The Interpeduncular-Ventral Hippocampus Pathway Mediates Active Stress Coping and Natural Reward.

Maladaptive stress-related behaviors are integral to multiple complex psychiatric disorders, and it has been well established that serotonergic signaling mediates various aspects of these maladaptive states. In these studies, we sought to uncover the function of a previously undefined serotonergic pathway, which projects from the interpeduncular nucleus (IPN) to the ventral hippocampus (vHipp). Intersectional retrograde and chemogenetic viral manipulation strategies were employed to manipulate the function of the IPN-vHipp pathway during a variety of behavioral measures in male mice. We found a significant effect of circuit inhibition on behaviors associated with coping strategies and natural reward. Specifically, inhibition of the IPN-vHipp pathway dramatically increased active stress-induced escape behaviors, in addition to moderately affecting sucrose consumption and food self-administration. During inhibition of this pathway, agonist activation of serotonergic 5-HT2A/2C receptors in the vHipp reversed the effects of IPN-vHipp circuit inhibition on active escape behaviors, thereby supporting a synaptic mechanism underlying the behavioral effects evidenced. IPN-vHipp inhibition did not induce differences in generalized locomotion, anxiety-associated behavior, and intravenous nicotine self-administration. Importantly, these findings are in opposition to the canonical understanding of serotonin in such escape behaviors, indicating that serotonin exerts opposing effects on behavior in a pathway-specific manner in the brain. Taken together, these findings thereby have important implications for our understanding of serotoninergic signaling and associated therapeutic approaches for the treatment of disease symptomology.Significance Statement Deficits in serotonergic signaling are associated with depression-associated behaviors, such as a reduction in escape behaviors (e.g., learned helplessness) and anhedonia, whereas global pharmacological approaches that increase synaptic serotonin, such as SSRIs, ameliorate these behaviors in animal models. In these studies, we found that inhibition of a previously undefined pathway, consisting of serotonergic projections from the interpeduncular nucleus (IPN) to the ventral hippocampus (vHipp), increases active stress-induced escape behaviors, food self-administration, and natural reward consumption. Importantly, these findings define the function of this novel pathway, and, in doing so, provide evidence that decreased serotonergic signaling in this pathway leads to excessive active escape behaviors under stress conditions, which may represent symptoms associated with the pathological state.