Functional analysis II and RNAi in vivo application

Genetic but also environmental factors, in particular stress, are involved in the development of alcoholism. The corticotropin-releasing hormone (CRH) and its type 1 receptor (CRHR1) are key regulators of the stress response. The CRHR1 is expressed throughout the human and mouse brain. Using knockout mice we could demonstrate that the CRHR1 in the brain, but also in the context of the hormonal stress response, plays an important role in the development of alcohol dependence. Up to know it was unclear on what type of neurons the CRHR1 is present and in which way these CRHR1-positive neurons control the stress response and development of addiction. In the framework of this project we could demonstrate for the first time that CRHR1 is present on neurons using glutamate (Glu), gamma aminobutyric acid (GABA), dopamine (DA) or serotonin (5HT) as neurotransmitter, respectively. The targeted inactivation of CRHR1 allowed to address the specific function of the CRHR1 within these different types of neurons. We could demonstrate that knockout mice lacking CRHR1 on glutamate producing (glutamatergic) neurons (CRHR1-Glu) showed reduced anxiety-related behaviour. Reduced anxiety-related behaviour was accompanied by reduced CRH-dependent neuronal activity in the amygdala and hippocampus, which are key brain structures of the limbic system involved in addiction and anxiety. In contrast, knockout mice lacking CRHR1 in dopamine producing (DA) neurons (CRHR1-DA) showed increased anxiety-related behaviour. Simultaneously, a reduced dopamine release in these animals suggests a direct stress-related control of dopamine release by the CRHR1. Dopamine is the central neurotransmitter of the organism´s reward system and significantly involved in the development of addiction. The bidirectional control of anxiety-related behaviour through CRHR1 in dependence of its localization suggests that an imbalance of CRHR1-controlled glutamatergic and dopaminergic neuronal networks could be of causal relevance for the development of addictive disorders but also of other stress-related psychiatric disorders.

Schematic cross-section through the mouse brain illustrates the distribution of CRHR1 positive neurons and their messengers. Mice lacking CRHR1 in glutamatergic neurons (CRHR1-Glu) are less anxious compared to their control littermate. Mice lacking CRHR1 in dopaminergic neurons (CRHR1-DA) show increased anxiety.