experiments and during electrophysiological recording; neurons labeled by axon transport methods (biotin dextran amine, wheat germ agglutinin-conjugated colloidal gold), including methods which allow retrograde transynaptic/transneuronal transfer (rabies virus), as well as neurons injected with biocytin at the end of the electrophysiological recording.

Voditelj:
Prof.dr.sc. Nataša Jovanov-Milošević,
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Osoblje:
Maja Horvat, ing.lab.diag.,
Božica Popović, lab.teh.

Laboratorij za immunohistokemiju i in situ hibridizaciju pruža histološka bojanja rezova tkiva različitih dijelova živčanog sustava čovjeka i animalnih modela (miš, štakor, mačka). Kombinirajući različite histološke tehnike prikazuje se ekspresija gena u citoarhitektonski očuvanim uzorcima tkiva. Fiksacija i uklapanje tkiva, vibratomski, parafinski i smrznuti rezovi, rezovi fiksirani na staklo ili “free-floating”, jednostruka, višestruka bojanja i preko 20 različitih histoloških i histokemijskih bojanja specifičnih za neuroznanosti.
Tehnička podrška laboratorija ima preko 20 godina iskustva u obradi moždanog tkiva fetusa i odrasla čovjeka i animalnih modela.

Znanstveni interes:
praćenje prostorne i vremenske distribucije specifičnih proteina u kontekstu razvitka čeonog i limbičkog režnja telencefalona čovjeka, njegove plastičnosti i degeneracije. Poseban interes su morfološko-kemijske značajke prolaznih razvojnih struktura i zona te kortikalnih veza, tijekom normalnog razvitka, nakon hipoksično-ishemičnog oštećenja mozga i u razvojnim anomalijama.

Znanstveni projekti u tijeku:

• 2013. - „Komparativni histološko –MRI istraživački pristup poboljšanju dijagnostike perinatalnih oštećenja mozga čovjeka“ (akronim HIMRICO od Histological-MRI COmparative research) (PI: N. Jovanov Milosevic)
• 2013. – Suradnik istraživač, „Histological, MRI and gene expression analysis of the reorganizational processes in the medial (limbic) wall of developing human cerebrum (PI: M. Vukšić)
• 2011.- 2014. COST BM1001: Brain Extracellular matrix in health an disease” (MC N. Jovanov Milosevic, PI A. Dityatev)
• 2007.- UKF projekt: Neuroimiging, neurogenomics and pharmacogenomics of the frontal lobe connectivity: normal development and abnormalities in developmental disorders, (PI I. Kostović)
• 2006.-“Razvitak i plastičnost kortikalnih putova mozga čovjeka”, dio programa: Razvojna neurobiološka osnova kognitivnih, duševnih i neuroloških bolesti” (PI I. Kostović)

Head:
Associated professor Nataša Jovanov Milošević
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Personnel
Božica Popović, lab. technician,
Maja Horvat, Bachelor of medical laboratory diagnostic This email address is being protected from spambots. You need JavaScript enabled to view it.

Laboratory for Immunohistochemistry and In situ hybridization provides histological, immunohistochemical and in situ hybridization (non-radioactive) staining of human and animal nervous system tissue sections. The tissue fixation and embedding, resin, paraffin and frozen sectioning on-slides and free-floating, mono and double immuno-labelling, in situ (non-radioactive) hybridization, and more than 20 different histological and histochemical staining methods specific for neuroscience.
Core staff of the Laboratory has more than two decades of experience in processing fetal and adult human and animal brain tissue.

Scientific scope
Follow up study of spatial-temporal distribution of specific proteins in a context of frontal and limbic lobe development, plasticity and degeneration. Special emphasis is given to morphological-chemical phenotype characterization of the transient developmental features (zones, compartments and cells) and cortical connections of human fetal brain during normal development and in different developmental disorders.

