Somatostatin peptide signaling dampens cortical circuits and promotes exploratory behavior

Abstract

BackgroundSomatostatin (SST) neurons in the prelimbic (PL) cortex mediate a variety of behavioral states, ranging from alcohol consumption to fear learning and avoidance-related behaviors. However, little is known about the role of somatostatin peptide signaling itself to cortical functioning and behavior. Here, we sought to characterize the unique physiological and behavioral roles of the SST peptide in the PL cortex.MethodsWe employed a combination of ex vivo 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 C57BL/6J male and female mice in pyramidal and GABAergic neurons of the PL cortex to characterize the pharmacological mechanism of SST signaling. Fiber photometry recordings of GCaMP6f fluorescent calcium signals from SST neurons were conducted to characterize the activity profile of SST neurons during exploration of an elevated plus maze (EPM) and open field (OF). We further used local delivery of a broad SST receptor (SSTR) agonist into bilateral PL cortex to test causal effects of SST signaling on these same exploratory behaviors.ResultsSSTR activation broadly hyperpolarized layer 2/3 pyramidal neurons in the PL cortex in both male and female mice ex vivo, 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 OF 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.ConclusionsHere we reveal a novel role for the SST peptide system within the PL cortex, by demonstrating a peptide-induced hypoexcitability of PL circuits and modulation of PL-dependent exploratory behaviors.

Adolescent binge drinking leads to long-lasting changes in cortical microcircuits in mice

“…Studies assessing changes in anxiety-like behavior following adolescent alcohol have found mixed results, with some showing increases in anxiety-like behavior after adolescent drinking (Lee et al, 2017; Varlinskaya et al, 2020) and others showing no change (Amodeo et al, 2018). While the current study did not explore the behavioral ramifications of long-term SST excitability, the literature has long suggested a broad role for these neurons in fear learning (Cummings and Clem, 2020), threat response (Joffe et al, 2022), and alcohol use itself (Dao et al, 2021), and we have recently shown their active engagement during exploratory behaviors (Brockway et al, 2022, preprint). Therefore, the consequences of a lifelong increase in SST function may be catastrophic to the individual brain.…”

“…Although limited work has assessed changes in SST peptide release or expression in substance use disorders, SST represents a potential therapeutic target for a variety of neuropsychiatric illnesses (Brockway and Crowley, 2020). Future experiments should investigate changes in SST peptide release throughout development and following alcohol exposure using both optogenetic techniques (Dao et al, 2019), in vivo recording (Brockway et al, 2022, preprint), and novel biosensors (Wang et al, 2022, preprint; Xiong et al, 2021, preprint).…”