Saturday, May 17, 2025
5/17/2025
Endogenous Cannabinoid Control of Reward Substrates - PROJECT SUMMARY One of the primary functions of the brain is to calculate the most adaptive action for the organism to make under a given set of environmental conditions. This process requires learning which features in the environment predict ethological relevance and subsequently deciding which actions to take, given the probable outcome of those actions. Hence, neural substrates for reward prediction must interact with those controlling behavioral output. The neuromodulator dopamine is a critical component of this interaction. Dopaminergic neurons in the midbrain are excited by rewards not predicted by the current environment. However, when stimuli reliably predict reward, they decrease activity time locked to the reward and shift to the environmental predictors themselves. Therefore, dopamine is thought of as a teaching signal that broadcasts stimuli-related reward predictions. Data from the previous funding cycles showed that endocannabinoids in the ventral tegmentum sculpt cue-induced surges in dopamine release in the nucleus accumbens during reward seeking. We hypothesized, but never unambiguously demonstrated, that this arises from release of the endocannabinoid 2AG from dopamine neurons themselves, which lessens their level of inhibition. This disinhibition mechanism is highly conserved as we found that it occurs during the pursuit of apetitive rewards but also during the avoidance of punishment. However, the precise excitatory input to the ventral tegmentum responsible for the on-demand release of 2AG from dopamine neurons is not known. Here, we propose experiments to further elucidate the role of endocannabinoid signaling in encoding of reward-related cues and its role in motivation. First, we will assess, using genetic dissection approaches, whether 2AG is indeed released from dopamine neurons for their activity to conform to reward prediction theories and whether it can causally influence behavior (aim 1). Next, we will determine which CB1 receptor-expressing afferents to dopamine neurons in the VTA are responsible for the disinhibitory actions of 2AG during cue-driven reward seeking. We will provide further mechanistic insight to these questions by studying the excitatory afferents that give rise to 2AG-dependent dopamine neuron disinhibition during the pursuit of rewards (aim 2). Thus, we will isolate the different components necessary for endocannabinoid signaling to modulate motivational processes using a methodologically-integrated approach, as specific genetic control of 2AG production and CB1 receptor expression will allow explicit tests of current hypotheses of endocannabinoid modulation of motivated behavior. The present proposal makes use of tools not yet applied to these questions to generate new insights on therapeutic strategies for the treatment of motivational disorders such as maladaptive drug seeking.
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