Somatostatin peptide signaling dampens cortical circuits and promotes exploratory behavior

We sought to characterize the unique role of somatostatin (SST) in the prelimbic (PL) cortex in mice. We performed slice electrophysiology in pyramidal and GABAergic neurons to characterize the pharmacological mechanism of SST signaling and fiber photometry of GCaMP6f fluorescent calcium signals from SST neurons to characterize the activity profile of SST neurons during exploration of an elevated plus maze (EPM) and open field test (OFT). We used local delivery of a broad SST receptor (SSTR) agonist and antagonist to test causal effects of SST signaling. SSTR activation hyperpolarizes layer 2/3 pyramidal neurons, an effect that is recapitulated with optogenetic stimulation of SST neurons. SST neurons in PL are activated during EPM and OFT exploration, and SSTR agonist administration directly into the PL enhances open arm exploration in the EPM. This work describes a broad ability for SST peptide signaling to modulate microcircuits within the prefrontal cortex and related exploratory behaviors. [Display omitted] •SST peptide signaling confers broad inhibitory control in the prefrontal cortex•Optogenetic activation of SST neurons mimics pharmacological effects of SST•SST neurons display task-relevant activity during exploratory behaviors in vivo•Pharmacological administration of SST receptor targeting drugs promotes exploratory behavior Brockway et al. demonstrate a role for somatostatin peptide signaling in the cortex of mice. Here, they show somatostatin inhibits both cortical microcircuits and output populations. SST neurons are active during exploratory behaviors, and exploration is enhanced when SST receptor targeting drugs are administered to the cortex.