Adaptive fear responses to external threats rely upon efficient relay of computations underlying contextual encoding to subcortical circuits. Brain-wide analysis of highly co-activated ensembles following contextual fear discrimination identified the Dorsolateral septum (DLS) as a relay of the dentate gyrus-CA3 circuit. Retrograde mono-synaptic tracing and electrophysiological whole-cell recordings demonstrated that DLS somatostatin-expressing interneurons (SST-INs) receive direct CA3 inputs. Longitudinal in vivo calcium imaging of DLS SST-INs in awake, behaving mice identified a stable population of footshock responsive SST-INs during contextual conditioning whose activity tracked and predicted non-freezing epochs during subsequent recall in the training context but not in a similar, neutral context or open field. Optogenetic attenuation or stimulation of DLS SST-INs bidirectionally modulated conditioned fear responses and recruited proximal and distal subcortical targets. Together, these observations suggest a role for a potentially hard-wired DLS SST-IN subpopulation as arbiters of mobility that calibrate context appropriate behavioral fear responses.

Long‐term synaptic plasticity, represented by long‐term depression (LTD) and long‐term potentiation (LTP) comprise cellular processes that enable memory. Neuromodulators such as serotonin regulate hippocampal function, and the 5‐HT4‐receptor contributes to processes underlying cognition. It was previously shown that in the CA1‐region, 5‐HT4‐receptors regulate the frequency‐response relationship of synaptic plasticity: patterned afferent stimulation that has no effect on synaptic strength (i.e., a θm‐frequency), will result in LTP or LTD, when given in the presence of a 5‐HT4‐agonist, or antagonist, respectively. Here, we show that in the dentate gyrus (DG) and CA3 regions of freely behaving rats, pharmacological manipulations of 5‐HT4‐receptors do not influence responses generated at θm‐frequencies, but activation of 5‐HT4‐receptors prevents persistent LTD in mossy fiber (mf)‐CA3, or perforant path‐DG synapses. Furthermore, the regulation by 5‐HT4‐receptors of LTP is subfield‐specific: 5‐HT4‐receptor‐activation prevents mf‐CA3‐LTP, but does not strongly affect DG‐potentiation. These data suggest that 5‐HT4‐receptor activation prioritises information encoding by means of LTP in the DG and CA1 regions, and suppresses persistent information storage in mf‐CA3 synapses. Thus, 5‐HT4‐receptors serve to shape information storage across the hippocampal circuitry and specify the nature of experience‐dependent encoding. © 2016 The Authors Hippocampus Published by Wiley Periodicals, Inc.