No abstract

The ventromedial prefrontal cortex (vmPFC) plays a critical role in stress resilience through top-down inhibition of key stress-sensitive limbic and hindbrain structures, including the dorsal raphe nucleus (DRN). In a model of experience-dependent stress resistance, socially dominant Syrian hamsters display fewer signs of anxiety following acute social defeat when compared to subordinate or control counterparts. Further, dominants activate vmPFC neurons to a greater degree during stress than do subordinates and become stress-vulnerable following pharmacological inhibition of the vmPFC. Dominants also display fewer stress-activated DRN neurons than subordinates do, suggesting that dominance experience gates activation of vmPFC neurons that inhibit the DRN during social defeat stress. To test whether social dominance alters stress-induced activity of a vmPFC-DRN pathway, we injected a retrograde tracer, cholera toxin B (CTB), into the DRN of dominant, subordinate, and control hamsters and used a dual-label immunohistochemical approach to identify vmPFC neurons colabeled with CTB and the defeat-induced expression of an immediate early gene, cFos. Results indicate that dominant hamsters display more cFos+ and dual-labeled cells in layers V/VI of infralimbic and prelimbic subregions of the vmPFC compared to other animals. Furthermore, vmPFC-DRN activation corresponded directly with proactive behavioral strategies during defeat, which is indicative of stress resilience. Together, results suggest that recruiting the vmPFC-DRN pathway during acute stress corresponds with resistance to the effects of social defeat in dominant hamsters. Overall, these findings indicate that a monosynaptic vmPFC-DRN pathway can be engaged in an experience-dependent manner, which has implications for behavioral interventions aimed at alleviating stress-related psychopathologies.

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.