Ongoing research projects

• 2013. –“Histological-MRI comparative research approach for improvement of diagnostic procedures for developmental disorders of the human brain, acronim HIMRICO, (PI: N. Jovanov Milosevic)
• 2013. – “Histological, MRI and gene expression analysis of the reorganizational processes in the medial (limbic) wall of developing human cerebrum (PI: Mario Vukšić)
• 2011.- COST BM1001: Brain Extracellular matrix in health an disease” (PI A. Dityatev, MC, Jovanov Milosevic)
• 2007-2011,- “Neuroimaging, neurogenomics and pharmacogenomics of the frontal lobe connectivity”, Unity through Knowledge Fund, (PI: I. Kostovic)

• Milosevic, Natasa Jovanov; Judas, Milos; Aronica, Eleonora; et al. Neural ECM in laminar organization and connectivity development in healthy and diseased human brain. BRAIN EXTRACELLULAR MATRIX IN HEALTH AND DISEASE, Progress in Brain Research, Volume: 214, Pages: 159-178, 2014
• Kostovic, Ivica; Kostovic-Srzentic, Mirna; Benjak, Vesna; et al. Developmental dynamics of radial vulnerability in the cerebral compartments in preterm infants and neonates. Frontiers in neurology, Volume: 5, Pages: 139, 2014
• Hladnik, Ana; Dzaja, Domagoj; Darmopil, Sanja; Jovanov Milosevic, Natasa; Zdravko Petanjek. Spatio-temporal extension in site of origin for cortical calretinin neurons in primates FRONTIERS IN NEUROANATOMY, Volume: 8, Article Number: 50 Published: JUN 26 2014
• Mlinac K, Jovanov Milošević N, Heffer M, Smalla KH, Schnaar RL, Kalanj Bognar S. Neuroplastin expression in the hippocampus of mice lacking complex gangliosides. J Mol Neurosci.;48(1):161-6, 2012.
• Jovanov-Milošević N, Petrović D, Sedmak G, Vukšić M, Hof PR, Simić G. Human fetal tau protein isoform: Possibilities for Alzheimer's disease treatment Int J Biochem Cell Biol. 44/8: 1290-4, 2012.
• Jovanov-Milošević N, Petanjek Z, Petrović D, Judaš M, Kostović I. Morphology, molecular phenotypes and distribution of neurons in developing human corpus callosum. Eur J Neurosci. 32(9):1423-32, 2010.
• Judaš M, Šimić G, Petanjek Z, Jovanov-Milošević N, Pletikos M, Vasung L, Vikšić M, Kostović I. The Zagreb Collection of human brains: A unique versatile but underexploited resource for the neuroscience community. Ann N Y Acad Sci. 1225 Suppl 1:E105-30. doi: 10.1111/j.1749-6632.2011.05993.x, 2011.
• Vasung L, Jovanov-Milošević N, Pletikos M, Mori S, Judaš M, Kostović I. Prominent periventricular fiber system related to ganglionic eminence and striatum in the human fetal cerebrum. Brain Struct Funct. 215(3-4):237-53, 2011.
• Jovanov-Milošević N, Petanjek Z, Petrović D, Judaš M, Kostović I. Morphology, molecular phenotypes and distribution of neurons in developing human corpus callosum. Eur J Neurosci. 32(9):1423-32, 2010.
• Judaš M, Sedmak G, Pletikos M, Jovanov-Milošević N. Populations of subplate and interstitial neurons in fetal and adult human telencephalon. J Anat. 217(4):381-99., 2010.
• Vasung L, Huang H, Jovanov-Milošević N, Pletikos M, Mori S, Kostović I. Development of axonal pathways in the human fetal fronto-limbic brain: histochemical characterization and diffusion tensor imaging. J Anat. 217(4):400-17, 2010.
• Jovanov-Milošević N, Čuljat M, Kostović I. (2009) Growth of the human corpus callosum: modular and laminar morphogenetic zones. Front Neuroanat. 3(6):1-10, 2009.
• Šimić G, Stanić G, Mladinov M, Jovanov-Milošević N, Kostović I, Hof PR.(2009) Annotation - Does Alzheimer's disease begin in the brainstem? Neuropathol Appl Neurobiol. 35: 432-554, 2009.

