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Postdoctoral Researcher

Tiel, The Netherlands

Wageningen UR (MSc), Utrecht University (PhD)

Behavioural Neuroscience, Developmental Biology

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Although neurodevelopmental disorders have been described for quite some time, most of the treatments are still focusing on symptom removal, while the underlying molecular mechanisms for the development of these distinct pathways are still elusive. The cerebral cortex in general and the prefrontal cortex (PFC) in particular is involved in the pathology of many of these neurodevelopmental disorders (e.g. Readler et al., 1998). The intricate organization of specialized areas in the mature cortex is achieved by coordinate programs in cells that seed this structure during development. Based upon intrinsic expression of (transcription) factors, morphology, physiological properties and connectivity of cells within a cortical layer, distinction can be made between the different cortical areas. However, the precise temporal aspects for this complex developmental script remain unclear.

Therefore, my current research is aimed at understanding the development of two cortical areas which will eventually help us to better comprehend the etiology of neurodevelopmental disorders.

 

Unraveling the mechanisms of development of two cortical areas.

Cells of the developing cerebral cortex are generated in a precise temporal pattern that is translated into the spatial layout of the embryonic cerebral wall, such that immature, dividing cells populate the deeper layers and more mature, post-mitotic cells reside in the more superficial layers (Kolk et al., 2006). In addition to this horizontal layering, the cerebral cortex can be divided in anatomically distinct areas reflecting different functions (Miller et al., 2006). Layer V pyramidal cells are the main cortical output neurons and we know now that they exist in different morphological and functional classes in two sublayers of the rat somatosensory cortex (S1) (Schubert et al., 2001; 2006). Yet, whether the heterogeneity between classes can be explained by birth-date is not known.

To follow the development of layer V pyramidal cells at an exact developmental time-point within a certain brain area in vivo, cells will be transfected at exactly E15.5 with a fluorescent marker (GFP). To this end, we will take advantage of the novel innovative technique of in utero electroporation (IUE)-mediated gene transfer to monitor proper brain development (Fig. 1; Kolk et al., 2009). We will assess the intrinsic structural and functional cellular characteristics of transfected cells (Kolk et al., 2006; Schubert et al., 2007). For this we will make use of coronal slices of the rat brain in which we perform single or paired whole cell patch clamp recordings of layer V pyramidal neurons in two cortical areas that play a role in neurodevelopmental disorders: the somatosensory (S1) and prefrontal cortex (PFC).

The labeled cells will be physiologically characterized using state-of-the-art in vitro assays. In this way we will be able to compare a structurally and physiologically defined group of cortical cells of the same age within and between different cortical areas. We hypothesize that the characteristics of layer V cells born at an exact developmental time-point are cell-type specific and may differ between the somatosensory and prefrontal cortex.

Figure 1 A) Diagram of in utero electroporation (IUE)-mediated gene transfer in mouse embryos B) Low power view of a coronal section through a mouse forebrain electroporated with a control construct (green) in the somatosensory cortex (S1, in between arrowheads) costained with the neuronal marker Tuj1 (red) and fluorescent Nissl (blue). C) Schematic representation of the IUE paradigm to label mouse layer V pyramidal cells. diu, days in utero; hrs, hours; sac, sacrifice).

Elucidating mechanisms of pathological development of the prefrontal cortex.

Cognitive and behavioural impairments seen in the apomorphine-susceptible (APO-SUS) Wistar rats housed at the Central Animal Facility of the Radboud University Nijmegen resemble features of neurodevelopmental disorders. At least part of this phenotype can be attributed to differences in dopaminergic wiring in general, more specifically the mesoprefrontal projections. The IUE technique will be used to again label layer V pyramidal cells within the cortex of APO-SUS versus APO-UNSUS animals at exactly E15.5. Cellular characteristics of both the S1 as well as the PFC will be assessed and compared between SUS and UNSUS animals. Specifically the prefrontal cortex is of interest as it is known that the dopaminergic innervation differs between these two lines affecting the physiological state of layer V pyramidal neurons. We hypothesize that layer V pyramidal cells within the prefrontal cortex born at an exact developmental time-point differ between APO-SUS and APO-UNSUS rats.

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Research Career
 
2004-2009
Ph.D. degree in Behavioral Neuroscience. Ph.D. thesis is entitled “Behavioral trait genetics in mice; opportunities for translational research of psychiatric endophenotypes” Promotores: Prof. Dr. Berend Olivier (Utrecht University, Utrecht, The Netherlands) and Prof. Dr. Peter Burbach (Rudolf Magnus Institute of Neurosciences, UMC Utrecht, Utrecht, The Netherlands); co-promotor: Dr. Martien Kas (Rudolf Magnus Institute of Neurosciences, UMC Utrecht, Utrecht, The Netherlands) .
1998-2003
Masters Degree in Biology, March 2004, Wageningen University and Research Centre, The Netherlands.
 
