Endocannabinoid Control of Cholinergic Transmission and the Pursuit of Reward

PROJECT SUMMARY Studies using animal models and human subjects have provided evidence for the importance of acetylcholine (ACh) in cognition. The medial septum-diagonal band of Broca complex (MS) serves as a significant source of cholinergic innervation to the hippocampus (HC), a brain region important for memory processes. Cannabinoid type 1 (CB1R) receptors, the main negative feedback modulators of activity in the brain, are expressed on cholinergic HC terminals, where they fine-tune ACh-dependent behavioral responses. While the involvement of ACh in encoding of spatial information and memory formation is well-established, emerging evidence suggests that cholinergic signaling in the HC is also recruited for reward seeking. The anatomical framework that will be investigated here is a neural substrate involved in the generation and modulation of theta oscillations in the HC and in the computations that give rise to working memory (WM) and associative learning necessary for the motivated pursuit of rewards. Our exciting preliminary data supports an interaction between CB1R and ACh in WM, as animals with a conditional deletion of CB1R specifically on ACh terminals arising from the MS outperform their wild-type litter mates in an instrumental delayed non-match-to-sample (DNMTS) task. Surprisingly, our preliminary findings also show that these animals have enhanced motivation for natural rewards observed in progressive ratio (PR) and behavioral economics (BE) tasks. Because physiological data suggests that high ACh levels may set appropriate dynamics for sustained activity and theta oscillations in HC, we hypothesize that CB1R deletion from cholinergic terminals in the HC enhances the broadcast of theta oscillations to executive regions such as the prefrontal cortex (PFC) or limbic-motor integrators such as the nucleus accumbens (NAc), thereby increasing performance. We will test this hypothesis across two different domains: 1) WM and 2) motivation. This has never been directly tested because doing so requires selective modulation of CB1R activity and signaling at anatomically precise brain loci time-locked to behavior as well as rapid measurement of ACh dynamics, which will be achieved with the use of a fluorescent sensor paired with photometric detection. Specific optogenetic control of ACh release and HC theta power will allow explicit tests of current hypotheses of CB1R-mediated modulation of coordinated neuronal activity between HC, PFC and NAc required for behavioral performance. Thus, through the study of interactions between cholinergic and CB1R signaling, the present proposal will provide novel therapeutic strategies aimed at recovery and gain of function in conditions characterized by memory loss and diminished motivation.