Forward genetics has led to major advances in our understanding of the cellular and molecular mechanism of the circadian clock but there is no comparable understanding of the interval timing mechanism, which enables us to estimate durations and intervals between events. This is unfortunate because the ability to anticipate recurring events is essential for an orgranism’s survival. In this project, we propose an investigation of the neurobiological processes underlying interval timing using two approaches. First, we will use a reverse genetics approach to investigate the role of synaptic plasticity in timing. There is increasing evidence that interval timing involves dopamine modulation of cortico-striatal loops. However, no studies have tested whether synaptic plasticity is necessary for this process. We will address this question by testing mice with whole-brain or area-restricted mutations of the CaMKII gene on a timing task. CaMKII is required for plasticity in many areas of the brain, thus the mutation should interfere with temporal estimation if plasticity is involved in this process. Our second strategy follows a forward genetics approach, similar to the one pioneered by Seymour Benzer when he revealed the molecular machinery of the circadian clock. In our case, we will incorporate a timing task in the battery of automated screens used by NeuroBsik, a consortium, of which the Host is a member, engaged in large-scale phenotyping of mutant mice. These mice have random but easily identifiable mutations. This will allow us to discover new genes that are involved in interval timing.