Conferences and Courses Attended
 
2008
21st ECNP Congress, Barcelona, Spain 2008, Invited speaker in Breaking News symposium. Title of presentation: Behavioural genetics of avoidance; a mouse phenotype linked to a human mood disorder.
2008
7th Dutch Endo-Neuro-Psycho Meeting, Doorwerth, The Netherlands 2008, poster presentation.
2008
ECNP Workshop on Neuropsychopharmacology for Young Scientists in Europe, Nice, France 2008, poster presentation.
2007
Euron workshop “Drug treatment of psychiatric and neurological disorders, Bad Honneff, Germany 2007, poster presentation.
2007
Figon Dutch Medicine Days, Lunteren, The Netherlands 2007, poster presentation.
2007
9th Annual Meeting of the International Behavioural and Neural Genetics Society (IBANGS), Doorwerth, The Netherlands 2007. Seminar in “selected papers” session. Title of presentation: Genetic dissection of avoidance behavior and motor activity levels using chromosome substitution strains of mice.
2005
4th Dutch Endo-Neuro-Psycho Meeting, Doorwerth, The Netherlands 2005. Seminar in a session on the genetic dissection of complex behaviors. Title of presentation: Refined behavioural analysis for the genetic dissection of food exploration strategies.
2005
Measuring Behavior, Wageningen, The Netherlands 2005, poster presentation.
2005
Course Radiation Safety 4B, Utrecht, The Netherlands 2005
2005
European Summer School for Whole Animal Pharmacology, Behavioural Pharmacology, Oss, The Netherlands 2005.
2003
Course Experimental Animal Sciences, Wageningen, The Netherlands 2003.
 
Awards and Grants
 
2008 7th Dutch Endo-Neuro-Psycho Meeting Poster Award, Doorwerth, The Netherlands 2008.
2008
Travel grant from the Dutch foundation for pharmacological sciences to attend the 21st ECNP congress, Barcelona, Spain 2008.
2007
Travel award for 9th Annual Meeting of the International Behavioural and Neural Genetics Society (IBANGS), Doorwerth, The Netherlands 2007.
 
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Peer-reviewed Articles
 
De Mooij-van Malsen J.G., van Lith H., Oppelaar H., Hendriks J., de Wit M., Teerds K.J., Kostrzewa E., Pedroso I., Breen G., Collier D.A., Olivier B., Kas M.J. (2009). Interspecies trait genetics reveals association of adenylyl cyclase 8 with mouse avoidance behavior and a human mood disorder. Biological Psychiatry. 66:1123-30.
De Mooij-van Malsen J.G., van Lith H., Oppelaar H., Olivier B., Kas M.J.H. (2009). Evidence for epigenetic interactions for loci on mouse chromosome 1 regulating open field activity. Behav Genet. Mar;39(2):176-82.
Kas M.J., Mooij-van Malsen J.G., de Krom M., van Gassen K.L., van Lith H.A., Olivier B., Oppelaar H., Hendriks J., de Wit M., Groot Koerkamp M.J., Holstege F.C., van Oost B.A., de Graan P.N. (2009). High resolution genetic mapping of mammalian motor activity levels in mice. Genes Brain Behav. Feb;8(1):13-22.
de Mooij-van Malsen A.J., Olivier B., Kas M.J. (2008). Behavioural genetics in mood and anxiety: A next step in finding novel pharmacological targets. Eur. J. Pharmacol. 585, 436-440.
Kas M.J., de Mooij-van Malsen A.J., Olivier B., Spruijt B.M., Van Ree J.M. (2008). Differential genetic regulation of motor activity and anxiety-related behaviors in mice using an automated home cage task. Behav. Neurosci. 122, 769-776.
Mooij-van Malsen J.G., Olivier B., Herzhog H., Kas M.J.H. (2008). P.2.15 Behavioural changes in NPY-Y2 and 5HT-1a receptor deficient mice in an automated home cage task for avoidance behaviour. Eur. Neuropsychopharmacol. 18, s48-s49.
Nordquist R.E., Voorn P., de Mooij-van Malsen J.G., Joosten R.N., Pennartz C.M., Vanderschuren L.J. (2007). Augmented reinforcer value and accelerated habit formation after repeated amphetamine treatment. Eur. Neuropsychopharmacol. 17, 532-540.
Nordquist R.E., Voorn P., de Mooij-van Malsen J.G., Joosten R.N.J.M.A., Pennartz, C.M.A., Vanderschuren L.J.M.J. (2005) Opposing short-term and long-term effects of amphetamine sensitization on operant responding for a food reinforcer. Basal Ganglia VIII. Eds. Bolam, J.P., Ingham, C.A. and Magill, P.J. Kluwer Academic/Plenum Publishers, New York.