Neuronal Circuits in Health & Disease
The substrate that underlies every behavior, from simple reflexes to the most sophisticated cognitive functions, is ultimately determined by the intricate circuitry formed by the basic functional units, the nerve cells. Our research interests focus on the mechanisms that guide the emergence of neuronal circuitry during development, on the environmental and genetic influences that shape the plastic adaptations of neuronal connections in response to experience or injury, and on common molecular mechanisms between neurodevelopmental processes and human neurodegenerative diseases.
With our work, we aim at harnessing these mechanisms to design rational approaches that will boost regenerative and adaptive nerve fiber growth to alleviate the consequences of intrinsic (genetic) or extrinsic (environmental) insults to the integrity of the neural circuitry. We also apply this concept to the development and validation of cell transplantation-based regenerative therapies of neurological diseases to assess the anatomical and functional integration of cell transplants into existing circuitry.
Consequently, our research group „Neuronal Circuits in Health and Disease“ follows a research program with projects that fall into three categories
Contact:
Dr. Andrea Huber Brösamle
Phone: +49 (0)89 3187 4117
Fax: +49 (0)89 3187 3099
Email: andrea.huber@helmholtz-muenchen.de
Funding:
We gratefully acknowledge support by the following funding agencies:
most important publications:
Huettl RE, Soellner H, Bianchi E, Novitch BG, Huber AB. Npn-1 contributes to axon-axon interactions that differentially control sensory and motor innervation of the limb. PLoS Biology 2011. 9(2):e1001020
Piaton G, Aigrot MS, Williams A, Moyon S, Tepavcevic V, Moutkine I, Gras J, Matho KS, Schmitt A, Soellner H, Huber AB, Ravassard P, Lubetzki C. Class 3 semaphorins influence oligodendrocytes precursor recruitment and remyelination in adult central nervous system. Brain 2011. 134(Pt 4):1156-67
Haupt C, Langhoff J, Huber AB. Adenylate Cyclase 1 modulates peripheral nerve branching patterns. Mol Cell Neurosci 2010. 45(4):439-48
Haupt C, Kloos K, Faus-Kessler T, Huber AB. Semaphorin 3A-Neuropilin-1 signaling regulates peripheral axon fasciculation and pathfinding but not developmental cell death patterns. Eur J Neurosci 2010. 31(7):1164-72
Huber AB, Kania A, Tran TS, Gu C, De Marco N, Lieberam I, Johnson D, Jessell TM, Ginty DD, Kolodkin AL. Distinct roles for secreted semaphorin signaling in spinal motor axon guidance. Neuron 2005. 48(6):949-64
Project 1: Molecular mechanisms that govern neuronal circuit formation.
Growing axons establish the projections to their targets by reading guidance cues present along their paths, at specific choice points, and on axons of other neurons. The challenges encountered by a neuron growing out during development, a regenerating fiber that has to re-establish its connection with the former target, or a transplanted neuron that has to join the correct synaptic partners, are very similar. We investigate the molecular interactions of the growing axon tip with its environment and how these interactions are translated into directed axon growth and a correct connectivity pattern. In the last years, we developed the tools to selectively identify, label, and purify populations of neurons based on their projection patterns. We have used these tools in four differential expression screens to analyze motor and sensory axon guidance to the extremities. We performed in vitro assays, e.g. motoneuron collapse or single growth cone turning assays, and loss- and gain-of-function studies in vivo in chick and mouse to assess the candidates’ role in the dorsal/ventral guidance decision. Further, we are using a combination of algorithms to predict in silico miRNAs that are involved in the regulation of genes identified in our dorsal-ventral microarray screen. Using gain- and loss-of-function approaches in the chicken embryo we analyzed the roles of various miRNAs in the specification and organization of spinal motoneurons.
Project 2: Environmental and genetic mechanisms of adaptive plasticity
Environmental and genetic mechanisms of adaptive plasticity as a basis for future therapeutic strategies in the treatment of traumatic and degenerative CNS diseases. Even though long-distance regeneration is absent in the CNS of mature mammals, a remarkable degree of adaptation to developmental abnormalities and injury to nervous system wiring is observed. To understand how anatomical defects determine specific functional deficits and how adaptive plasticity can lead to recovery of function, we have characterized the behavioral capacities of mice with well-described genetically induced wiring defects. We have previously shown that loss of Sema3F-Npn-2 signaling causes severe pathfinding errors of motor axons, which predict dramatic behavioral consequences (Huber et al., 2005). We assessed motor deficits in mutant mice using a battery of locomotor tests. We find specific defects in motor coordination that are corrected by housing animals in enriched environments. We are currently exploring specific training regimens and the underlying anatomical and physiological substrates.
Project 3: Signaling mechanisms underlying degenerative motoneuron diseases
Signaling mechanisms underlying degenerative motoneuron diseases, such as amyotrophic lateral sclerosis (ALS). Based on the discovery that cytoplasmic accumulation and aggregation of the DNA/RNA binding protein TDP-43 occur in many cases of ALS, we explore the role of RNA metabolism in the formation of protein aggregates leading to neurodegeneration. Using primary motoneuron cultures we characterize cell biological parameters of mutant neurons including RNA metabolism, axonal transport, and the formation of protein aggregates under normal and stressed conditions. The exploration of developmental processes of motor circuitry formation puts will help us to develop and test repair strategies in motoneuron disease models and study outgrowth and integration of transplanted motoneurons into existing neuronal networks.