Endogenous cannabinoid control of reward substrates

大脑的主要功能之一是计算有机体在什么情况下做出最适应的动作 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 行为学上的相关性，并随后决定采取哪些行动，给定这些行动的可能结果 行为。因此，奖励预测的神经基础必须与控制行为输出的神经基础相互作用。 神经调节剂多巴胺是这种相互作用的关键成分。中脑中的多巴胺能神经元 被当前环境预测不到的回报所激动不已。然而，当刺激可靠地预测奖励时， 他们减少了锁定在奖励上的活动时间，并转向了环境预测者自己。因此， 多巴胺被认为是一种传播与刺激相关的奖励预测的教学信号。数据来自 之前的资金周期显示，腹侧被盖雕刻线索中的内源性大麻素诱导的 在寻找奖赏的过程中，伏隔核内释放多巴胺。我们假设了，但从未明确提出过 证明这是由于多巴胺神经元本身释放了内源性大麻素2AG， 这降低了他们的抑制程度。这种去抑制机制是高度保守的，因为我们发现它发生在 在追求贪得无厌的回报的同时，也在逃避惩罚。然而，准确的 腹侧被盖的兴奋性输入负责多巴胺神经元按需释放2AG 是未知的。在这里，我们建议进行实验，以进一步阐明内源性大麻素信号在 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