Somatostatin peptide signaling dampens cortical circuits and promotes exploratory behavior

SUMMARY Somatostatin (SST) neurons in the prelimbic (PL) cortex mediate a variety of behavioral states. However, little is known about the actions of somatostatin peptide signaling in shaping cortical functioning and behavior. Here, we sought to characterize the unique physiological and behavioral roles of the SST peptide in the PL cortex. We employed a combination of ex vivo pharmacologic and optogenetic electrophysiology, in vivo calcium monitoring, and in vivo peptide pharmacology to explore the role of SST neuron and peptide signaling in the mouse PL cortex. Whole-cell slice electrophysiology was conducted in pyramidal and GABAergic neurons in the PL cortex of C57BL/6J and SST-IRES-Cre male and female mice to characterize the pharmacological mechanism of SST signaling. Fiber photometry of GCaMP6f fluorescent calcium signals from SST neurons was conducted to characterize the activity profile of SST neurons during exploration of an elevated plus maze (EPM) and open field test (OFT). We further used local delivery of both a broad SST receptor (SSTR) agonist and antagonist into bilateral PL cortex to test causal effects of SST administration and receptor blockade on these same exploratory behaviors. SSTR activation broadly hyperpolarized layer 2/3 pyramidal neurons in the PL cortex in both male and female mice ex vivo , an effect that was recapitulated with optogenetic stimulation of SST neurons, through both monosynaptic and polysynaptic GABA neuron-mediated mechanisms of action. This hyperpolarization was blocked by pre-application of the SSTR antagonist cyclo-somatostatin (cyclo-SST) and was non-reversible. SST neurons in PL were activated during EPM and OFT exploration, indicating task-related recruitment of these neurons. Lastly, in line with this exploration-related activity profile, SSTR agonist administration directly into the PL enhanced open arm exploration in the EPM, while in vivo administration of an antagonist had no effect. Together, this work describes a broad ability for SST peptide signaling to modulate microcircuits within the prefrontal cortex and related exploratory behaviors.