Endocannabinoids facilitate transitory reward engagement through retrograde gain-control

Neuromodulatory signaling is poised to serve as a neural mechanism for gain control, acting as a crucial tuning factor to influence neuronal activity by dynamically shaping excitatory and inhibitory fast neurotransmission. The endocannabinoid (eCB) signaling system, the most widely expressed neuromodulatory system in the mammalian brain, is known to filter excitatory and inhibitory inputs through retrograde, pre-synaptic action. However, whether eCBs exert retrograde gain control to ultimately facilitate reward-seeking behaviors in freely moving mammals is not established. Using a suite of in vivo physiological, imaging, genetic and machine learning-based approaches, we report a fundamental role for eCBs in controlling behavioral engagement in reward-seeking behavior through a defined thalamo-striatal circuit.