Neuroimaging, neurogenomics and pharmacogenomics of the frontal lobe connectivity: normal development and abnormalities in developmental cognitive disorders

 

 

Voditelj

Akademik Ivica Kostović, Medicinski fakultet Sveučilišta u Zagrebu

 

Su-voditelj

Prof.dr.sc. Pasko Rakic, School of Medicine Yale University

 

Institucije partneri

School of Medicine Yale University

McGill University & Montreal Neurological Institute

 

Iznos potpore

200.000,00 eura

 

Trajanje projekta

3 godine

 

SAŽETAK PROJEKTA

The objective of project is to supplement neuroimaging studies at the School of Medicine University of Zagreb with neurogenomics (with Yale University) and functional neuroimaging (with Montreal Neurological Institute and Harvard). This cutting-edge approach (genes – structure – functions) is based on analysis of prefrontal cortical areas in normal development and cognitive disorders, and developing protocols for genome-based pharmacotherapy of depression. The project develops new approach to studying abnormal development of cortical circuitry in cognitive disorders (autism), introduces new technologies in Croatia, ensures research use of new 3 Tesla MR, enhances return of scientists from Diaspora, and secures international grant applications (FP7). Specific aims are: 1) To analyze areal differentiation of human frontal (orbital, dorsolateral, and precingulate) cortex and related nuclei (amygdala, thalamus) from fetal life to adolescence, using developmental criteria for specification of cortical areas, layers, modules and molecular phenotypes of pyramidal neurons. To identify cortical pathways, areas and layers. To determine cellular and molecular correlates of gene expression in prefrontal and language-related areas with focus on transient fetal neurons, cytoarchitectonic zones and pyramidal neurons. To analyze cellular determinants of cortical thickness and perinatal cortical reorganization. To compare developmental and gene expression data obtained in humans with those obtained in rhesus monkey and mouse. 2) To describe histological correlates of structural MRI changes in normal and disordered cortex from fetal period to adolescence. 3) To combine MR spectroscopy with genomic analysis in studying frontal cortical areas of young adolescents with depression, after antidepressant medication. Methodology: Histological studies – immunocitochemistry, DiI, Golgi morphometry; Neuroimaging – structural in vivo and in vitro MRI with 3D-volumetry, DTI tractography, fMRI; Neurogenomics- overall gene expression analysis together with gene expression profiling of specific brain regions by microarray technology, real-time PCR and in situ hybridization Neuroproteomics – structures and functions related study of protein expression profile within brain Pharmacogenomics –proton MRS and microarray analysis. The main contribution of the project is development of scientific infrastructure in Croatia (hightech research with 3Tesla MR device). We expect to: delineate sensitive periods in development of prefrontal connectivity and timing of gene expression in principal neurons; unravel abnormalities of cortical circuitry underlying cognitive disorders; and develop individualized treatment based on pharmacogenomics. The project benefits Croatian biomedical centers by introducing neurogenomic tools. It also helps combat brain disorders, which (by representing 30% of total health costs) have great socioeconomic impact (depression-5% of population). The results will be communicated through high impact publications, conferences and symposia.

 

PUBLIKACIJE PROIZAŠLE IZ PROJEKTA

 

