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，使它们对环境的相关特征的反应更加敏锐。这种可塑性取决于每个神经元上成千上万的兴奋性突触和几千个抑制性突触的变化。学习过程中单个突触的变化是一个挑战性的研究。即使已知突触特性的平均变化，也不能直接将其与网络中单个神经元的特性变化联系起来。因此，人们对学习是依赖于少数强突触的变化，还是依赖于大量突触上分布更广的变化，仍然知之甚少。突触变化是成簇的，驱动非线性树突状事件吗？在学习和注意过程中，大多数突触的变化是自上而下的（在顶树突）还是自下而上的（在基底树突），或者是在几天内跨越这些领域的转移？该项目将解决这些问题，通过测量活动在个别突触棘使用多日在体内双光子钙成像在视觉皮层作为小鼠学习视觉辨别任务，随后执行注意力转换任务（Poort... Khan等人2022）。这些技术已经在主机实验室中建立和常规使用。我们将使用多学科的方法，包括光遗传学，成像GCaMP 7 f融合PSD-95 Fingrs和gephyrin-Fingrs，和计算建模。个体棘的活动与同一神经元的索马体的活动及小鼠的行为有关。最后，我们将研究如何局部平衡的兴奋性和抑制性突触短伸展的树突被修改，以及如何这涉及到可塑性在皮层神经元（格里洛... Burrone等人Neuron 2018）。

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).