Behavioral pattern separation and cognitive flexibility are essential cognitive abilities which are disrupted in many brain disorders. Better understanding of the neural circuitry involved in these abilities will open paths to treatment. In humans and mice, discrimination and adaptation rely on integrity of the hippocampal dentate gyrus (DG) which both receive glutamatergic input from the entorhinal cortex (EC), including the lateral EC (LEC). Inducible increase of EC-DG circuit activity improves simple hippocampal-dependent associative learning and increases DG neurogenesis. Here we asked if the activity of LEC fan cells that directly project to the DG (LEC→DG neurons) regulates behavioral pattern separation or cognitive flexibility. C57BL6/J male mice received bilateral LEC infusions of a virus expressing shRNA TRIP8b, an auxiliary protein of an HCN channel or a control virus (SCR shRNA); this approach increases the activity of LEC→DG neurons. Four weeks later, mice underwent testing for behavioral pattern separation and reversal learning (touchscreen-based Location Discrimination Reversal [LDR] task) and innate fear of open spaces (elevated plus maze [EPM]) followed by counting of new DG neurons (doublecortin-immunoreactive cells [DCX+] cells). TRIP8b and SCR shRNA mice performed similarly in general touchscreen training and LDR training. However, in late LDR testing, TRIP8b shRNA mice reached the first reversal more quickly and had more accurate discrimination vs. SCR shRNA mice, specifically when pattern separation was challenging (lit squares close together or small separation). Also, TRIP8b shRNA mice achieved more reversals in late LDR testing vs. SCR shRNA mice. Supporting a specific influence on cognitive behavior, SCR shRNA and TRIP8b shRNA mice did not differ in total distance traveled or in time spent in the closed arms of the EPM. Supporting an inducible increase in LEC-DG activity, DG neurogenesis was increased. These data indicate TRIP8b shRNA mice had better pattern separation and reversal learning and more neurogenesis vs. SCR shRNA mice. This work advances fundamental and translational neuroscience knowledge relevant to two cognitive functions critical for adaptation and survival —behavioral pattern separation and cognitive flexibility — and suggests the activity of LEC→DG neurons merits exploration as a therapeutic target to normalize dysfunctional DG behavioral output.

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