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      Septal cholinergic neurons gate hippocampal output to entorhinal cortex via oriens lacunosum moleculare interneurons

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          Significance

          Memory formation is a complex process that involves information transfer to the hippocampus for temporary storage (i.e., encoding) and the reciprocal circuit that relays the temporary information back to the neocortex for long-term storage (i.e., consolidation). Acetylcholine has been shown to play a critical role in memory function by differentially modulating encoding and consolidation, but the underlying mechanism is yet unclear. We found that acetylcholine suppresses the hippocampus–entorhinal cortex pathway, which is the gateway to the consolidation pathway. We show that this inhibition is mediated by oriens lacunosum moleculare interneurons and that the ablation of these interneurons impairs proper memory encoding. We provide evidence that demonstrates how acetylcholine tones down the memory consolidation pathway for efficient memory encoding.

          Abstract

          Neuromodulation of neural networks, whereby a selected circuit is regulated by a particular modulator, plays a critical role in learning and memory. Among neuromodulators, acetylcholine (ACh) plays a critical role in hippocampus-dependent memory and has been shown to modulate neuronal circuits in the hippocampus. However, it has remained unknown how ACh modulates hippocampal output. Here, using in vitro and in vivo approaches, we show that ACh, by activating oriens lacunosum moleculare (OLM) interneurons and therefore augmenting the negative-feedback regulation to the CA1 pyramidal neurons, suppresses the circuit from the hippocampal area CA1 to the deep-layer entorhinal cortex (EC). We also demonstrate, using mouse behavior studies, that the ablation of OLM interneurons specifically impairs hippocampus-dependent but not hippocampus-independent learning. These data suggest that ACh plays an important role in regulating hippocampal output to the EC by activating OLM interneurons, which is critical for the formation of hippocampus-dependent memory.

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          Most cited references60

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          Neocortical excitation/inhibition balance in information processing and social dysfunction.

          Severe behavioural deficits in psychiatric diseases such as autism and schizophrenia have been hypothesized to arise from elevations in the cellular balance of excitation and inhibition (E/I balance) within neural microcircuitry. This hypothesis could unify diverse streams of pathophysiological and genetic evidence, but has not been susceptible to direct testing. Here we design and use several novel optogenetic tools to causally investigate the cellular E/I balance hypothesis in freely moving mammals, and explore the associated circuit physiology. Elevation, but not reduction, of cellular E/I balance within the mouse medial prefrontal cortex was found to elicit a profound impairment in cellular information processing, associated with specific behavioural impairments and increased high-frequency power in the 30-80 Hz range, which have both been observed in clinical conditions in humans. Consistent with the E/I balance hypothesis, compensatory elevation of inhibitory cell excitability partially rescued social deficits caused by E/I balance elevation. These results provide support for the elevated cellular E/I balance hypothesis of severe neuropsychiatric disease-related symptoms.
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            Memory, navigation and theta rhythm in the hippocampal-entorhinal system.

            Theories on the functions of the hippocampal system are based largely on two fundamental discoveries: the amnestic consequences of removing the hippocampus and associated structures in the famous patient H.M. and the observation that spiking activity of hippocampal neurons is associated with the spatial position of the rat. In the footsteps of these discoveries, many attempts were made to reconcile these seemingly disparate functions. Here we propose that mechanisms of memory and planning have evolved from mechanisms of navigation in the physical world and hypothesize that the neuronal algorithms underlying navigation in real and mental space are fundamentally the same. We review experimental data in support of this hypothesis and discuss how specific firing patterns and oscillatory dynamics in the entorhinal cortex and hippocampus can support both navigation and memory.
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              SELECTIVE LOSS OF CENTRAL CHOLINERGIC NEURONS IN ALZHEIMER'S DISEASE

              P DAVIES (1976)
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                Author and article information

                Journal
                Proc Natl Acad Sci U S A
                Proc. Natl. Acad. Sci. U.S.A
                pnas
                pnas
                PNAS
                Proceedings of the National Academy of Sciences of the United States of America
                National Academy of Sciences
                0027-8424
                1091-6490
                20 February 2018
                7 February 2018
                : 115
                : 8
                : E1886-E1895
                Affiliations
                [1] aNeurobiology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services , Research Triangle Park, NC 27709
                Author notes
                1To whom correspondence should be addressed. Email: yakel@ 123456niehs.nih.gov .

                Edited by Bruce S. McEwen, The Rockefeller University, New York, NY, and approved January 12, 2018 (received for review July 13, 2017)

                Author contributions: J.H., G.C., and J.L.Y. designed research; J.H. and J.Z. performed research; J.H. analyzed data; and J.H., J.Z., G.C., and J.L.Y. wrote the paper.

                Author information
                http://orcid.org/0000-0002-3341-7756
                Article
                PMC5828580 PMC5828580 5828580 201712538
                10.1073/pnas.1712538115
                5828580
                29437952
                962b995a-9d82-4a8d-aa42-6fa5938b2a2a
                Copyright @ 2018

                Published under the PNAS license.

                History
                Page count
                Pages: 10
                Funding
                Funded by: HHS | NIH | National Institute of Environmental Health Sciences (NIEHS) 100000066
                Award ID: 1 ZIA ES090089-20
                Categories
                PNAS Plus
                Biological Sciences
                Neuroscience
                PNAS Plus

                photometry,memory,hippocampus,oriens lacunosum moleculare interneurons,acetylcholine

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