Cell-type specific signal processing in the medial entorhinal cortex deep layer micronetwork
Final Report Abstract
Local neuronal networks express highly coordinated spatio-temporal patterns of activity, which form neuronal correlates of elementary cognitive-behavioral states. In many cases, such coordinated activity patterns propagate along chains or loops of interconnected networks supporting (amongst others) mnemonic functions. The entorhinal cortex (EC) and the hippocampus form a major neuronal circuit that is critically involved in spatial navigation, episodic memory and learning. Multimodal sensory information enters the hippocampal formation via neurons located in superficial layers of EC (layers II and III). In turn, the deeply located layers (layer V (LV) and layer VI (LVI)) receive a substantial part of the hippocampal output and, therefore, play a key role in transferring transiently stored hippocampal information to long-term engrams in neocortical networks. This project was inspired by findings that the medial EC (MEC) LV is divided into two functionally separate sublayers with different circuit integration. Layer Va (LVa) contains neurons which form the major source of telencephalic projections. In contrast, cells in layer Vb (LVb) targets superficial MEC layers, which, in turn, form projections back to the hippocampus. Notably, previous work has proposed LVb excitatory cells as the main targets of afferent fibers from the hippocampus, and revealed a lack of direct projections from the hippocampus to telencephalic-projecting LVa neurons. This structural organization predicts a central role for locally projecting LVb neurons in hippocampal output processing and raises the question how signals reach LVa neurons for further propagation to downstream neocortical networks. In this project, we performed a detailed examination of the structural and functional organization of deep layers (LV and LVI) of MEC in mice. We further analyzed the hippocampal-entorhinal connectivity pattern along the dorsoventral axis. Together, we made major advances in elucidating the propagation of network activity from the hippocampus to MEC. A major finding was that connectivity between MEC LVa, LVb and LVI excitatory neurons is very sparse, suggesting that signals in MEC deep layers are processed in largely parallel streams of activity. Using anterograde tracing and in vitro electrophysiology, we found a markedly differential dorsoventral organization of the hippocampal projection to MEC. Whereas dorsal hippocampal projections are confined to the dorsal MEC and preferentially target LVb over LVa neurons, the ventral hippocampus innervates LVa neurons along the entire dorsoventral extent of MEC. In consequence, the ventral hippocampus might control the flow in hippocampal-entorhinal-neocortical circuits. Finally, we could show that spontaneously occurring hippocampal sharp wave-ripple complexes (SPW-R) reliably propagate from area CA1 of the hippocampus to MEC LVI, LVb and LVa neurons, in some cases preserving the high-frequency temporal structure of ripple oscillations. Together, these results establish principles of signal flow in the hippocampal-entorhinal output circuit. The detailed insights into the MEC deep layer network might be important for our understanding of the integration of emotional, spatial, contextual and episodic contents into a coherent, multidimensional signal from the hippocampal memory system to the neocortex.
Publications
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Processing of Hippocampal Network Activity in the Receiver Network of the Medial Entorhinal Cortex Layer V. The Journal of Neuroscience, 40(44), 8413-8425.
Rozov, Andrei; Rannap, Märt; Lorenz, Franziska; Nasretdinov, Azat; Draguhn, Andreas & Egorov, Alexei V.
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Hippocampal-medial entorhinal circuit is differently organized along the dorsoventral axis in rodents. Cell Reports, 42(1), 112001.
Ohara, Shinya; Rannap, Märt; Tsutsui, Ken-Ichiro; Draguhn, Andreas; Egorov, Alexei V. & Witter, Menno P.
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Persistent sodium currents in neurons: potential mechanisms and pharmacological blockers. Pflügers Archiv - European Journal of Physiology, 476(10), 1445-1473.
Müller, Peter; Draguhn, Andreas & Egorov, Alexei V.
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Regulation of hippocampal mossy fiber-CA3 synapse function by a Bcl11b/C1ql2/Nrxn3(25b+) pathway. eLife, 12.
Koumoundourou, Artemis; Rannap, Märt; De Bruyckere, Elodie; Nestel, Sigrun; Reissner, Carsten; Egorov, Alexei V.; Liu, Pengtao; Missler, Markus; Heimrich, Bernd; Draguhn, Andreas & Britsch, Stefan
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Functional and structural organization of medial entorhinal cortex layer VI. iScience, 28(4), 112207.
Rannap, Märt; Ohara, Shinya; Winterstein, Janis; Roth, Fabian C.; Draguhn, Andreas & Egorov, Alexei V.