Voditelj:
Prof. dr. sc. Goran Šimić, dr. med.
Redoviti profesor neuroznanosti i anatomije
Predstojnik Zavoda za neuroznanost i Pročelnik Vijeća predmeta "Temelji neuroznanosti"
Zavod za neuroznanost, Hrvatski institut za istraživanje mozga
Medicinski fakultet Sveučilišta u Zagrebu
Šalata 12, 10000 Zagreb, Republika Hrvatska
Translational Neuroscience, glavni i odgovorni urednik http://www.degruyter.com/view/j/tnsci
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Suradnici:
Mirjana Babić, mag.biol.mol.
Zavod za neuroznanost, Hrvatski institut za istraživanje mozga
Medicinski fakultet Sveučilišta u Zagrebu
Šalata 12, 10000 Zagreb, Republika Hrvatska
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Istraživački interesi:
Istraživački interesi Laboratorija za razvojnu neuropatologiju usmjereni su na proučavanje: (1) mehanizama starenja i neurodegeneracije, napose selektivne vulnerabilnosti neurona u Alzheimerovoj bolesti, (2) etiopatogeneze spinalnih mišićnih atrofija i drugih razvojnih neuromišićnih bolesti, te (3) ustrojstva, djelovanja i poremećaja moždane kore, te njezine kemijske neuroanatomije. U posljednjih nekoliko godina je glavni cilj laboratorija bilo određivanje bioloških biljega Alzheimerove bolesti iz cerebrospinalne tekućine i plazme, te usporedba dobivenih vrijednosti s rezultatima komplementarnih dijagnostičkih postupaka neuropsihološkog testiranja, evociranih potencijala, genetičkih i neuroslikovnih bioloških biljega (http://alzbiotrack.hiim.hr/). U našem laboratoriju također odnedavno rabimo inovativni neinvazivni test skrivenog objekta kojim se procjenjuje poremećaj prostorne orijentacije kao jedan od najranijih znakova Alzheimerove bolesti. Pored određivanja polimorfizama gena povezanih sa sporadičnom Alzheimerovom bolešću s kasnim početkom, te njihove uloge u patogenezi bolesti, naš je krajnji cilj postavljanje pouzdane rane dijagnoze bolesti u pacijenata s blagim spoznajnim poremećajem, ali također i njezino diferencijalno-dijagnostičko razlikovanje od drugih primarnih uzroka demencije. Koristeći nekoliko različitih kultura živčanih stanica istražujemo i učinke potencijalno neuroprotektivnih spojeva na patološke promjene tipične za Alzheimerovu bolest, posebice fosforilaciju tau proteina. Usporedno s navedenim istraživanjima demencije, pomoću mikropostrojbene analize i konfokalne imunofluorescencijske mikroskopije nedavno smo započeli istraživati i promjene izraženosti gena te podvrsti dopaminergičkih receptora na postmortalnim uzorcima mozgova bolesnika sa shizofrenijom.

Projekti:
0108-1081870-1942 MZOŠ „Fosforilacija tau proteina u razvitku I Alzheimerovoj bolesti“
09/16 HRZZ „Otkrivanje i praćenje bioloških biljega radi rane terapijske intervencije u sporadičnoj Alzheimerovoj bolesti“
CMST COST Action CM1103 “Structure-based drug design for diagnosis and treatment of neurological diseases: dissecting andmodulating complex function in the monoaminergic systems of the brain”

Znanstvena suradnja:
dr. Patrick R. Hof, prof., Mount Sinai School of Medicine, New York, Sjedinjene Američke Države
dr. Adrian Danek, prof., Groβhadern Klinika, Ludwig-Maximilian Sveučilište, München, Njemačka
dr. Glenn E. Morris, prof., Robert Jones and Agnes Hunt Ortopedic Hospital, Oswestry, Keele Sveučilište, Ujedinjeno Kraljevstvo
Rohan de Silva, DPhil, University College London, Ujedinjeno Kraljevstvo
Andrea Diana, PhD, Zavod za biomedicinske znanosti Sveučilišta Cagliari, Italija

