DDAH/ADMA pathway and brain function

DDAH1 serves the enzymatic degradation of methylated arginines such as ADMA, an endogenous competitive inhibitor of NO-Synthase. Thus, DDAH1 is widely recognised as modulator of the atypical messenger molecule nitric oxide (NO). The discovery of NO, received a Nobel Prize and today NO is known to be a critical regulator of many biological functions. A wealth of clinical and basic studies associate the DDAH1/ADMA system with the pathogeneses of diseases such as heart failure, chronic kidney failure, stroke or diabetes. As a result, profound effort has been taken to develop potent and specific inhibitors of DDAH1. Pathophysiological effects are predominantly conveyed over endothelial NO dysfunctions, in addition altered ADMA/NO levels have been suggested to link these disorders with the often-high prevalence of co-morbid depression. At the same time, DDAH is highly expressed in the brain suggesting a central function, which has not yet been fully addressed. Supportive of our hypothesis altered ADMA/NO levels are observed in patients with affective disorders and schizophrenia that share some symptomatology. However, causality and mechanism are unknown and may be resolved using relevant preclinical models.

Proposed implications of the DDAH/ADMA pathway in neuropsychiatric symptomatology

The resarch is now  supprted through DFG Funding within the  International Research Training Group “Risks and Pathomechanisms of Affective Disorders” IRTG2773.

Collaboration partners:

• Roman Rodionov, TU Dresden
• Arduino Mangoni, Flinders University
• Raul Gainetdinov, Saint Petersburg State University
• Dr. Jens Martens-Lobenhoffer / Prof. Dr.med. Dr.h.c. S.M. Bode-Böger, Otto-von-Guericke-Universität Magdeburg
• Nadja Freund, Ruhr-University/LWL University Hospital, Bochum
• Anthony Vernon, King's College London

Context-dependent effects of non-invasive brain stimulation on the neural circuitry and behaviour 

Multiple studies using non-invasive magnetic resonance imaging (MRI) provide evidence that the positive impact on patient’s symptoms of brain stimulation treatments is linked to changes in brain function and the re-organization of neuroanatomy. Back-translating these findings to rodent models combined with MRI further supports this view. In this context, we recently reported that non-invasive transcranial direct current stimulation (tDCS) of the rat prefrontal cortex alleviated some (but not all) behavioural deficits in offspring exposed to maternal immune activation, a model of relevance for schizophrenia and autism Hadar et al. 2020. By contrast, the same stimulation induced behavioural deficits in control offspring, suggesting a context-dependent effect of tDCS on neural circuitry and behaviour. It is unclear however whether these context dependent effects of tDCS on behaviour are accompanied or mediated by neuroanatomical remodelling, as measured by MRI. Given the emerging interest in the use of tDCS to treat neuropsychiatric disorders, such as schizophrenia, it is critical to address these gaps in our knowledge. We will use data driven computational voxel-wise analyses to determine stimulation induced neuroanatomical remodelling  and cutting edge multivariate statistics to identify the key brain circuits involved in the beneficial and adverse behavioral effects of neuromodulation. The Project is supported through the transCampus^® .

Collaboration partners:

• Anthony Vernon, King's College London
• Ravit Hadar, Charité Berlin
• Stefan Ehrlich, TU Dresden

Neuroprosthetics in alcohol use disorders

Neuroprosthetics are microelectronic systems applied to understand the neuronal basis of behaviour and in case of neurological and psychiatric diseases of altered behaviour via recording of electrical activity from the central nervous system. Through stimulation, neural implants further aim at modulating behaviour to restore lost or impaired function. Within the project, we test the further applications of this innovative technology by introducing a flexible multimodal neural interface into the context of alcohol use disorder (AUD). AUD is one of the most frequent addictive diseases going along with a high burden on affected individuals and society. The duration of clinical treatment for alcohol addiction is in the range of several months. The probability of relapse high. In AUD distinct alterations in neural activity are associated with an impaired behaviour control and a higher relapse probability, therefore considered biomarkers and predictors for the relapse risk after alcohol withdrawal. As conventional behavioural and systemic pharmaceutical therapies to treat AUD reveal a lack of efficacy, brain stimulation techniques to normalize disturbed neural activity offer an alternative approach. The neuroprosthetic device used in this project enables stimulation and neuromonitoring in one device allowing immediate investigation of stimulation effects on neural activity. Besides electrical stimulation, an integrated microfluidic channel (chemotrode) provides local administration of medical substances. This might lead to an improved outcome with reduced side effects compared to conventional systemic pharmacological treatment involving oral application of medication.

Closed-loop detection and modulation of drug-induced neural activity patterns (event-related potentials, ERP) using multimodal flexible bioelectronics to improve behaviour control and prevent relapse.

Collaboration partners

• Ivan Minev, University of Sheffield
• Mahnaz Arvaneh, University of Sheffield
• Dzmitry Afanasenkau, Microstructure Facility, Center for Molecular and Cellular Bioengineering, TU Dresden
• Rainer Spanagel, ZI Mannheim

Neuromodulation in Autism

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with significant social, communication and behavioural challenges. ASD has a complex etiology comprising genetic risk factors and additionally environmental factors. The heritability is between 40 and 80%, and predominantly polygenetic. There are, however three monogenetic syndromes identified inducing the ASD phenotype with high probability, one of them Tuberous Sclerosis Complex (TSC). A neurocutaneous disorder characterized by multisystem hamartomas and associated with neuropsychiatric features. Currently, ASD core symptoms cannot be cured. With the aim to generate new potential treatment approaches, we work with a rodent model of ASD in TSC. The so-called “Eker” rat originated as a spontaneous mutation of the Tsc2 gene and expresses changes in learning and memory and deficits in social behaviour relevant to ASD as well as impaired long-term potentiation and depression (LTP, LTD), fundamental aspects of synaptic plasticity. The model thus exhibits high value for testing experimental therapies for ASD phenotypes, especially in the combined context of TSC mutation, early epilepsy and or developmental impacts.

Collaboration partners

• Robert Waltereit, Universitätsmedizin Göttingen
• Tomáš Petrásek, NUDZ

Dopamine and psychiatric disorders

We are particularly interested in the dopamine system, which is unique among the brain’s modulatory systems in that it has discrete projections to specific brain regions involved in motor behavior, cognition and emotion. Disruptions within this regulatory system have been associated to the pathophysiology of several psychiatric disorders including addiction, schizophrenia, depression or repetitive symptomatology. One still unsolved question in this context, however, concerns the interplay between dopamine dysfunction and altered interneuron functionality for behavioral outcomes. Another area of interest concerns dopamine signaling, reward and cognitive functioning.

Disentangling the longitudinal effects of dopamine on interneuron development in preclinical rodent models of psychiatric disorders.

Collaboration partners

• Christine Winter, Charité Berlin
• Alexander Garthe, DZNE Dresden