András Szőnyi1, Katalin E. Sós1, Rita Nyilas2, Dániel Schlingloff1, Albert Barth1, Andor Domonkos1, Virág T. Takács1, James Priestley2, Balázs Pósfai1, Panna Hegedüs1, Andrew Gundlach3, Viktor Varga1, Attila I. Gulyás1, Attila Losonczy2, Tamás F. Freund1, Gábor Nyiri1
1 Laboratory of Cerebral Cortex Research, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary
2 Department of Neuroscience, Kavli Institute for Brain Science, Columbia University, New York, USA
3 Neuropeptides and Behavioural Neuroscience Divisions, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Australia
Introduction: Formation of memory engram components stored in hippocampal CA1 pyramidal cell (PC) assemblies play an important role in contextual memory formation. During salient sensory events, basal forebrain cholinergic and glutamatergic cells activate CA1 oriens-lacunosum molecure (OLM) interneurons. In return, OLM cells inhibit PC dendrites to exclude disruptive primary sensory inputs from CA1, to allow contextual memory formation.
Aims: Although OLM cells are critical in this process, it was unknown whether they received extra-hippocampal inhibition to counterbalance this process. We wanted to examine if NI cells receive such a functional extra-hippocampal inhibition.
Methods and Results: Here, we show using light- and electron microscopy that the GABAergic cells of the pontine nucleus incertus (NI) selectively inhibit OLM cells directly and also indirectly via the inhibition of basal forebrain cholinergic and glutamatergic cells. Contextual fear conditioning experiments showed that optogenetic activation of NI GABAergic cells during aversive inputs can effectively disrupt, while their optogenetic inhibition can excessively enhance contextual fear memory formation. Using monosynaptic rabies tracing, we also show that NI GABAergic cells receive inputs from brain areas related to the processing of salient environmental information. Two-photon calcium-imaging in head-restraint behaving mice showed that in vivo, NI fibers are preferentially activated by salient sensory stimuli after OLM cells inhibited PC dendrites.
Conclusion: This suggests that by controlling the activity of OLM cells, NI GABAergic cells can reset the hippocampal network and prepare it for the reception of the next memory engram components.
Acknowledgements: this study was supported by the ÚNKP-17-3-III-SE-9 New National Excellence Program of the Ministry of Human Capacities.
Doctoral School: János Szentágothai Doctoral School of Neurosciences
Program: Neuromorphology and Cell Biology
Supervisor: Gábor Nyiri
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