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Abstract

Our daily life activities are highly dependent on rewards and their ability to drive our motivational and goal-directed behaviours. Rewards are essential for all individuals as they enable us to satisfy our most basic needs and desires. The processing of exteroceptive and interoceptive stimuli within the reward system help us to evaluate the rewarding value of certain actions and reward entities. In this regard, the reward system is originally responsible for processing of information related to natural rewards including food, water and sex. However, it can also be hijacked by drugs of abuse, which are able to manipulate the system with their reinforcing properties. Drugs of abuse are thereby able to drive learning processes, as a result of which external stimuli, such as odours, sounds or visual cues, become associated with the respective drug. For addicts, exposure to these stimuli triggers drug seeking, which results in drug consumption and, for abstinent individuals, relapse of compulsive drug use. In order to improve relapse prevention with pharmacological or therapeutical interventions the underlying mechanisms must be understood on a neuronal level. Today, it is widely accepted that distinct memories, such as learned cue-reward associations, are encoded in sparsely distributed subsets of neurons, so called neuronal ensembles, to achieve given tasks. Rewarding stimuli are thereby thought to activate distinct neurobiological patterns within the reward system. Thus, the associative learning process might result in the formation of neuronal ensembles that encode cue-reward associations, which are reward specific. This thesis therefore aimed to examine the shared and distinct properties of neuronal ensembles encoding different cue-reward associations, investigating different drugs of abuse and the natural reward saccharin. In a first set of experiments, we identified co-active neurons encoding for the investigated cue-induced reward seeking behaviour within the extended reward system. The natural reward saccharin as well as the three drugs of abuse (ethanol, cocaine, nicotine) showed broadly overlapping neuronal activity patterns within the prefrontal cortex, specifically within its orbitofrontal part. On a subcortical level similar activation patterns could be found within the caudate putamen. Despite these similarities, each reward also displayed distinct changes in neuronal activity. Cue-induced ethanol seeking, for example, increased activity within the basolateral amygdala, whereas cue-induced seeking for both psychostimulants displayed elevated activity within the nucleus accumbens core. Saccharin trained animals, however, showed activity reduction within the ventral tegmental area. A second set of experiments characterized the previously identified ensembles on a neurochemical level. The focus was thereby put on ensembles activated within the orbitofrontal cortex, the brain region with the highest activity during cue-induced reward seeking. Immunohistochemical co-localizations showed that all ensembles activated during reward seeking were entirely neuronal and did not comprise any neuroglia. Most remarkably however was the finding that neuronal ensembles within the orbitofrontal cortex displayed a reward specific neurochemical composition. Whereas the neuronal ensemble activated by cue-induced saccharin seeking showed a balanced participation of glutamatergic and GABAergic neurons, the ensemble induced by ethanol seeking was primarily GABAergic and the ensemble triggered by cocaine seeking was predominantly glutamate driven. In a further experiment, the previously identified neuronal ensembles within the orbitofrontal cortex were functionally validated for their involvement in cue-induced saccharin seeking or cue-induced cocaine seeking behaviour. It was found that inactivation of neuronal ensembles responsible for cue-induced saccharin seeking within the orbitofrontal cortex had an impact on reward seeking behaviour whereas abolition of neuronal ensembles involved in cue-induced cocaine seeking showed no effect on the behavioural output. Finally, neuronal ensembles within the infralimbic cortex mediating ethanol and saccharin seeking were investigated. Examination of participating neurons revealed that both ensembles were largely overlapping but also displayed distinct components specific to each reward. Overall, the present work contributes to a better understanding of the organisation and functionality of neuronal ensembles involved in cue-induced reward seeking behaviour. The discovered reward dependent neurochemical distinctness of neuronal ensembles encoding cue-reward associations may provide the opportunity for new therapeutical approaches focusing on the distinct features. However, further studies are necessary to further clarify the role of these distinct reward specific components. Nevertheless, the findings of this thesis provide a good starting point to gain more knowledge about neuronal ensembles and their underlying mechanisms and how these might be addressed in a drug-specific manner during addiction treatment.