Habenular neurons expressing mu opioid receptors promote negative affect in a projection-specific manner

ABSTRACT

BACKGROUND

The mu opioid receptor (MOR) is central to hedonic balance, and produces euphoria by engaging reward circuits. MOR signaling may also influence aversion centers, and notably the habenula (Hb), where the receptor is highly dense. Our previous data suggest that the inhibitory activity of MOR in the Hb may limit aversive states. To investigate this hypothesis, we here tested whether neurons expressing MOR in the Hb (Hb-MOR neurons) promote negative affect.

METHODS

Using Oprm1-Cre knock-in mice, we combined tracing and optogenetics with behavioral testing to investigate consequences of Hb-MOR neuron stimulation in approach/avoidance (real-time place preference), anxiety-related responses (open field, elevated plus maze and marble burying) and despair-like behavior (tail suspension)

RESULTS

Opto-stimulation of Hb-MOR neurons elicited avoidance behavior, demonstrating that these neurons promote aversive states. Anterograde tracing showed that, in addition to the interpeduncular nucleus (IPN), Hb-MOR neurons project to the dorsal raphe nucleus (DRN). Opto-stimulation of Hb-MOR/IPN terminals triggered avoidance and despair-like responses with no anxiety-related effect, whereas light-activation of Hb-MOR/DRN terminals increased levels of anxiety with no effect on other behaviors, revealing two dissociable pathways controlling negative affect.

CONCLUSION

Together, the data demonstrate that Hb neurons expressing MOR facilitate aversive states via two distinct Hb circuits, contributing to despair-like behavior (Hb-MOR/IPN) and anxiety (Hb-MOR/DRN). The study supports the notion that inhibition of these neurons by either endogenous or exogenous opioids may relieve negative affect, a mechanism that would have implications for hedonic homeostasis and addiction.