  1. Vukšić M, Radoš M, Kostović I (2008) Structural basis of developmental plasticity in the corticostriatal system. Coll Antropol 32(Suppl 1):155-9
  2. Zeba M, Jovanov-Milosević N, Petanjek Z. (2008) Quantitative analysis of basal dendritic tree of layer III pyramidal neurons in different areas of adult human frontal cortex. Coll Antropol. 32(Suppl 1):161-9
  3. Kostović I, Jovanov-Milosević N. (2008) Subplate zone of the human brain: historical perspective and new concepts. Coll Antropol 32 (Suppl 1):3-8.
  4. Petanjek Z, Dujmović A, Kostović I, Esclapez M. (2008) Distinct origin of GABA-ergic neurons in forebrain of man, nonhuman primates and lower mammals. Coll Antropol 32(Suppl 1):9-17
  5. Benjak V, Culjat M, Pavlović M, Kostović-Srzentić M. (2008) Changes of the corpus callosum in children who suffered perinatal injury of the periventricular crossroads of pathways Coll. Antropol 32(Suppl 1):25-9
  6. Judaš M, Sedmak G, Radoš M (2009) POMT1-associated walker-warburg syndrome: a disorder of dendritic development of neocortical neurons. Neuropediatrics 40(1):6-14
  7. Simic G, Stanic G, Mladinov M, Jovanov-Milosevic N, Kostovic I, Hof PR. (2009) Does Alzheimer's disease begin in the brainstem? Neuropathol Appl Neurobiol. 35(6):532-54
  8. Jovanov-Milošević N, Culjat M, Kostović I. (2009) Growth of the human corpus callosum: modular and laminar morphogenetic zones. Frontiers in Neuroanatomy 2009;3:6. Epub 2009 Jun 9.
  9. Fertuzinhos S, Krsnik Ž, Kawasawa YI, Rašin MR, Kwan KY, Chen JG, Judaš M, Hayashi M, Šestan N (2009) Selective depletion of molecularly defined cortical interneurons in human holoprosencephaly with severe striatal hypoplasia. Cerebral Cortex 19:2196-2207
  10. Petanjek Z, Berger B, Esclapez M (2009) Origins of cortical GABAergic neurons in the cynomolgus monkey Cerebral Cortex. 19(2):249-62
  11. Ayoub AE, Kostović I. (2009) New Horizons for the Subplate Zone and Its Pioneering Neurons. Cerebral Cortex. 19(8):1705-7
  12. Petanjek Z, Kostović I, Esclapez M. (2009) Primate-specific origins and migration of cortical GABAergic neurons. Frontiers in Neuroanatomy 3:26
  13. Kostović I, Vasung L. (2009) Insights from in vitro fetal MRI of cerebral development Seminars in Perinatology 33(4):220-33
  14. Steenweg ME, Salomons GS, Yapici Z, Uziel G, Scalais E, Zafeiriou DI, Ruiz-Falco ML, Mejaski-Bosnjak V, Augoustides-Savvopoulou P, Wajner M, Walter J, Verhoeven-Duif NM, Struys EA, Jakobs C, van der Knaap MS. (2009) L-2-Hydroxyglutaric aciduria: pattern of MR imaging abnormalities in 56 patients. Radiology251(3):856-65
  15. Darmopil S, Petanjek Z, Mohammed AH, Bogdanović N. (2009) Environmental enrichment alters dentate granule cell morphology in oldest-old rat. J Cell Mol Med. 13(8B):1845-56
  16. Defelipe J, Fields RD, Hof PR, Höistad M, Kostovic I, Meyer G, Rockland KS. (2010) Cortical white matter: beyond the pale remarks, main conclusions and discussion. Frontiers in Neuroanatomy 4:4
  17. Kostović I, Judaš M. (2010) The development of the subplate and thalamocortical connections in the human foetal brain. Acta Paediatrica 99(8):1119-1127
  18. Uher R, Perroud N, Ng MY, Hauser J, Henigsberg N, Maier W, Mors O, Placentino A, Rietschel M, Souery D, Zagar T, Czerski PM, Jerman B, Larsen ER, Schulze TG,Zobel A, Cohen-Woods S, Pirlo K, Butler AW, Muglia P, Barnes MR, Lathrop M, Farmer A, Breen G, Aitchison KJ, Craig I, Lewis CM, McGuffin P. Genome-wide pharmacogenetics of antidepressant response in the GENDEP project. Am J Psychiatry. 167(5):555-64
  19. Vasung L, Hao H, Jovanov-Milošević N, Pletikos M, Mori S, Kostovic I (2010) Development of axonal pathways in the human fetal fronto-limbic brain: histochemical characterization and diffusion tensor imaging. J Anat. 217(4):400-17
  20. Jovanov-Milošević N, Petanjek Z, Petrović D, Judaš M, Kostović I. (2010) Morphology, molecular phenotypes and distribution of neurons in developing human corpus callosum. Eur J Neurosci. 32(9):1423-32
  21. Judaš M, Sedmak G, Pletikos M, Jovanov-Milošević N.(2010) Populations of subplate and interstitial neurons in fetal and adult human telencephalon. J Anat. 217:381-99
  22. Judaš M, Sedmak G, Pletikos M. (2010) Early history of subplate and interstitial neurons: from Theodor Meynert (1867) to the discovery of the subplate zone (1974). J Anat. 217(4):344-67
  23. Lodygensky GA, Vasung L, Sizonenko SV, Hüppi PS. (2010) Neuroimaging of cortical development and brain connectivity in human newborns and animal models. J Anat. 217(4):418-28
  24. 24. Cosić K, Popović S, Kostović I, Judas M.(2010) Virtual reality adaptive stimulation of limbic networks in the mental readiness training. Stud Health Technol Inform. 154:14-9
  25. Vasung L, Jovanov-Milošević N, Pletikos M, Mori S, Judaš M, Kostović I. (2010) Prominenent periventricular fiber system related to ganglionic eminence and striatum in the human fetal cerebrum. Brain Struct Funct. doi: 10.1007/s00429-010-0279-4
  26. Kostović I, Judaš M, Sedmak G. (2010) Developmental history of the subplate zone, subplate neurons and interstitial white matter neurons: relevance for schizophrenia. Int J Dev Neurosci. 217:400-417
  27. Malki K, Uher R, Binder JP, Rietschel M, Zobel A, Mors O, Hauser J, Henigsberg N, Jerman B, Souery D, Placentino A, Ng MY, Cohen-Woods S, Sluyter F, Farmer A, Aitchison KJ, Craig IW, Lewis CM, McGuffin P, Schalkwyk LC. Convergent Animal and Human Evidence Suggests a Role of PPM1A Gene in Response to Antidepressants. Biol Psychiatry. 69:360-365
  28. 28. Kostovic I, Pletikos M. (2010) Connectivity in the Human Fetal Brain. IFMBE Proceedings 28 227-229
  29. Judas M, Pletikos M. (2010) The discovery of the subpial granular layer in the human cerebral cortex. Translational Neuroscience 1:255-260
  30. Judas M, Pletikos M. (2010) A note on the sea-horse in the human brain. Translational Neuroscience 1:335-337
  31. 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 Neurology29(5):442-448
  32. Judaš M, Cepanec M (2010) Oskar Vogt: The first myeloarchitectoic map of the human frontal cortex. Translational Neuroscience 1(1):72-94.
  33. Cepanec M, Judaš M (2010) Postnatal development of layer IV in fronto-opercular region (Broca’s area). Translational Neuroscience 1(1):24-29.
  34. Culjat M, Benjak V, Dasovic-Buljevic A, Ozretic D, Fumic K, Acquaviva C, Baric I. (2010) Magnetic resonance findings in a neonate with nonketotic hyperglycinemia: case report. J Comput Assist Tomogr. 34(5):762-5.

 

  • Print