The impact of neuronal activity on functional re-wiring of hippocampal CA1 excitatory neurons.

人们普遍认为，学习激活了一小部分神经元，并在这些神经元中诱导了持续的物理/化学变化。在记忆回忆过程中，这些变化使这些“印记”神经元通过相关线索重新激活，从而恢复记忆。到目前为止，这些持续变化的性质仍然难以捉摸。有人提出，在复杂的电路中，选择性地增加神经元组内的连通性会导致编码特定记忆的印记神经元集合的出现。新大脑皮层的活体研究支持这一理论，表明学习会影响神经元突触结构的可塑性。然而，目前尚不清楚这一特征是否普遍存在于哺乳动物的大脑中，或者更确切地说，是特定于大脑中长期存储信息的区域，如新皮质。此外，尚不清楚这种神经元集合的形成在多大程度上导致了连接性的实际变化，以及这种重新连接在多大程度上对记忆的形成起作用。在这里，我们将使用慢性脑深部双光子光学成像来研究当神经元被自然刺激或人工光遗传刺激激活时，海马CA1区锥体神经元的结构突触动力学。我们将探索可能导致突触结构稳定的突触机制，并测试结构突触稳定与突触传递增加相对应的程度。最后，我们将剖析固有的CA1兴奋性与结构和功能CA3上的突触活动对CA1连通性的贡献。本项目建议使用互补的方法和尖端技术来获得支持学习和记忆的神经元群的形成的机制解释。这项工作将提供的知识将极大地加深我们对神经元网络中信息编码和回忆的理解。

It is commonly believed that learning activates a small ensemble of neurons and it induces in these neurons persistent physical/chemical changes. During memory recall these changes enable reactivation of these “engram” neuronal ensembles by relevant cues and hence retrieval of memory. Until now the nature of these persistent changes has remained elusive. It has been proposed that selective increase in connectivity within groups of neurons in a complex circuit results in the emergence of engram neuronal ensembles encoding specific memories. In vivo studies in the neocortex support this theory, showing that learning influences neuronal synaptic structural plasticity. Still, it is not known whether this feature is universal in the mammalian brain or rather specific for brain regions that store information for long-term such as the neocortex. Moreover, it is unclear to what extent the formation of such neuronal ensembles leads to actual changes in connectivity and to what extent such re-wiring is functional to the formation of memories.Here we will use chronic deep-brain two-photon optical imaging to investigate structural synaptic dynamics in hippocampal CA1 pyramidal neurons as neurons get activated either by naturalistic stimuli or by artificial optogenetic stimulation. We will probe synaptic mechanisms that might lead to synaptic structural stabilization and test the extent to which structural synaptic stabilization corresponds to increased synaptic transmission. Finally we will dissect the contribution of intrinsic CA1 excitability versus synaptic activity on structural and functional CA3 to CA1 connectivity.This project proposes to use complementary approaches and cutting-edge technologies to attain a mechanistic explanation for the formation of neuronal ensembles that support learning and memory. The knowledge this work will provide will significantly deepen our understanding of information encoding and recalling in neuronal networks.