A distinct entorhinal cortex to hippocampal CA1 direct circuit for olfactory associative learning

A R T I C L E S

A distinct entorhinal cortex to hippocampal CA1 direct circuit for olfactory associative learning

Yiding Li13,8, Jiamin Xu4,8, Yafeng Liu5, Jia Zhu1,3, Nan Liu2, Wenbo Zeng6, Ning Huang7, Malte J Rasch2, Haifei Jiang6, Xiang Gu2, Xiang Li2, Minhua Luo6, Chengyu Li1, Junlin Teng7, Jianguo Chen7, Shaoqun Zeng5, Longnian Lin4 & Xiaohui Zhang2

Lateral and medial parts of entorhinal cortex (EC) convey nonspatial what and spatial where information, respectively, into hippocampal CA1, via both the indirect EC layer 2 hippocampal dentate gyrusCA3CA1 and the direct EC layer

3CA1 paths. However, it remains elusive how the direct path transfers distinct information and contributes to hippocampal learning functions. Here we report that lateral EC projection neurons selectively form direct excitatory synapses onto a subpopulation of morphologically complex, calbindin-expressing pyramidal cells (PCs) in the dorsal CA1 (dCA1), while medial EC neurons uniformly innervate all dCA1 PCs. Optogenetically inactivating the distinct lateral ECdCA1 connections or the postsynaptic dCA1 calbindin-expressing PC activity slows olfactory associative learning. Moreover, optetrode recordings reveal that dCA1 calbindin-expressing PCs develop more selective spiking responses to odor cues during learning. Thus, our results identify a direct lateral ECdCA1 circuit that is required for olfactory associative learning.

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The hippocampus is a medial temporal lobe structure that is critically involved in spatial navigation and formation of declarative memory. Multimodal information from many cortices converges into the hippocampus primarily through the EC13. The medial part of EC (MEC) contains strongly position-modulated neurons4,5, while the lateral EC (LEC) contains neurons encoding other features, for example, object68 and odor913. It is generally thought that MEC and LEC transfer spatial5 and nonspatial6, or context- and content-related14 information, respectively, into the hippocampus, through two efferent synaptic pathways: the perforant path (PP), from EC layer 2 stellate cells to hippocampal dentate gyrus (DG), and the temporoammonic path (TA), from EC layer 3 PCs to hippocampal CA1. These two pathways are also known as the indirect and direct paths, respectively, relative to the CA11,3. A large body of experimental evidence has revealed the synaptic organization of the indirect path and its critical roles in spatial navigation and declarative memory formation15,16. In contrast, neural functions of the direct TA...