Final Activity Report Summary - ZSN PHD-PROGRAM (International, interdisciplinary PhD-program of the Center for Systems Neuroscience Hannover) The scientific focus of the ZSN is unique Europe-wide and worldwide. Research concentrates on three areas of special interest and exceptional proficiency with a multidisciplinary, systemic approach.The areas were further developed and focused on during the funding period:1. Hearing and communicationThe central approach of the studies was the development of research strategies which shed light on the processes of acoustics, psychoacoustics and neural processing of emotion at different levels of brain complexity (animal/human).1)In contrast to humans, laterality in handedness is not linked to asymmetries in communication call processing in the early primate brain. Caller characteristics, such as caller identity, are reliably reflected in voice, even in early primates with less complex social systems. Auditory laterality in these primates is more strongly affected by caller characteristics than by emotional valence.2) In focal dystonias such as Torticollis it could be demonstrated that patients do not solely suffer from motor disorders but also from subtle deficits in emotional processing of language - a novel and interesting finding, demonstrating that movement disorders can also affect limbic circuits. 3) Pianists suffering from musician's dystonia also have a deficit in front-temporal connectivity related to complex behaviours such as error-monitoring.4) In healthy pianists committing errors while playing a complex piano piece, the brain produces an error signal before the error is actually committed. This demonstrates the highly efficient and rapid action monitoring system in trained musicians.5) In patients with schizophrenia deficits of the connectivity in the frontal cortex top-down processing could be demonstrated by the use of functional magnetic resonance imaging and electroencephalogram.6) Melatonin and sex steroids affected neurochemical plasticity of the brain in animal models strongly and predictably.2. Epilepsy and other paroxysmal disturbancesDuring the funding period, research in this area concentrated mainly on three areas. 1) characterisation of mechanisms of epileptogenesis and therapy-resistant epilepsy in rat and mouse models;2) development and characterisation of new models for multiple sclerosis; and3) nervous system defects in polysialic acid-deficient mouse models. In each of these areas, new and medically important results were obtained, including 1) enhanced understanding of the role of multidrug transporters at the blood-brain barrier in the development of pharmacoresistance in epilepsy; 2) genetic differences between mouse strains and substrains in sensitivity to convulsants such as pilocarpine, thus allowing genes involved in ictogenesis and epileptogenesis to be identified;3) a comparative approach for developing different antiepileptogenic strategies with the aim of preventing epilepsy in patients at risk;4) new data on the role of cytokines, MMPs and TIMPs in the pathogenesis of demyelination in canine distemper virus encephalitis and Theiler's murine encephalomyelitis; and5) new aspects of cell interactions via the neural cell adhesion molecule (NCAM) and particularly its functional modification by glycosylation with a sugar polymer called polysialic acid.3. Disturbances of motor systemsTwo major outcomes in these research fields are: 1) In an animal model, new strategies were developed to produce dopaminergical neurons for transplantation in Parkinson's disease. The effect of modified polysialic acid based hydrogels on primary neurons and glia cells was already published and neurotrophic factors were identified which enhance the growth and maturation of neurons.2) A new animal model was introduced allowing the studying of the development and differentiation of human motor neurons in vivo. The integration, differentiation and the outgrowth of human motor neurons indicates promising results in this animal model for cell transplantation.