Endogenous cannabinoid control of reward substrates

大脑的主要功能之一是计算生物体在环境中做出的最具适应性的行动。 一组给定的环境条件。这个过程需要学习环境中的哪些特征可以预测 行为学的相关性，并随后决定采取哪些行动，考虑到这些行动的可能结果， 行动因此，奖励预测的神经基质必须与控制行为输出的神经基质相互作用。 神经调节剂多巴胺是这种相互作用的关键成分。中脑的多巴胺能神经元 对当前环境无法预测的奖励感到兴奋。然而，当刺激可靠地预测奖励时， 他们减少了锁定奖励的活动时间，并转向环境预测因素本身。因此，我们认为， 多巴胺被认为是一种教学信号，传播与刺激相关的奖励预测。的数据 以前的资助周期表明，腹侧被盖中的内源性大麻素雕刻线索诱导的激增， 在奖赏寻求过程中丘脑核释放多巴胺。我们假设过，但从来没有明确过 证明，这是由多巴胺神经元本身释放内源性大麻素2AG引起的， 从而降低他们的抑制水平。这种去抑制机制是高度保守的，因为我们发现， 在追求欲望奖励的过程中，也在避免惩罚的过程中。然而，精确 负责多巴胺神经元按需释放2AG的腹侧被盖兴奋性输入 不知道。在这里，我们提出了实验，以进一步阐明内源性大麻素信号的作用， 奖励相关线索的编码及其在动机中的作用。 1

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 appetitive 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. 1