Inhibiting Inhibition: Circuit-level and Behavioral Functions of Interneuron-Specific Interneurons in Cortico-Hippocampal Networks

• Applicant: Professor Dr. Imre Vida
• Subject Area: Cognitive, Systems and Behavioural Neurobiology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2017 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 384230557

The dentate gyrus (DG) acts as a gateway to the hippocampus filtering and processing multimodal sensory information arriving from neocortex via the entorhinal cortex. Its principal neurons, the granule cells (GCs), fire sparsely both in vivo and ex vivo. Sparse firing not only serves as a protective mechanism for preventing overexcitation of hippocampal circuits, but also enables the transformation of the rich cortical code into discrete representations (orthogonalized code). In addition to the intrinsic properties of GCs, gamma-Aminobutyric acid-mediated, GABAergic inhibition provides an essential contribution to the sparse coding in the DG. Inhibition is mediated by multiple types of morphologically-, physiologically- and neurochemically-distinct interneuron (IN) types. The various types of INs are thought to serve a division of labor and differentially influence information flow in DG networks. Relative to excitatory activation of INs by long-range and local inputs, our knowledge about the inhibition of INs by local circuit INs is much more scarce. Among the various types, vasoactive intestinal peptide(VIP)-expressing INs are known to selectively target INs and thereby directly modulate the GABAergic system. However, several fundamental questions with respect to IN-specific inhibition remain to be answered: (1) What are the functional and anatomical properties of VIP INs in the DG? (2) What is the molecular specification of VIP INs? (3) What are the precise cellular and subcellular targets of VIP INs? (4) How are VIP INs activated by excitatory inputs and contribute to feedforward and feed-back inhibition onto DG INs? (5) What is the functional consequence of VIP IN-mediated disinhibition on hippocampal circuits? (6) Lastly, what is the behavioral relevance of VIP IN-mediated disinhibition? To answer these questions, in a collaborative effort with a Taiwanese partner, we will apply a combined neuroanatomical, electrophysiological, optogenetic and behavioral approach. We will examine genetically-defined VIP INs using VIP::Cre;Ai14 transgenic mice. To investigate physiological and morphological characteristics and synaptic inputs and outputs of the INs, ex vivo whole-cell recordings will be performed from single cells and synaptically coupled pairs. To gain more insights into the molecular specification of VIP INs, we will take advantage of the RiboTag method to analyze genetic components in genetically identified VIP INs. Finally, to investigate their roles on the synaptic, circuit and behavioral levels, we will use optogenetic and chemogenetic tools to activate or inactivate VIP INs in both ex vivo brain slices and in vivo freely moving animals. Information gained as a result of this multi-level multidisciplinary approach will provide essential insights into the self-organization of the GABAregic inhibitory system in cortical networks.

• DFG Programme: Research Grants
• International Connection: Taiwan
• Partner Organisation: National Science and Technology Council (NSTC)
• Cooperation Partner: Professor Cheng-Chang Lien, Ph.D.