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SFB-F44 - Cell signaling in chronic CNS disorders

Project 17:
Dopamine regulation of amygdala inhibitory circuits: relevance for pathological fear structures

Francesco Ferraguti

Parkinson´s disease (PD) is classically considered as a movement disorder resulting from the loss of dopaminergic (DAergic) neurons. However, a number of non-motor symptoms, including pathological fear and anxiety, predate the emergence of motor impairment. PD could then be seen as a multidimensional disease. Dopamine exerts a pivotal role in the regulation of fear responses most likely by affecting GABAergic transmission within the amygdaloid complex. We postulates that pathological fear in early PD results from altered associative plasticity in the basolateral amygdala (BLA) mostly dependent on the reduced function of DA on specific local interneurons. In addition, we propose that enhanced phasic DAergic transmission during fear extinction training facilitates extinction learning and the concurrent plasticity. These hypotheses will be experimentally addressed by means of a multidisciplinary approach combining optogenetics, viral monotransynaptic tracing and novel ultrastructural techniques. A mouse model for non-motor symptoms of early PD, lacking motor impairments, will also be established and characterized. Therefore, this project will complement other investigations within this SFB on aberrant signaling mechanisms leading to selective neurodegeneration (e.g. PD), altered neural plasticity and abnormal fear memory processing.