Investigating whether developmentally and genetically defined mDA subcircuits encode functional modules within the dopaminergic system
1 Neurodevelopmental Genetics, Institute of Reconstructive Neurobiology, University of Bonn School of Medicine & University Hospital Bonn, Bonn, Germany
2 Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Bonn, Germany
3 Institute of Molecular and Cellular Anatomy, Ulm Univeristy, Germany
4 Neurology Department, University Hospital Cologne, Cologne, Germany
5 Institute of Experimental Epileptology and Cognition Research (EECR), Medical Faculty, University of Bonn, 53127 Bonn, Germany
mDA neurons have been classified into three distinct regions primarily on the basis of anatomical features: retrorubral field, substantia nigra pars compacta (SNc) and ventral tegmental area (VTA). Advances in transcriptomic profiling of individual cells have facilitated the identification of molecularly defined subtypes of mDA neurons within these anatomically defined regions of the mDA system. Thus, considerable progress has been made in identifying mDA neuron subtypes. mDA neurons are a class of neurons critical for controlling voluntary movement, creating associations with rewarding stimuli, attending to salient environmental stimuli, motivating behavior, maintenance of working memory and the regulation of emotion. Just as proper function of these neurons is critical to basic behavior of animals, changes to this neural population are implicated across many neurological and psychiatric disorders, including Parkinson's disease, schizophrenia and drug addiction Yet, it is still not clear how the DA signal is used to encode different aspects of behavior and how this is integrated into overall behavioral outcomes. Current models assume that discrete quantities, i.e., expected value and reward received, are computed in specific afferent areas and transmitted to the midbrain to calculate value-related signals. However, this assumption of precise compartmentalization does not fit with the anatomy of the input-output relationships characterized so far in the DA system, which states that mDA neurons projecting to a specific region in the forebrain receive inputs from across the brain. What has not yet been considered in the interpretation of this anatomical evidence is that mDA subcircuits could encode a precise behavioral output by targeting a group of substructures within the classical mDA projection targets which in turn potentially also receive a selected set of afferents. To investigate whether specific aspects of behaviors are encoded by mDA subcircuits that have one or several precise anatomical targets, we propose to examine how genetically determined mDA subcircuits contribute to different facets of social behavior by chemogentically inhibiting or activating subcircuits of Bcl11a-expressing mDA neurons using intersectional approaches. To achieve these goals, it will be essential to observe natural behavior in detail and to develop theoretical models linking subcircuit recruitment and behavior.