DESCRIPTION (provided by applicant): Numerous recent experiments in humans and other animals demonstrate impaired temporal coordination of neuronal activity in many psychiatric diseases. A prevalent hypothesis is that temporal coordination in high associational areas of the brain, critical for cognition, is brought about by the multiple hierarchies of rhythms the brain generates. Since most brain rhythms are based on inhibition, the goal of this proposal is to examine the contribution of the variety of interneuron classes to the different oscillations and temporal coordination of principal cell assemblies. Inhibition, both oscillatory and non-oscillator, can flexibly congregate and segregate neuronal populations to support fundamental cortical operations. However, the exact contribution of the different classes of interneurons and their cooperation in these flexible operations are poorly understood. The goal of this proposal is to uncover these mechanisms. Our target is the hippocampus because the mechanisms of several oscillations (theta, gamma, sharp wave ripples) and their contribution to navigation and memory have been extensively studied in this brain region. We will follow two strategies to explore and explain the mechanisms of interneuron-controlled grouping and segregation of principal cells. First, we will quantify the firing rate and phase correlations of the various interneuron types uniquely embeddedness in the various network patterns, using optogenetic identification and large scale recording of the neurons in mice. Second, a closed-loop optogenetic activation and silencing of the identified interneurons will be performed to interfere with native network pattern locally. These combined experiments will therefore identify the causal role of the specific interneuron classes in the organization of cell assemblies supporting spatial navigation and memory. The findings will have important implications for mental disease associated with impaired temporal coordination.

PUBLIC HEALTH RELEVANCE: Temporal coordination of neuronal activity within and across brain regions is among the most fundamental neuronal operations and impairment of time management is an underlying mechanism of a variety of mental disorders. Our aim is to explain the role of different interneuron classes in the hippocampus in brain state dependent oscillations and the flexible formation of cell assemblies that support spatial navigation and memory. To achieve this goal we combine optogenetic and large-scale recording methods in behaving mice.