The aim of the research program of the Section Psychopharmacology is to provide the scientific rationale for the development of an innovative pharmacotherapeutical approach of psychiatric disorders, in particular drug- and alcohol addiction and Attention Deficit Hyperactivity Disorder (ADHD).
Drug addiction continues to extract enormous human and financial costs on our western society. Whereas numerous compounds have been tested clinically in the past, available treatments are as yet inadequate for most people and even after extended periods of abstinence, the risk of relapse to active drug use remains very high. The central feature of addiction is compulsive drug use, i.e. loss of control over apparently voluntary acts of drug seeking and drug taking. Currently, the leading view on addiction is that repeated drug consumption by vulnerable individuals (genotype) causes compulsive drug-seeking behavior (phenotype) due to long-lasting changes in neuronal communication within the motivational (mesocorticolimbic) system.
The impact of ADHD on society is enormous in terms of financial costs, stress to families, adverse academic and vocational outcomes and negative effects on self-esteem. ADHD is generally considered to be due to aberrant functioning of dopaminergic and noradrenergic neurotransmission in the forebrain, giving rise to deficient sustained attention, hyperactivity and motor and cognitive impulsiveness. There is a great need for innovative medicines to safely and effectively treat ADHD. In this respect, the identification of the primary targets in the brain that underlie the neurobiology of ADHD is expected to revolutionize the field. It is of interest to note that impulsivity is a risk factor for the development and persistence of addictive behaviour, that addictive drugs are effective in reducing major symptoms of ADHD and that there is a high co-morbidity between ADHD and drug addiction.
Our behavioural studies in rodents (primarily rats) include the pharmacological analysis of cognitive, emotional and motivational processes underlying addictive behaviour and ADHD, employing a variety of operant behavioural paradigms in rats. The pharmacology of impulsivity, anxiety and drug-seeking behaviour and the role of individual differences in neurocognitive traits in addictive behaviour are currently of particular interest.
A limited number of bachelor students (Biomedical Sciences, Experimental Psychology), master students (Neuroscience) as well as students doing an HBO (Zoology) are welcome to do an internship in behavioural pharmacology. This internship consist of at least 5 months of practical work. Students are expected to present their results orally during our informal weekly group meetings as well as by giving 2 seminars (about 2 months after the start and at the end of the internship). Moreover, a thesis on the research should be written. Students will receive marks for the research, the final seminar and the thesis.
The role of the enzyme tissue transglutaminase in Aβ deposition in Alzheimer’s disease
Cerebral amyloid angiopathy (CAA) is characterised by deposition of the amyloid beta (Aβ) protein in the vessel wall. This results in degeneration of the vessel wall and haemorrhages leading to cognitive decline. CAA is an important hallmark of Alzheimer’s disease.
The enzyme tissue transglutaminase (tTG) is present in the vessel wall, where it is involved in remodelling of extracellular matrix proteins ultimately leading to vessel stiffness. Increased tTG activity is associated with CAA; however the role of tTG in CAA is unclear.
We hypothesise that increased tTG expression and activity during ageing underlies CAA development.
In this project we will use rat and mouse brain vessels to study the effect of tTG and several of its regulators on vessel wall remodelling and on Aβ deposition in the vessel wall. Furthermore, the effect of Aβ on tTG expression and activity will be studied. In this way, we hope to get more insight in the role of tTG in the pathogenesis and onset of CAA.
The main techniques that will be used are:
- Isolation of brain vessels from wild type and transgenic rats and mice
- Wire myograph to study vessel remodelling
- Immunofluorescence and confocal laser scanning microscopy to study Aβ deposition and tTG activity
This project is a collaboration of the Department of Anatomy & Neurosciences at the VUmc and the department of Biomedical Engineering & Physics at the AMC. Experiments will be carried out at the AMC.
Duration of internship: preferable >5 months
The VP MicroLab system is a 3D virtual reality environment. The Department has an operational VP Microlab system. With this system it is possible to perform real time virtual 3D dissection of tissues and organs, and even of complete body parts like the head.
Basically, a dataset (MRI, CT, TIFF series) containing information in the third dimension is loaded into memory and processed through a series of highly sophisticated and user-changeable and user-defineable filters. In addition, highly interactive slicing in 3D is possible. We are using this system to develop applications that enhance the teaching of the anatomy of the human brain. We are looking for Medical students who are interested in an Internship developing mobile-media applications for the teaching of Gross Anatomy, Anatomy for specialist groups (e.g. Radiology, Neuroradiology, Cardiopulmovascular, Otolaryngology, Urology). Also, visualization in 3D of large datasets (confocal imaging, serial (aligned) micrographs of tissues and organs is within the capabilities of this unique system. Movies featuring scenes made with VP Microlab can be seen at the website www.anatomie-amsterdam
The dopaminergic neurons in the substantia nigra (SN-DA neurons) exert a profound influence on the basal gangia. In this project we zoom in to specific SN-DA neurons, notably those that project to the dorsal striatum. This part of the basal ganglia has strong connections with sensorimotor cortex. What regulates the SN-DA neurons. Material is available from neuroanatomical tracing experiments: SN cells containing the fluorescent tracer Fluorogold which as been accumulated in the cells after retrograde transport via their axons from the dorsal striatum where the Fluorogold was originally injected. These cells will be subjected to triple immunofluorescence staining with various cocktails of antibodies: for glutamate (marker for excitation) vesicular glutamate transporter 1 or 2, for GABA or vesicular GABA transporter (marker for inhibition), Fluorogold, or choline acetyltransferase (marker for cholinergic input), and tyrosine hydroxylase (marker for dopaminergic neurons) and imaged in a multichannel confocal laser scanning microscope. This will make it possible to count and compare the number of glutamatergic, GABAergic and cholinergic contacts on these striatum-projecting SN dopaminergic neurons.
The substantia nigra (Latin for ‘black stuff’ because of the black pigmented neurons) is located in the mesencephalon. The area consists of two parts, the pars compacta (SNc) and pars reticulata (SNr). The SNc is crowded with dopaminergic neurons while the SNr contains mostly GABAergic neurons with some scattered dopaminergic neurons.
Where do the dopaminergic and GABAergic cells get their input from? Some of the sources have been traced, others remain to be found. How do the GABAergic SNr neurons and the SNc neurons relate synaptically? This type of cellular network questions are addressed in this internship.
techniques: neuroanatomical tracing, intracellular injection, confocal microscopy, electron microscopy.
internship for: undergraduate students Biology, Medicine, but also informatics, Computer science.