The claustrum, a subcortical structure situated between the insular cortex and striatum, is reciprocally connected with almost all neocortical regions. Based on this connectivity, the claustrum has been postulated to integrate multisensory information and, in turn, coordinate widespread cortical activity. Although studies have identified how sensory information is mapped onto the claustrum, the function of individual topographically arranged claustro-cortical pathways has been little explored. Here, we investigated the organization and function of identified claustro-cortical pathways in mice using multiple anatomical and optogenetic techniques. Retrograde and anterograde tracing demonstrated that the density of anterior claustrum-to-cortical projection differs substantially depending on the target cortical areas. One of the major targets was the medial entorhinal cortex (MEC) and the MEC-projecting claustral neurons were largely segregated from the neurons projecting to primary cortices M1, S1, or V1. Exposure to a novel environment induced c-Fos expression in a substantial number of MEC-projecting claustral neurons and some M1/S1/V1-projecting claustral neurons. Optogenetic silencing of the MEC-projecting claustral neurons during contextual fear conditioning impaired later memory retrieval without affecting basal locomotor activity or anxiety-related behavior. These results suggest that the dense, anterior claustro-MEC pathway that is largely separated from other claustrocortical pathways is activated by novel context and modulates the MEC function in contextual memory.
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