Experience-driven plasticity of visual circuits

 描述（由申请人提供）：感觉输入在大脑中没有忠实地表示。相反，它们与动物内部状态提供的信息相结合，这些信息受到唤醒，注意力，预测和经验等因素的影响。这种整合过程在精神疾病如精神分裂症和注意缺陷多动障碍中受损。尽管科学和临床的重要性，我们的知识是有限的神经回路机制如何外部感官（“自下而上”）的信息和内部生成（“自上而下”）的信息是集成的，以及这些过程是如何影响经验和学习。 我们建议联合收割机尖端技术，以获得一个机械的洞察到的动力学和调节的自下而上和自上而下的输入到初级视觉皮层（V1）的小鼠。我们将研究这些过程如何受到被动感觉经验和学习的影响。为了实现这一目标，我们已经开发了一个视觉引导的主动回避任务的头部固定的小鼠。在目标1中，我们将使用慢性双光子钙成像来记录V1 L2/3兴奋性神经元的活动及其在被动体验和联想学习过程中自下而上和自上而下输入的来源。我们假设：1）感觉经验增加了自上而下的输入的权重，降低了自下而上的输入的权重; 2）联想学习诱导L2/3神经元发出相关事件的潜在时间信号，这些信息包含在自上而下的输入活动中。在目标2中，我们将测试局部抑制回路的活动如何受到视觉经验的影响。L2/3神经元的自下而上的输入到达它们的体周区，而自上而下的输入到达它们的远端树突。因此，树突靶向的、表达生长抑素的抑制性神经元（SOM-INs）可以调节自上而下的输入，而核周靶向的、小清蛋白阳性的抑制性神经元（PV-INs）可以控制自下而上的输入。我们假设学习导致SOM-IN活性降低和PV-IN活性增加。这种变化可以适应V1 L2/3神经元自下而上和自上而下影响平衡的转变。在目标3中，我们将执行操作实验来测试我们模型的一些预测。我们将测试学习引起的活动时间的变化是否 V1 L2/3神经元的激活需要1）来自更高皮层区域的自上而下的输入和2）SOM-IN活性的降低。我们将通过1）灭活更高区域和2）在使用光遗传学在逐个试验的基础上学习后激活SOM-IN，同时用钙成像监测V1 L2/3神经元的活性来测试这些可能性。这些实验将揭示控制动态感觉表征的精细电路机制，并建立一个范式，将联合收割机结合起来，在未来应用于其他形式的学习和行为。

 DESCRIPTION (provided by applicant): Sensory inputs are not represented faithfully in the brain. Rather, they are integrated with the information provided by the animal's internal states that are affected by factors including arousal, attention, prediction and experience. This integration process is impaired in psychiatric disorders such as schizophrenia and attention deficit hyperactivity disorder. Despite the scientific and clinical importance, our knowledge is limited as to the neural circuit mechanisms of how external sensory (`bottom-up') information and internally-generated (`top-down') information are integrated and how these processes are affected with experience and learning. We propose to combine cutting-edge techniques to gain a mechanistic insight into the dynamics and regulation of bottom-up and top-down inputs onto the primary visual cortex (V1) of mice. We will study how these processes are influenced by passive sensory experience and learning. Towards this goal, we have developed a visually-guided active avoidance task for head-fixed mice. In Aim 1, we will use chronic two-photon calcium imaging to record the activity of V1 L2/3 excitatory neurons and the sources of their bottom-up and top-down inputs during passive experience and association learning over days. We hypothesize that 1) sensory experience increases the weight of top-down inputs and decreases that of bottom-up inputs and 2) association learning induces L2/3 neurons to signal the potential timing of the associated event and this information is contained in top-down input activity. In Aim 2, we will test how the activity of local inhibitory circuits is influenced by visal experience. Bottom- up inputs to L2/3 neurons arrive at their perisomatic regions while top-down inputs arrive at their distal dendrites. Therefore, dendrite-targeting, somatostatin-expressing inhibitory neurons (SOM-INs) could regulate top-down inputs, and perisomatically-targeting, parvalbumin-positive inhibitory neurons (PV- INs) could control bottom-up inputs. We hypothesize that learning causes a reduction in SOM-IN activity and an increase in PV-IN activity. Such changes could accommodate the shift in the balance of bottom-up and top-down influences on V1 L2/3 neurons. In Aim 3, we will perform manipulation experiments to test some of the predictions of our model. We will test whether the learning-induced shift of activity timing of V1 L2/3 neurons requires 1) top-down inputs from higher cortical areas and 2) the reduction of SOM-IN activity. We will test these possibilities by 1) inactivating higher areas and 2) activating SOM-INs after learning on a trial-by-trial basis using optogenetics while monitoring the activity of V1 L2/3 neurons with calcium imaging. These experiments will reveal fine-scale circuit mechanisms governing dynamic sensory representations and also establish a paradigm to combine cutting-edge technologies that can be applied to other forms of learning and behaviors in the future.