Multimodal Neuroimaging x Optogenetics: A Novel Approach to Study Reward Processing Under Pathological Conditions

背景：中脑多巴胺神经元在奖赏处理和随后的目标导向行为中起着关键作用。多巴胺能活动改变和奖赏处理功能障碍会出现在几种精神疾病中。特别是在吸毒成瘾方面，目标导向的行为受到严重损害，因为吸毒者的行为活动越来越以毒品为导向，而牺牲了所有其他日常活动。在成瘾行为的发展、维持和可能的缓解过程中，奖赏过程发生变化的潜在神经生物学机制还知之甚少。通过多模式9.4T磁共振成像，研究呈现成瘾行为的大鼠中脑多巴胺神经元的动态变化及其在奖赏系统中的连接。在长时间静脉注射可卡因后，自我给药约.15%的老鼠表现出类似上瘾的行为，类似于被诊断为瘾君子的人类可卡因使用者。使用这个动物模型，通过重复的多模式磁共振成像，纵向研究成瘾动物和表现出对成瘾行为的恢复力的动物的奖赏处理和潜在的多巴胺能活动和连接性的变化。这些研究将为成瘾行为背景下的奖赏处理和潜在的多巴胺能功能和连接性的变化提供基本的新见解。鉴于实验动物的结果测量将来自神经成像研究，这些发现将直接转化为人类的情况，并将极大地影响我们对药物成瘾、病理性赌博、抑郁症和其他几种精神疾病的知识。

Background: Midbrain dopamine neurons play a key role in reward processing and subsequent goaldirected behaviour. Altered dopaminergic activity and dysfunctional reward processing occurs in several psychiatric disorders. Especially in drug addiction goal-directed behaviour is severely impaired, as the behavioural activities of a drug addict become increasingly drug-oriented at the expense of all other daily activities. The underlying neurobiology of altered reward processing during the development, maintenance, and possible remission of an addicted behaviour is poorly understood. Goa/s.'To study the dynamics of midbrain dopamine neurons and their connectivity within the reward system by multimodal 9.4T magnetic resonance imaging (MRI) in rats that show addictive-like behaviour. Following a prolonged period of intravenous cocaine self-administration approx. 15% of rats develop addictive-like behaviour similar to that seen in human cocaine users diagnosed as addicts. Using this animal model, alterations in reward processing and underlying dopaminergic activity and connectivity will be studied longitudinally by means of repeated multimodal MRI in animals that become addicted versus animals that show resilience to addictive behaviour.Outcome.'These studies will provide fundamental new insights into reward processing and underlyingalterations in dopaminergic function and connectivity in the context of addictive behaviour. Given thatoutcome measures from experimental animals will be derived from neuroimaging studies the findingswill be directly translatable to the human condition and will dramatically impact on our knowledge ofdrug addiction, pathological gambling, depression, and several other psychiatric disorders.