The synaptic basis of learning and attention

动物非常善于灵活地适应它们的行为，这种能力对于在不断变化的环境中生存至关重要。在学习(几天)和注意力(几秒钟)的过程中，神经元改变了它们的反应特性，增强了它们对环境相关特征的反应。这种可塑性取决于每个神经元上存在的数万个兴奋性突触和数千个抑制性突触的变化。个体突触在学习过程中的变化对研究来说是具有挑战性的。即使已知突触属性的平均变化，也不能直接将其与单个神经元在网络中发挥作用时的属性变化联系起来。因此，人们仍然很难理解学习是依赖于少数强突触的变化，还是更广泛地分布在大量突触的变化。突触变化是否聚集在一起，以驱动非线性树突事件？在学习和注意过程中，大多数突触的变化是自上而下的(在顶端树突中)还是自下而上的(在基底树突中)，或者是随着时间的推移这些区域之间的转移？这个项目将通过使用多天活体双光子钙成像在小鼠学习视觉辨别任务并随后执行注意力切换任务(Poort...可汗等人2022年)。这些技术已经被建立起来，并在主办实验室中被常规使用。我们将使用多学科的方法，包括光遗传学，GCaMP7f与PSD-95 FingRs和geporrin-FingRs的融合成像，以及计算模型。个体棘突的活动将与相同神经元的胞体活动和老鼠行为有关。最后，我们将研究如何改变短树突上兴奋性和抑制性突触的局部平衡，以及这如何与皮质神经元的可塑性有关(Grillo…Burrone et al Neuron 2018年)。

Animals are remarkably adept at flexibly adapting their behaviour, and this ability isessential for survival in an ever-changing environment. During learning (over days),and attention (over seconds), neurons change their response properties, sharpeningtheir responses to relevant features of the environment. This plasticity depends onchanges in the tens of thousands of excitatory synapses and several thousandinhibitory synapses present on each neuron. Changes in individual synapses duringlearning are challenging to study. Even when average changes in synaptic propertiesare known, it is not straightforward to relate then to the changes in the properties ofindividual neurons as they function in a network. Thus, it remains poorly understoodwhether learning relies on changes in a small number of strong synapses, or morewidely distributed changes across a large number of synapses. Are synaptic changesclustered, to drive non-linear dendritic events? Are most synaptic changes duringlearning and attention top-down (in apical dendrites) or bottom up (in basal dendrites),or is there transfer across these domains over days? This project will address thesequestions by measuring activity in individual synaptic spines using multi-day in-vivotwo-photon calcium imaging in visual cortex as mice learn a visual discrimination taskand subsequently perform an attention-switching task (Poort... Khan et al 2022). Thesetechniques are already established and routinely used in the host lab. We will use amultidisciplinary approach, including optogenetics, imaging GCaMP7f fused with PSD-95 Fingrs and gephyrin-Fingrs, and computational modeling. The activity of individualspines will be related the activity of the soma of the same neurons and the mousebehaviour. Finally, we will investigate how the local balance of excitatory andinhibitory synapses on short stretches of dendrites is modified and how this relates toplasticity in cortical neurons (Grillo... Burrone et al Neuron 2018).