Correlates of motivation and reward

关于大脑奖励系统的科学问题是因为发现动物学会了杠杆按压以获得对特定大脑区域的电刺激，这种现象被称为颅内自我刺激。从那时起，许多应用解剖学、药理学和电生理学方法的研究证实，腹侧被盖区(VTA)的多巴胺神经元(VTA)是关键的奖赏底物。最近利用光遗传学的研究证实，动物学会了自我刺激VTA多巴胺神经元，这表明兴奋的多巴胺神经元足以产生奖赏。问题仍然是VTA多巴胺神经元的兴奋如何影响下游的大脑区域。我们试图确定在NAC中编码多巴胺神经元介导的奖赏的放电模式。我们将AAV-ChR2病毒注射到TH：：CRE小鼠的VTA区，并将光纤植入TH：：CRE小鼠的VTA区，这是一种允许我们通过光刺激特异性激活多巴胺神经元的程序；一束8个四极管(32根导线)植入NAC壳中，用于记录神经活动。我们发现，在行为自由的小鼠中，VTA光刺激在NAC诱发了快速兴奋性局部场电位(LFP)反应，并且LFP的幅度与动物的自我刺激率有很好的相关性。与LFP活动一致的是，记录到的NAC神经元中有35%呈现快速时相兴奋，提示VTA多巴胺神经元对NAC有兴奋性输入。我们还记录了显示时相抑制的神经元(17%)。为了确定这些放电模式的改变是否是由多巴胺介导的，小鼠被系统地注射了多巴胺D1受体拮抗剂SCH 23390。尽管拮抗剂减少了NAC的大部分基础放电，但它并不能消除光刺激诱发的神经反应，这表明VTA多巴胺神经元释放了多巴胺以外的其他递质。鉴于最近的体外研究表明，多巴胺神经元也可以释放谷氨酸和GABA来去极化或超极化突触后神经元，我们的结果可能是通过兴奋的多巴胺神经元释放谷氨酸或GABA来解释的。VTA多巴胺神经元可能使用多种神经递质来产生奖赏。

Scientific questions on brain reward systems were prompted by the discovery that animals learn to lever-press for electrical stimulation of certain brain areas, a phenomenon known as intracranial self-stimulation. Since then, numerous studies using anatomy, pharmacology and electrophysiology methods have established dopamine neurons in the ventral tegmental area (VTA projecting to the nucleus accumbens (NAc) as a key reward substrate. Recent studies using optogenetics confirmed that animals learn to self-stimulate VTA dopamine neurons, suggesting that excitation of dopamine neurons is sufficient in inducing reward. The question remains how excitation of VTA dopamine neurons influences downstream brain areas. We sought to identify firing patterns that encode dopamine neuron-mediated reward in the NAc. We injected the AAV-ChR2 viruses and implanted optical fibers in the VTA area of TH::Cre mice, a procedure that allowed us to specifically activate dopamine neurons through optical stimulation; a bundle of 8 tetrodes (32 wires) was implanted in the NAc shell for neural activity recording. We found that VTA optical stimulation in freely-behaving mice evoked fast excitatory local field potential (LFP) responses in the NAc, and the amplitudes of this LFP correlated well with the animals self-stimulation rates. Consistent with the LFP activity, 35% of the recorded NAc neurons showed fast phasic excitations, suggesting an excitatory input to the NAc from VTA dopamine neurons. We also recorded neurons that showed phasic inhibitions (17%). To determine whether these firing pattern changes were mediated by dopamine, mice were systemically injected with the dopamine D1 receptor antagonist SCH 23390. Although the antagonist decreased most basal firing in the NAc, it did not abolish optical stimulation-evoked neural responses, suggesting that transmitters other than dopamine were released by VTA dopamine neurons. In light of recent in vitro studies showing that dopamine neurons can also release glutamate and GABA to depolarize or hyperpolarize post-synaptic neurons, our results may be explained by excited dopamine neurons releasing glutamate or GABA. VTA dopamine neurons may employ multiple neural transmitters for inducing reward.