Dopaminergic modulation of visual cortical circuits

描述（由申请人提供）：中脑多巴胺神经元对奖励和预测奖励的线索表现出阶段性反应。在联想学习过程中，当感觉刺激（如闪光或听觉音调）与奖励配对时，通过训练，感觉刺激会预测奖励。这就提出了一个有趣的问题。既然动物在任何给定时刻都能接收到大量的感官信息，那么是什么将与奖励相关的感官信息与其他传入信息区分开来呢？一种可能性是，多巴胺编码的神经调节性奖励信号改变了感觉皮层中奖励预测刺激的表征（例如，通过优先增强奖励预测刺激引起的神经元反应的增益），因此它们可以与其他感觉输入区分开来。初级视觉皮层（V1）的细胞和电路特性已被广泛表征；因此，它是一个理想的模型系统来测试多巴胺能信号调节感觉信息的增益。在Aim 1中，通道视紫红质-2 （ChR2）将在腹侧被盖区（VTA）的多巴胺神经元中选择性表达，该区域向皮层提供多巴胺能投射。快速扫描循环伏安法（FSCV）将用于建立光诱发多巴胺在V1释放的层流剖面。为了测试多巴胺信号是否调节视觉诱发活动的反应特性，将制作来自特定细胞类型的体内单单位和双光子靶向细胞附加记录。由特定方向的光栅组成的视觉刺激神经元反应将被记录下来。在每只动物中，随机选择的取向将通过配对V1中的多巴胺能纤维或VTA中表达ChR2的多巴胺神经元细胞体的光遗传激活来调节。该实验将确定将感觉输入与局部（V1光遗传刺激）或全局（VTA刺激）多巴胺能信号配对是否可以改变视觉刺激的表征，以及特定细胞类型如何参与这种调节。在Aim 2中确定体内多巴胺能信号的作用后，将进行体外机制研究。不同的细胞类型，特别是分子定义的抑制细胞亚型，对感觉加工有特定的贡献。因此，多巴胺可能优先招募特定类型的细胞来发挥其作用。在

DESCRIPTION (provided by applicant): Midbrain dopamine neurons display phasic responses to rewards and cues that predict rewards. During associative learning, when a sensory stimulus (such as a light flash or auditory tone) is paired with a reward, with training th sensory stimulus comes to predict the reward. This raises an interesting question. Since an animal receives a vast amount of sensory data at any given moment, what distinguishes the sensory information associated with a reward from other incoming information? One possibility is that neuromodulatory reward signals encoded by dopamine alter the representation of reward-predicting stimuli in sensory cortices (for instance, by preferentially enhancing the gain of neuronal responses elicited by reward-predicting stimuli), so that they can be differentiated from other sensory inputs. The cellular and circuit properties of the primary visual cortex (V1) have been extensively characterized; hence, it is an ideal model system to test the hypothesis that dopaminergic signaling modulates the gain of sensory information. In Aim 1, channelrhodopsin-2 (ChR2) will be selectively expressed in dopamine neurons of the ventral tegmental area (VTA), which provides dopaminergic projections to the cortex. Fast-scan cyclic voltammetry (FSCV) will be used to establish the laminar profile of light-evoked dopamine release in V1. To test if dopamine signaling modulates the response properties of visually evoked activity, in-vivo single-unit and two-photon targeted cell-attached recordings from specific cell-types will be made. Neuronal responses to visual stimuli consisting of gratings at specific orientations will be recorded. In each animal, a randomly chosen orientation will be conditioned by pairing with optogenetic activation of dopaminergic fibers in V1 or of the ChR2- expressing cell bodies of dopamine neurons in the VTA. This experiment will establish whether pairing sensory input with local (optogenetic stimulation of V1) or global (VTA stimulation) dopaminergic signaling can modify the representation of visual stimuli, and how specific cell-types contribute to this modulation. After establishing the role of dopaminergic signaling in-vivo in Aim 2 mechanistic studies will be performed in-vitro. Different cell-types, especially molecularly-defined subtypes of inhibitory cells, make specific contributions to sensory processing. Hence, dopamine may preferentially recruit specific cell-types to exert its effects. In order to understand the cellular mechanisms of dopamine action, how dopamine impacts the intrinsic and synaptic properties of excitatory and subtypes of inhibitory cells will be determined Together, these studies will test the hypothesis that dopaminergic signals modify the encoding of sensory stimuli in V1 and will provide a solid groundwork for future work to investigate the role of dopamine signaling in the visual cortex during associative learning.