Head:
Goran Šimić, MD, PhD
Professor of Neuroscience and Anatomy
Chair, Department of Neuroscience
Croatian Institute for Brain Research
University of Zagreb Medical School
Šalata 12, HR-10000 Zagreb, Republic of Croatia
Translational Neuroscience, Editor-in-Chief and Managing Editor http://www.degruyter.com/view/j/tnsci
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Staff:
Mirjana Babić, mag.biol.mol.
Croatian Institute for Brain Research
University of Zagreb Medical School
Šalata 12, HR-10000 Zagreb, Croatia
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Research interests:
The research interests of the Laboratory for Developmental Neuropathology are centered on (1) the mechanisms of brain aging and neurodegeneration, especially the study of selective neuronal vulnerability in Alzheimer's disease, (2) the etiopathogenesis of spinal muscular atrophy and other developmental neuromuscular diseases, and (3) the structure, function, and disorders of the human cerebral cortex and its chemical neuroanatomy. In recent years the main objective of the laboratory was the determination of early Alzheimer's disease biomarkers in cerebrospinal fluid and plasma, in the context of complementary diagnostic modalities, such as neuropsychological testing, evoked potentials, and genetic and neuroimaging biomarkers (http://alzbiotrack.hiim.hr/). We are also using an innovative non-invasive hidden-goal task to detect spatial orientation impairment, one of the earliest signs of Alzheimer's disease. Besides identification of gene polymorphisms associated with late-onset, sporadic Alzheimer's disease, and their role in disease pathogenesis, our ultimate goal is to establish reliable early diagnosis of the disease in patients with mild cognitive impairment, and to differentiate it from other primary causes of dementia. We are also using several neuronal cell lines to investigate the effects of potentially neuroprotective compounds on typical Alzheimer's disease pathological changes, particularly tau phosphorylation. In parallel to these studies of dementia, by using microarray analysis and a panel of novel monoclonal antibodies for immunofluorescence confocal microscopy we have initiated studies of changes in gene expression and localization of dopaminergic receptor subtypes in brains of patients with schizophrenia.

Projects:
0108-1081870-1942 MZOŠ „Phosphorylation of tau proteins during development and Alzheimer’s disease”
09/16 CSF „ Detection and tracking of biological markers for early therapeutic intervention in sporadic Alzheimer’s disease “
CMST COST Action CM1103 “Structure-based drug design for diagnosis and treatment of neurological diseases: dissecting and

Scientific collaboration:
dr. Patrick R. Hof, prof., Mount Sinai School of Medicine, New York, NY, United States of America
dr. Adrian Danek, prof., Groβhadern Klinika, Ludwig-Maximilian University, München, Germany
dr. Glenn E. Morris, prof., Robert Jones and Agnes Hunt Ortopedic Hospital, Oswestry, Keele University, United Kingdom
Rohan de Silva, DPhil, University College London, United Kingdom
Andrea Diana, PhD, Department for Biomedical Sciences, Cagliari, Italy

• Šimić G, Mladinov M, Šešo-Šimić Đ, Jovanov-Milošević N, Islam A, Pajtak A, Barišić N, Sertić J, Lucassen PJ, Hof PR, Krušlin B (2008) Abnormal motoneuron migration, differentiation, and axon outgrowth in spinal muscular atrophy. Acta Neuropathol. 115: 313-326.
• Šimić G (2008) The pathogenesis of proximal autosomal recessive spinal muscular atrophy. Acta Neuropathol. 116: 223-234.
• Šimić G, Stanić G, Mladinov M, Jovanov-Milošević N, Kostović I, Hof PR (2009) Does Alzheimer’s disease begin in the brainstem? Neuropathol. Appl. Neurobiol. 35: 532-554.
• Rhaganti M-A, Šimić G, Watson S, Stimpson CD, Hof PR, Sherwood CC (2011) Comparative analysis of the nucleus basalis of Meynert in primates. Neuroscience 185: 1-15.
• Petanjek Z, Judaš M, Šimić G, Rašin MR, Uylings HBM, Rakic P, Kostović I (2011) Extraordinary neoteny of synaptic spines in the human prefrontal cortex. Proc. Natl. Acad. Sci. 108: 13281-13286.
• Boban M, Malojčić B, Mimica N, Vuković S, Zrilić I, Hof PR, Šimić G (2012) The reliability and validity of the mini-mental state examination in the elderly Croatian population. Dement. Geriatr. Cogn. Disord. 33: 385-392.
• Jovanov Milošević N, Petrović D, Sedmak G, Vukšić M, Hof PR, Šimić G (2012) Human fetal tau protein isoform: possibilities for Alzheimer's disease treatment. Int. J Biochem. Cell Biol. 44: 1290-1294.
• Babić M, Švob Štrac D, Mück-Šeler D, Pivac N, Stanić G, Hof PR, Šimić G (2014) Update on the core and developing cerebrospinal fluid biomarkers for Alzheimer’s disease. Croat. Med. J 55: 347-365.
• Šimić G, Babić M, Borovečki F, Hof PR (2014) Early failure of the default-mode network and the pathogenesis of Alzheimer's disease. CNS Neurosci. Ther. 20: 692-698.
• Šimić G, Hof PR (2015) In search of the definitive Brodmann's map of cortical areas in human. J. Comp. Neurol. 523: 5-14.