VIP interneuron-mediated disinhibition underlies cortical network plasticity & perceptual learning

VIP 中间神经元介导的去抑制是皮质网络可塑性的基础

• 批准号: BB/V005405/1
• 负责人: Leena Williams
• 金额: $ 38.85万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FV005405%2F1
• 关键词: VIP; interneuron; mediated; disinhibition; underlies

One of the most compelling questions of modern neuroscience is: How does the brain change when we learn? Sensory experience and perceptual learning is thought to be associated with Long Term Potentiation (LTP), i.e. a strengthening of synaptic connections. LTP is a fundamental underpinning of neuronal plasticity in the Somatosensory Cortex (S1). My previous research has demonstrated that LTP is dependent upon concerted activation of subtype specific GABAergic interneurons. However, it remains to be seen if this LTP and its' cellular and circuit underpinnings drive cortical network plasticity in the awake mouse and if this underlies learning. I hypothesize that activation of disinhibitory GABAergic circuits in S1 underlies cortical network plasticity and tactile-based perceptual learning. The mouse dedicates a large part of S1 to the barrel cortex (BC) which cortically represents the whisker, an essential sensory modality for the mouse. LTP can be induced in Layer (L) 2/3 Pyramidal Neurons (PNs) of the BC after a brief period of rhythmic whisker stimulation (RWS, 8Hz, 1min). Previously, I found that this is driven by repetitive inputs from sensory- related and high-order thalamic inputs. This pairing increases the activity of vasoactive-intestinal-peptide-positive (VIP) interneurons, a subtype of interneurons that suppress the activity of somatostatin positive (SST) interneurons, which are the gate keepers of L2/3PN inputs. I found that this switching on and off of inhibitory interneurons, aka disinhibition, is a driving force for plasticity. Interestingly, the higher-order thalamic inputs are thought to provide important feedback signals needed for correct sensory processing and perceptual learning. My proposed research aims to understand if disinhibitory circuitry underlies plasticity and perceptual learning within the network in the awake mouse. Using 2-Photon Laser Scanning Microscopy (2PLSM) through a cranial window in awake, head-fixed, mice I will monitor Ca2+ responses in VIP & SST interneurons by injecting a Cre-dependent adeno-associated viral vector (AAV) GCamp6s, Ca2+ indicator, directly into the BC of VIP-Cre & SST-Cre mouse lines. Then I will monitor changes in Ca2+ activity, a reflection of the cell spiking or activity, during passive Rhythmic Whisker Stimulation (RWS) versus during a perceptual whisker-basked task. Preliminary evidence suggests that VIP interneurons rapidly increase their activity upon RWS which bolsters my previous findings. I will continue to build upon these findings in both interneuron subtypes. Then, I will use a whisker-based tactile threshold detection task combined with 2PLSM to investigate the activity of VIP & SST interneurons to monitor the Ca2+ responses to test if disinhibitory circuitry is activated, i.e. an increase in VIP interneuron activity and a decrease in SST interneuron activity, during specific time points along the experimental timeline. Animals are presented with whisker deflections at angles within the subliminal to liminal detection range and are trained to report detectable deflections by licking to obtain water rewards. Finally, I can perform the two paradigms on the same 2PLSM, which provides the opportunity to return to the same field to record in the same interneurons. I will aim to determine if the activity, within a single interneuron, observed in one paradigm can predict its activity during the other paradigm. Ultimately, this work could reveal that disinhibition represents a prevalent motif for tuning neuronal circuits during learning. Which may prove important for the field of artificial neuronal networks and could provide targets to harness the mechanisms underlying cortical circuit adaptability, which may have wide sweeping implications for brain health and disease.

现代神经科学最引人注目的问题之一是：当我们学习时，大脑会发生什么变化？感觉经验和知觉学习被认为与长时程增强（LTP）有关，即突触连接的加强。LTP是躯体感觉皮层（S1）神经元可塑性的基础。我以前的研究表明，LTP依赖于亚型特异性GABA能中间神经元的协同激活。然而，这种LTP及其细胞和电路基础是否驱动清醒小鼠的皮层网络可塑性，以及这是否是学习的基础，还有待观察。我推测，激活的去抑制GABA能电路在S1皮层网络可塑性和斗争为基础的知觉学习。 小鼠将S1的大部分贡献给桶皮质（BC），其在皮质上代表胡须，这是小鼠的一种基本感觉方式。短时间节律性电刺激（RWS，8Hz，1 min）后，可在BC的L2/3层锥体神经元（PNs）中诱发LTP。以前，我发现这是由感觉相关的和高阶丘脑输入的重复输入驱动的。这种配对增加了血管活性肠肽阳性（VIP）中间神经元的活性，VIP是抑制生长抑素阳性（SST）中间神经元活性的中间神经元亚型，SST是L2/3 PN输入的守门人。我发现这种抑制性中间神经元的开关，也就是去抑制，是可塑性的驱动力。有趣的是，高阶丘脑输入被认为提供了正确的感觉处理和感知学习所需的重要反馈信号。我提出的研究目的是了解去抑制回路是否是清醒小鼠网络中可塑性和感知学习的基础。使用双光子激光扫描显微镜（2 PLSM）通过清醒的头部固定的小鼠的颅窗，通过将Cre依赖性腺相关病毒载体（AAV）GCamp 6s（Ca 2+指示剂）直接注射到VIP-Cre & SST-Cre小鼠系的BC中，监测VIP & SST中间神经元中的Ca 2+反应。然后，我将监测钙离子活动的变化，细胞尖峰或活动的反映，在被动的节奏胡须刺激（RWS）与知觉胡须晒任务期间。 初步证据表明，VIP中间神经元在RWS上迅速增加其活性，这支持了我以前的发现。我将继续建立在这两个中间神经元亚型的研究结果。然后，我将使用基于胡须的触觉阈值检测任务结合2 PLSM来研究VIP和SST中间神经元的活性，以监测Ca 2+响应，以测试在实验时间轴沿着特定时间点期间是否激活去抑制回路，即VIP中间神经元活性增加和SST中间神经元活性减少。向动物呈现在阈下到阈检测范围内的角度的胡须偏转，并训练动物通过舔来报告可检测的偏转以获得水奖励。最后，我可以在同一个2 PLSM上执行两个范例，这提供了返回到同一个字段以在同一个中间神经元中记录的机会。我的目标是确定在一个范例中观察到的单个中间神经元内的活动是否可以预测其在另一个范例中的活动。 最终，这项工作可以揭示，去抑制是一个普遍的主题，在学习过程中调整神经元回路。这可能对人工神经元网络领域很重要，并可能提供利用皮层回路适应性机制的目标，这可能对大脑健康和疾病产生广泛的影响。