Research efforts within the Cellular Neurosciences group are devoted primarily to identification and characterization of novel, overlapping, biochemical pathways critically involved in neuronal damage and cell loss occurring in common neurodegenerative disorders, in particular Parkinson's- and Alzheimer's disease and Multiple Sclerosis. Within this context, using a combination of human (disease and control) brain tissue and dedicated in vitro (cell culture) as well as in vivo (animal) disease models, important factors identified by us thus far include cellular stress (i.e. transglutaminases, quinone reductases, heat shock proteins) and inflammation (i.e. interleukin-1 and interleukin-10 cytokine families) related peptides and proteins. These factors, the expression and/or activity of which is altered during neurodegenerative processes, are also well known for their role in neuronal outgrowth and plasticity. Thus, our research line, which is embedded within the programs on Neurodegeneration and White Matter Diseases of the Neuroscience Campus Amsterdam of the VU University Medical Center, is currently driven by the hypothesis that inappropriate and/or untimely (over)activation of particular pathways, which play a crucial role during nervous system development, underlies neurodegeneration. Ultimate goal of our research is to evaluate putative pathogenic factors and mechanisms identified by us on their suitability to act as target for development of neuroprotective treatments and/or use as "surrogate markers" for disease identication and/or monitoring of disease progression.
Addiction to drugs of abuse (nicotine, amphetamine, cocaine, heroin, alcohol, cannabis) continues to extract enormous human and financial costs on our western society. Thus, this brain disease places a significant burden on health, social cohesion, crime and is co-morbid with other psychiatric disorders such as ADHD and depression. The central feature of drug addiction is compulsive drug use, i.e. loss of control over apparently voluntary acts of drug-seeking and drug taking. Addictive processes can be adequately investigated at the behavioural, molecular and cellular level using various validated animal (primarily rat) models. Apart from their greater neurobiological accessibility, a key point is that animals can be studied from the drug naïve state through psychic dependence, whereas clinical studies begin with an addicted individual who is usually seeking help to maintain abstinence. From a neurobiological perspective, the leading hypothesis is that addictive behaviour is maintained by persistent alterations in neuronal communication within the motivational (mesocorticolimbic) system leading to dysfunctioning of brain reward centers that subserve the survival of organisms. The search for (common) neuroadaptations induced by self-administration of drugs of abuse and their role in relapse behaviour upon (re)exposure of laboratory animals to stimuli that are known to induce craving and relapse in humans (cues, stressors, drugs) is a particularly important issue in neuroscience.
The abundant availability of calorically dense foods such as fats and sweets in western diets is largely responsible for the current obesity epidemic and neuroscience can make critical contributions to the further understanding and treatment of this problem. Traditionally, major focus has been directed to the hypothalamus. However, much less is known about how the hypothalamus functions within its associated neural networks that integrate other factors involved in appetite, such as emotional and cognitive processing in the motivational system. Just like drug addiction, obesity is due to foraging and ingestion habits that persist despite the threat of catastrophic consequences. Feeding and drug use involve learning habits and preferences that are stamped in by the reinforcing properties of powerful and repetitive rewards. Thus, food activates the brain reward circuitry through fast sensory inputs and slow post-ingestive consequences (such as central glucose concentrations), whereas drugs activate these same pathways through their pharmacological effects on the reward circuitry. Due to individual genetic differences not all humans who are exposed to high-fat, high-calorie foods become compulsive eaters, just as not all humans who are exposed to habit-forming drugs become addicted. Moreover, as early exposure to drugs of abuse during development increases the acquisition of drug addiction later in life, early exposure to calorically dense diets can enhance the acquisition of obesity during adolescence. Indeed, few research fields seem to offer as much potential for cross-fertilization as the fields of drug addiction and obesity research.
Against this background, the Psychopharmacology group (head: Prof. dr. A.N.M. Schoffelmeer) addresses the neurobiology of the development and persistence of high calorie food and drug seeking behaviour in rats. In this respect, we investigate how individual differences in cognitive performance (attention, impulsive behaviour, behavioural flexibility) determine the individual susceptibility to develop binge-eating behaviour and drug-seeking behaviour as well as relapse to food and drug seeking behaviour during long-term abstinence. Moreover, we have an interest in periadolescence as a unique time-window during which individuals are particularly sensitive to the effects of drugs of abuse (nicotine, cannabis, alcohol) on brain plasticity which may lead to motivational, cognitive and emotional disturbances in adulthood. Finally, we study the behavioural pharmacology and neurochemistry of cue/context-induced relapse to food and drug seeking behaviour and that of reconsolidation of food/drug-related memories during abstinence. The overall aim of our research is to provide the scientific rationale for the development of an innovative pharmacotherapeutical approach of addictive behaviour on the basis of these animal studies. This animal research is part of the program Addictive Behaviour of the Center for Neurogenomics and Cognitive Research of the VUmc/VU ( www.cncr.vu.nl ).
The primary research focus of the unit of Functional Neuroanatomy is the exploration of structural and functional changes that occur in neural circuits affected in certain neurodegenerative or neuropsychiatric disorders. These circuits comprise the connections between cerebral cortex, basal ganglia, thalamus and ascending monoaminergic systems in the brainstem. Experiments are aimed at establishing the neuroanatomical organization of these circuits in the (normal) human and rodent. These findings are used in cellular imaging studies in (behavioral and neurodegenerative) experimental rodent models, to interpret neuronal activity patterns that are visualized after different behavioral or pharmacological stimuli. At the anatomo-behavioral level our aim is to establish the neural substrate of cognitive changes in Parkinson's disease. These changes likely involve pathology in cortex, basal ganglia and monoaminergic systems. It is, therefore, necessary to determine possible spatiotemporal patterns in the progression of neuropathological changes. Such patterns are studied in post mortem material from patients at different stages of the disease using histological and molecular biological techniques. An important question is which brain regions are affected in the early, preclinical stages of the disease. One of these regions, the olfactory bulb, is a focus of our experimental attention.