Molecular approaches to emotional memories

As Charles Darwin (1872) first pointed out, emotional responses are highly conserved in the course of evolution. Even very simple animals show fear responses to aversive stimuli. Thus, unlike other mental disorders, anxiety disorders can be successfully studied in animal models. Classical fear conditioning whereby an initially neutral stimulus (CS) such as a tone gains fear-inducing properties after being paired with a noxious unconditioned stimulus (US) such as a footshock, is a powerful behavioral paradigm for the analysis for emotional memory. Our laboratory has recently developed a complementary appproach, safety conditioning: By negatively correlating a CS and a US, the US becomes an indicator of protection, signaling, shelter and safety, a reward-like stimulus (Rogan et al., 2005). Although we have a fair understanding about the brain regions, neuronal circuits and biochemistry involved in emotional learning, we are only beginning to investigate the underlying molecular principles. It is these molecular principles of emotional learning that I propose to set out to explore. The central idea is that emotional - like other forms of learning and memory - involves coordinated changes in gene and protein expression. To test this idea I will turn to the basolateral nucleus of the amygdala, widely accepted as mediating the behavioral fear response and as site of synaptic plasticity for emotional learning and memory. I will analyse the BLA gene expression pattern, elicited by the presentation of the CS in fear and safety conditioned mice. I aim to determine whether the gene expression profile induced by the retrieval of emotional memories is independent of the attributed emotional value or whether the recall of appetitive and aversive memories elicits distinct and specific gene expression patterns. At the protein level I intend to investigate the role of the gastrin- releasing-peptide receptor (GRPR)-signaling network for emotional memories. I will identify GRPR-interacting proteins and subsequently determine their expressional levels in the BLA of fear and safety conditioned mice after the memory recall test. Results of the gene and protein expression analyses will lead to the nomination of a candidate gene for restricted and inducible overexpression or ablation in the mouse amygdala. I herby seek to develop an animalmodel enabling further research on the molecular pathophysiology of anxiety disorders and leading to the identification of novel molecular drug targets guiding research to ultimate clinical studies for the treatment and cure of disorders of affective regulation.