Patterning valence specific amygdala memory by dorsal tegmental area (DTA) and ventral tegmental area (VTA) dopamine (DA) subsystems

杏仁核是巴甫洛夫条件反射(CS)与非条件性刺激(US)联系的关键结构。杏仁核基底外侧复合体(BLA)整合了来自听觉皮质的CS信息和来自丘脑和感觉皮质输入的厌恶US信息。然后，信号通过主要由中央杏仁外侧核(CEL)SST+和PKC Delta+神经元组成的抑制网络传递到基底前脑和脑干核团，从而控制恐惧行为(ToVote，2016)。多巴胺(DA)神经元位于背侧被盖区(DTA神经元)，与基底外侧核(BLA)-中央杏仁核(CE)回路相互连接。投射CE的DTA神经元向CE发送预测误差耦合的DAR能强化信号。重要的是，这个信号通过将权重从PKC Delta+转移到SST+突触，将BLA重新连接到细胞神经元。杏仁核主要被研究在厌恶恐惧学习中，但越来越多的人认识到BLA-CE网络也编码奖励行为。然而，与消极或积极经验相关的歧视性联想强化学习背后的特定BLA-CE回路重排尚未得到解决，腹侧被盖区(VTA)和中脑边缘奖赏系统也投射到BLA/CE网络。因此，我们提出BLACE电路分别通过DTA和VTA耦合强化信号来统一负联想学习和正联想学习。支持这一观点的是，VTA神经元活动和杏仁核DA水平可能来自VTA，在奖赏学习过程中增加。同样，DTA神经元活动和杏仁核DA水平，部分来自DTA细胞(未发表)，在暴露于厌恶体验期间强烈增加。因此，这两个回路可能代表了两个截然不同的中脑系统，它们是在正面和负面评价的学习范例中招募的。此外，D1VS D2DA受体在基因定义的神经元亚型中是不对称分布的。这里，一个简单的假设意味着DTA和VTA对SST+和PKC Delta+细胞有不同的神经支配。因此，我们假设，负效化的恐惧和正效化的奖励信号会产生记忆痕迹，这些记忆痕迹在遗传的BLA到SST+和BLA到PKC Delta+的电路结构上有差异地映射。我们认为，来自DTA的DA在恐惧学习过程中增强了BLA到SST+突触，而来自VTA的DA在奖赏学习过程中增强了BLA到细胞PKC Delta+突触。如果我们发现厌恶的刺激和奖励的刺激以相同的方向影响网络，那么这个简单的假设将不得不被摒弃，转而支持DA沿着解剖学的吻尾梯度而不是沿着基因定义的神经元类型控制突触传递。

The amygdala is a key structure for the association of Pavlovian conditioned (CS) to unconditioned (US) stimuli. The basolateral complex of the amygdala (BLA) integrates CS information from the auditory cortex and aversive US information from thalamic andsensory cortical inputs. Signals are then relayed via an inhibitory network of primarily central lateral amygdala (CEl) SST+ and PKC delta+ neurons to basal forebrain and the brainstem nuclei, thereby controlling fear behaviors (Tovote, 2016). Dopamine (DA) neurons located in the dorsal tegmental area (DTA neurons), are interconnected with the basolateral (BLA)- central amygdala (CE) circuitry. The CE-projecting DTA neurons send a prediction error coupled DAergic reinforcement signal to the CE. Importantly, this signal rewires the BLA to CEl neuronal connectivity by shifting the weight from PKC delta+ to SST+ synapses. The amygdala has been mostly investigated in aversive fear learning, but there is increasing recognition that the BLA-CE network encodes also reward behaviors. However, the specific BLA-CE circuit rearrangements underlying discriminatory associative reinforcement learning related to negative or positive experiences are not resolved.The ventral tegmental area (VTA) and the mesolimbic reward system also project to the BLA/CE network. Therefore, we propose that BLACE circuitry unifies both negative and positive associative learning by DTA and VTA coupled reinforcement signals, respectively. In support of this view, VTA neuron activity and amygdala DA levels, likely originating from the VTA, increase during reward learning. Likewise, DTA neuron activity and amygdala DA levels, in part originating from DTA cells (unpublished), are strongly increased during exposure to aversive experience. Thus, these two circuits might represent two distinctly different midbrain systems recruited during positively and negatively rated learning paradigms. Moreover, D1 vs. D2 DA receptors are asymmetrically distributed in the genetically defined neuronal subtypes. Here, a simple assumption would imply that DTA and VTA differentially innervate SST+ and PKC delta+ cells. We therefore hypothesize that negatively valenced fear and positively valenced reward signals generate memory traces that differentially map on the genetic BLA to SST+ and BLA to PKC delta+ circuit architecture. We propose that DA originating from the DTA reinforces BLA to SST+ synapses during fear learning, while DA arising from the VTA enhances BLA to CEl PKC delta+ synapses during reward learning. If we will find that aversive and rewarding stimuli affect the network in the same direction, the simple hypothesis would have to be rejected in favor of control of synaptic transmission by DA along the anatomical rostro-caudal gradients rather than along genetically defined neuronal types.