Grant: Operating Grant

The everyday life of humans and animals relies on spatial navigation and the recollection of previous experiences and information. These critical types of behavior are accomplished via the activation of several cortical structures, including the hippocampus. In freely moving rodents, two classes of hippocampal neurons are active during spatial navigation: excitatory pyramidal cells and inhibitory interneurons. There is ample evidence that pyramidal cells code for specific locations in an environment, whereas interneurons coordinate the activity of pyramidal cells by providing well-timed inhibition. Hence, hippocampal interneurons are considered as "traffic lights" responsible for the proper routing of information during navigation. However, this raises an important question: if inhibition is fundamental for hippocampal computations, are there specific inhibitory mechanisms that control the activity of interneurons themselves? Earlier anatomical reports indicate that a higher-level inhibitory circuitry specialized in innervating interneurons exists in the hippocampus. We discovered that some cells that express the vasoactive intestinal polypeptide (VIP) exhibit a remarkable and highly selective connectivity with hippocampal interneurons. These "VIP members" of the hippocampus control the activity of different inhibitory circuits, thus allowing the coordination of the whole hippocampal network. Moreover, alterations in interneuron inhibition occur in the elderly and in several pathologies, including epilepsy, traumatic brain injury, and Alzheimer disease. To find ways to prevent several disorders, we aim to understand the cellular and functional organization of the VIP circuitry, such as the number of different subtypes of VIP cells residing in the hippocampus, the nature of their targets, the mechanisms of their recruitment during network activity, and their functional role for hippocampal computations under normal conditions and during epileptogenesis.