Limbic system circuitries underlying fear and anxiety: Coord

Fear and anxiety are emotional reactions that are crucial for defense and even survival of an individual; their malfunctioning may be, however, destructive and even life threatening. In recent years, great scientific effort has been undertaken for obtaining a better understanding of neuronal mechanisms integrating and controlling these emotional processes. It emerges that the amygdala and the hippocampus, two key brain areas of the so-called limbic system, are central in this process. Our research project aims to identify the key molecular, synaptic and cellular components of amygdala and hippocampal circuitries and their interactions during processing of anxiety, learned fear and fear extinction, and to elucidate their malfunctioning and basic mechanisms potentially leading to future treatment strategies of pathological anxiety. Using in vivo electrophysiology in the mouse amygdala and hippocampus, we will investigate physiological changes during fear conditioning and extinction at the single cell level, and will then identify the underlying molecular, cellular and network constituents using light and electron microscopy. Moreover, based on behavioral data, we will focus on the role of specific neurotransmitter receptors involved in the generation of fear and anxiety and in mediating anxiolytic drug actions, in particular neuropeptide Y (NPY) and GABA A receptors. Using a transgenic mouse model that allows to regulate the activity of a restricted neuronal circuitry or even specific neurons in the brain by application of GABAergic drugs, we will study the function of the respective GABA A receptors and neurons in influencing cellular and network activity as well as in modulating fear and anxiety. Conditional knock out mice allowing selective and site-restricted deletion of NPY-Y1 and Y2 receptors by injection of a viral vector encoding cre-recombinase will be used to investigate the anatomical sites of the proposed anxiolytic and anxiogenic actions of NPY mediated by these receptors, respectively. In these models and in a genetic model of high trait anxiety HAB/LAB mice (bread for high and low anxiety behavior, respectively), possible changes in the pattern of activation of different anatomical circuitries or reliant on the NPY and GABAergic systems in conjunction with proposed changes in conditioned fear acquisition will be investigated. The proposed project represents a highly multidisciplinary approach integrating in vivo electrophysiology in the hippocampus and in the amygdala with molecular and behavioral pharmacology as well as with neuroanatomy at the light and electron microscopic level. As a short-term goal, we aim for a better understanding of the functioning of amygdalo-hippocampal circuitries and the role of the mentioned transmitter receptors in acquisition and extinction of fear and anxiety. In a long-term perspective we would like to identify novel drug targets for pathologically altered states of anxiety.