【作者】 王东；

【导师】 钱卓；

【作者基本信息】 华东师范大学 ， 生理学， 2011， 博士

【摘要】 大量研究表明中脑腹侧被盖区(VTA)多巴胺神经元的活动在奖励、动机、以及药物成瘾行为中起重要作用。以往电生理研究主要考察了多巴胺神经元对奖励相关外在刺激的反应规律。我们采用清醒小鼠多通道在体记录技术,主要研究以下两个问题。1)VTA多巴胺神经元如何编码处理奖励以及惩罚相关的激励信号?我们发现,绝大多数的VTA多巴胺神经元(89%)在给予奖励刺激时,其放电活动显著增强；而同一群多巴胺神经元也对惊吓刺激(比如自由降落、地震摇晃)作出反应,主要表现为放电抑制、以及惊吓事件结束后的放电活动兴奋性反弹。并且,多巴胺神经元的放电活动变化与惊吓事件的持续时间呈正相关。此外,同一个多巴胺神经元能够整合事件和环境场景信息,双向正反编码同一条件刺激信号：当该条件刺激预示奖励时,多巴胺神经元放电增加；当同一条件刺激预示惩罚时,多巴胺神经元放电减少。2)VTA多巴胺神经元是否编码处理动机相关的内在激励信号?我们在小鼠上开展两种自发跳跃行为学实验：基于食物奖励和基于厌恶逃避的跳跃。实验结果显示：绝大多数的VTA多巴胺神经元(95%)在以上两类跳跃的起始阶段,都表现出放电活动的显著增强。并且,多巴胺神经元还表现出与努力程度呈正相关的放电增加。此外,相对于失败的跳跃,多巴胺神经元在成功的跳跃行为中表现出更大的兴奋性。由于小鼠的跳跃起始是完全自发和内在驱动的,我们有理由相信,多巴胺神经元在跳跃起始阶段的兴奋性放电可能表征了一种内在的激励信号,一种追求食物奖励或者更好处境的激励信号。总的来说,以上各项实验结果表明：在奖励或者惩罚相关的趋进、逃避等动机行为中,VTA多巴胺神经元可能同时整合事件信息和环境场景信息,来表征处理各种内在和外在的激励信号。更多还原

【Abstract】 Dopamine neurons in the ventral tegmental area (VTA) have been traditionally studied for their roles in reward-related motivation or drug addiction. Electrophysiology studies have mainly examined how the dopamine neurons would respond to external conditioned or unconditioned stimuli. By using multi-tetrode extracellular recording in the VTA of freely behaving mice,1) we study how the VTA dopamine neurons may process both positive and negative motivational experiences. We find that the majority of the putative dopamine neurons in the VTA exhibit significant activation in response to the conditioned tone that predicts food reward, while the same dopamine neurons exhibit suppression and offset-excitation in response to fearful experiences such as free fall and shake. Importantly, VTA putative dopamine neurons exhibit the temporal dynamic activity:their firing change durations are proportional to the fearful event durations. Moreover, VTA putative dopamine neurons can bi-directionally respond to the same conditioned tone when it has different meanings in distinct contexts, which suggests that VTA dopamine neurons may employ the convergent encoding strategy with integration of cues and environmental context for processing both positive and negative experiences.2) We also study how the VTA dopamine neurons would react during internal motivation and internally guided actions. Mice are engaged in effort-based reward-seeking or aversion-escaping tasks in which they need to jump on a platform to get food reward (food-motivated jump) or jump out of an aversive chamber to escape from it (escape-motivated jump). Our results reveal that the VTA putative dopamine neurons exhibit uniform burst activation at the initiation of both reward-and escape-motivated jumping behaviors. Moreover, dopamine neurons exhibit effort-based levels of activation: their firing changes are proportional to the heights of the jumps. Similarly, dopamine neurons exhibit higher levels of activation in successful jumps in compare with the failed attempted jumps. The timing of the jump initiation is internally guided and completely voluntary, therefore, we suggest that the burst activation of the VTA dopamine neuron at jump initiation represents an internal motivational signal that is associated with expected positive or better outcomes. Taken together, our results suggest that VTA dopamine neurons may employ the convergent encoding strategy with integration of cues and environmental context for processing both internally and externally associated positive and negative motivational signals.更多还原