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Abstract

The medial prefrontal cortex (mPFC) is critically involved in cognitive flexibility and top down control of behavior. Dysfunction of this brain region is a hallmark of many psychiatric disorders including addiction. The physiological and molecular mechanisms underlying mPFC function are largely unclear. A widely accepted theory posits that distinct memories are encoded in the brain by sparsely distributed sets of neurons, so called neuronal ensembles, which has been demonstrated for reward seeking behavior. However, in the case of alcohol seeking neuronal ensembles had not been identified and it is unclear how such ensembles might differ from those involved in natural reward seeking. Furthermore, excessive alcohol use causes damage to the mPFC, especially to its ventromedial subregion, also termed infralimbic cortex (IL). Long-term alcohol-induced changes in this brain area include a deficit in metabotropic glutamate receptor subtype 2 (mGluR2). These receptors modify the signaling properties of IL neurons to their projection targets and their dysfunction within corticostriatal projections of alcohol-dependent rats is known to be associated with loss of control over alcohol seeking behavior. Thus, this PhD thesis aims to provide insights into the organization of IL neuronal ensembles involved in alcohol and natural reward seeking and to further understand the role of an mGluR2 deficit for IL dependent control over alcohol seeking and cognitive flexibility.

In Study 1 we identify a functional neuronal ensemble in the IL involved in the control of alcohol seeking behavior, using a chemo-genetic inactivation method. In Study 2 we demonstrate that IL neuronal ensembles involved in alcohol and saccharin seeking are highly overlapping, but also contain reward specific components by using retrograde tracing techniques in combination with a novel two-reward operant task. In Study 3 we develop an advanced methodological framework for measuring neuronal ensemble activity during an operant reward seeking task using in-vivo calcium imaging. By using viral mGluR2 knockdown techniques, Study 4 and 5 establish an IL mGluR2 deficit as a common pathological mechanism for excessive alcohol seeking and impaired cognitive flexibility.

In summary, the results of this thesis provide important insights into the function and organization of neuronal ensembles involved in reward seeking. Possible changes of organization and function of neuronal ensembles in pathological conditions, like addiction, should be addressed in future studies. Furthermore an IL mGluR2 deficit is established as a common pathological mechanism for excessive alcohol seeking and impaired cognitive flexibility, thus leading to a deeper understanding of the underlying molecular mechanisms of this frequent comorbidity and providing a promising target for future medication therapies.