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显示阶段性反应。在联想学习过程中，当感官刺激（如闪光或听觉音调）与奖励配对时，通过训练，感官刺激会预测奖励。这提出了一个有趣的问题。既然动物在任何时候都能接收到大量的感官信息，那么与奖励相关的感官信息与其他传入信息有什么区别呢？一种可能性是，由多巴胺编码的神经调节性奖赏信号改变了奖赏预测刺激在感觉皮层中的表征（例如，通过优先增强奖赏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的假设，多巴胺能信号调节获得的感觉信息。 在目标1中，通道视紫红质-2（ChR 2）将在腹侧被盖区（VTA）的多巴胺神经元中选择性表达，该区域提供多巴胺能投射到皮质。将使用快速扫描循环伏安法（FSCV）建立V1中光诱发多巴胺释放的层流曲线。为了测试多巴胺信号传导是否调节视觉诱发活动的响应特性，将进行来自特定细胞类型的体内单单位和双光子靶向细胞附着记录。将记录对由特定方向的光栅组成的视觉刺激的神经元反应。在每只动物中，随机选择的方向将通过与V1中多巴胺能纤维或VTA中多巴胺神经元的ChR 2表达细胞体的光遗传学激活配对来调节。该实验将确定将感觉输入与局部（V1的光遗传学刺激）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有助于这种调节。 在确立了多巴胺能信号传导在Aim 2中的体内作用后，将在体外进行机制研究。不同的细胞类型，特别是分子定义的抑制细胞亚型，对感觉处理做出特定的贡献。因此，多巴胺可以优先招募特定的细胞类型来发挥其作用。在 为了了解多巴胺作用的细胞机制，多巴胺如何影响兴奋性和抑制性细胞亚型的内在和突触特性将被确定。这些研究将共同验证多巴胺能信号改变V1中感觉刺激编码的假设，并为将来研究多巴胺信号在联想学习过程中在视觉皮层中的作用提供坚实的基础。

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.