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-HT 2A/2C receptors in the vHipp reversed the effects of IPN-vHipp circuit inhibition on active escape behaviors, thereby supporting the 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 serotonergic signaling and associated therapeutic approaches for the treatment of disease symptomology.

The cholinergic system plays a crucial role in nervous system function with important effects on developmental processes, cognition, attention, motivation, reward, learning, and memory. Nicotine, the reinforcing component of tobacco and e-cigarettes, directly acts on the cholinergic system by targeting nicotinic acetylcholine receptors (nAChRs) in the brain. Activation of nAChRs leads to a multitude of immediate and long-lasting effects in specific cellular populations, thereby affecting the addictive properties of the drug. In addition to the direct actions of nicotine in binding to and opening nAChRs, the subsequent activation of circuits and downstream signaling cascades leads to a wide range of changes in gene expression, which can subsequently alter further behavioral expression. In this review, we provide an overview of the actions of nicotine that lead to changes in gene expression and further highlight evidence supporting how these changes can often be bidirectional, thereby inducing subsequent changes in behaviors associated with further drug intake.

Negative allosteric modulators, such as lynx1 and lynx2, directly interact with nicotinic acetylcholine receptors (nAChRs). The nAChRs are integral to cholinergic signaling in the brain and have been shown to mediate different aspects of cognitive function. Given the interaction between lynx proteins and these receptors, we examined whether these endogenous negative allosteric modulators are involved in cognitive behaviors associated with cholinergic function. We found both cell-specific and overlapping expression patterns of lynx1 and lynx2 mRNA in brain regions associated with cognition, learning, memory, and sensorimotor processing, including the prefrontal cortex (PFC), cingulate cortex, septum, hippocampus, amygdala, striatum, and pontine nuclei. Since lynx proteins are thought to play a role in conditioned associations and given the expression patterns across brain regions, we first assessed whether lynx knockout mice would differ in a cognitive flexibility task. We found no deficits in reversal learning in either the lynx1–/– or lynx2–/– knockout mice. Thereafter, sensorimotor gating was examined with the prepulse inhibition (PPI) assessment. Interestingly, we found that both male and female lynx1–/– mice exhibited a deficit in the PPI behavioral response. Given the comparable expression of lynx2 in regions involved in sensorimotor gating, we then examined whether removal of the lynx2 protein would lead to similar behavioral effects. Unexpectedly, we found that while male lynx2–/– mice exhibited a decrease in the baseline startle response, no differences were found in sensorimotor gating for either male or female lynx2–/– mice. Taken together, these studies provide insight into the expression patterns of lynx1 and lynx2 across multiple brain regions and illustrate the modulatory effects of the lynx1 protein in sensorimotor gating.

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