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      Disruption of circadian timing increases synaptic inhibition and reduces cholinergic responsiveness in the dentate gyrus

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          Abstract

          We investigated synaptic mechanisms in the hippocampus that could explain how loss of circadian timing leads to impairments in spatial and recognition memory. Experiments were performed in hippocampal slices from Siberian hamsters ( Phodopus sungorus) because, unlike mice and rats, their circadian rhythms are easily eliminated without modifications to their genome and without surgical manipulations, thereby leaving neuronal circuits intact. Recordings of excitatory postsynaptic field potentials and population spikes in area CA1 and dentate gyrus granule cells revealed no effect of circadian arrhythmia on basic functions of synaptic circuitry, including long‐term potentiation. However, dentate granule cells from circadian‐arrhythmic animals maintained a more depolarized resting membrane potential than cells from circadian‐intact animals; a significantly greater proportion of these cells depolarized in response to the cholinergic agonist carbachol (10 μM), and did so by increasing their membrane potential three‐fold greater than cells from the control (entrained) group. Dentate granule cells from arrhythmic animals also exhibited higher levels of tonic inhibition, as measured by the frequency of spontaneous inhibitory postsynaptic potentials. Carbachol also decreased stimulus‐evoked synaptic excitation in dentate granule cells from both intact and arrhythmic animals as expected, but reduced stimulus‐evoked synaptic inhibition only in cells from control hamsters. These findings show that loss of circadian timing is accompanied by greater tonic inhibition, and increased synaptic inhibition in response to muscarinic receptor activation in dentate granule cells. Increased inhibition would likely attenuate excitation in dentate‐CA3 microcircuits, which in turn might explain the spatial memory deficits previously observed in circadian‐arrhythmic hamsters.

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          T-maze alternation in the rodent.

          This protocol details a method for using a T-maze to assess the cognitive ability of rodents. The T-maze is an elevated or enclosed apparatus in the form of a T placed horizontally. Animals are started from the base of the T and allowed to choose one of the goal arms abutting the other end of the stem. If two trials are given in quick succession, on the second trial the rodent tends to choose the arm not visited before, reflecting memory of the first choice. This is called 'spontaneous alternation'. This tendency can be reinforced by making the animal hungry and rewarding it with a preferred food if it alternates. Both spontaneous and rewarded alternation are very sensitive to dysfunction of the hippocampus, but other brain structures are also involved. Each trial should be completed in under 2 min, but the total number of trials required will vary according to statistical and scientific requirements.
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            Circadian rest-activity rhythm disturbances in Alzheimer's disease.

            Previous studies showed circadian rhythm disturbances in patients with Alzheimer's disease. Rest-activity rhythm disturbances manifest themselves through a fragmentation of the rhythm, a weak coupling with Zeitgebers, and high levels of activity during the night. The aim of the present study was to investigate which factors contribute to the presence of these disturbances. Therefore, several rest-activity rhythm, constitutional, and environmental variables were assessed in a heterogeneous group of 34 patients with Alzheimer's disease, including presenile and senile patients living at home or in a nursing home, as well as in 11 healthy controls. Circadian rest-activity rhythm disturbances were most prominent in institutionalized patients. Regression analyses showed the involvement of the following variables. First stability of the rest-activity rhythm is associated with high levels of daytime activity and high levels of environmental light resulting from seasonal effects as well as from indoor illumination. Presenile onset contributed to instability of the rhythm. Second, fragmentation of periods of activity and rest is associated with low levels of daytime activity, and is most prominent in moderately severe dementia. Third, night-time activity level is higher during the times of the year when the days are getting shorter and lower when the days are growing longer. These findings indicate that rest-activity rhythm disturbances may improve by increasing environmental light and daytime activity, an assumption for which empirical evidence has recently been published.
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              Circadian activity rhythms and risk of incident dementia and mild cognitive impairment in older women.

              Previous cross-sectional studies have observed alterations in activity rhythms in dementia patients but the direction of causation is unclear. We determined whether circadian activity rhythms measured in community-dwelling older women are prospectively associated with incident dementia or mild cognitive impairment (MCI). Activity rhythm data were collected from 1,282 healthy community-dwelling women from the Study of Osteoporotic Fractures (SOF) cohort (mean age 83 years) with wrist actigraphy for a minimum of three 24-hour periods. Each participant completed a neuropsychological test battery and had clinical cognitive status (dementia, MCI, normal) adjudicated by an expert panel approximately 5 years later. All analyses were adjusted for demographics, body mass index (BMI), functional status, depression, medications, alcohol, caffeine, smoking, health status, and comorbidities. After 4.9 years of follow-up, 195 (15%) women had developed dementia and 302 (24%) had developed MCI. Older women with decreased activity rhythms had a higher likelihood of developing dementia or MCI when comparing those in the lowest quartiles of amplitude (odds ratio [OR] = 1.57; 95% CI, 1.09-2.25) or rhythm robustness (OR = 1.57; 95% CI, 1.10-2.26) to women in the highest quartiles. An increased risk of dementia or MCI (OR = 1.83; 95% CI, 1.29-2.61) was found for women whose timing of peak activity occurred later in the day (after 3:51 PM) when compared to those with average timing (1:34 PM-3:51 PM). Older, healthy women with decreased circadian activity rhythm amplitude and robustness, and delayed rhythms have increased odds of developing dementia and MCI. If confirmed, future studies should examine whether interventions (physical activity, bright light exposure) that influence activity rhythms will reduce the risk of cognitive deterioration in the elderly. Copyright © 2011 American Neurological Association.
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                Author and article information

                Contributors
                ruby@stanford.edu
                Journal
                Hippocampus
                Hippocampus
                10.1002/(ISSN)1098-1063
                HIPO
                Hippocampus
                John Wiley & Sons, Inc. (Hoboken, USA )
                1050-9631
                1098-1063
                13 January 2021
                April 2021
                : 31
                : 4 ( doiID: 10.1002/hipo.v31.4 )
                : 422-434
                Affiliations
                [ 1 ] Department of Molecular and Cellular Physiology Stanford University Stanford California USA
                [ 2 ] Biology Department Stanford University Stanford California USA
                Author notes
                [*] [* ] Correspondence

                Norman F. Ruby, Biology Department, Stanford University, 371 Jane Stanford Way Stanford, CA 94305‐5020.

                Email: ruby@ 123456stanford.edu

                Author information
                https://orcid.org/0000-0002-0447-951X
                Article
                HIPO23301
                10.1002/hipo.23301
                8048473
                33439521
                04450903-7174-4f7d-b782-a20610150973
                © 2021 The Authors. Hippocampus published by Wiley Periodicals LLC.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 28 December 2020
                : 13 June 2020
                : 02 January 2021
                Page count
                Figures: 6, Tables: 0, Pages: 13, Words: 9923
                Funding
                Funded by: G. Harold and Leila Y. Mathers Charitable Foundation , open-funder-registry 10.13039/100001229;
                Funded by: National Institute of Mental Health , open-funder-registry 10.13039/100000025;
                Award ID: MH065541
                Award ID: MH095837
                Award ID: MH111768
                Funded by: Women's Health and Sex Differences in Medicine Center, Stanford University
                Categories
                Research Article
                Research Articles
                Custom metadata
                2.0
                April 2021
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.0.2 mode:remove_FC converted:15.04.2021

                Neurology
                acetylcholine,carbachol,dentate,hippocampus,sex differences,siberian hamster
                Neurology
                acetylcholine, carbachol, dentate, hippocampus, sex differences, siberian hamster

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