Misaligned feeding impairs memories

ACCEPTED MANUSCRIPT Misaligned feeding impairs memories Dawn Hsiao-Wei Loh, Shekib A Jami, Richard E Flores, Danny Truong, Cristina A Ghiani, Thomas J O'Dell, Chris S Colwell DOI: http://dx.doi.org/10.7554/eLife.09460 Cite as: eLife 2015;10.7554/eLife.09460 Received: 16 June 2015 Accepted: 19 November 2015 Published: 10 December 2015 This PDF is the version of the article that was accepted for publication after peer review. Fully formatted HTML, PDF, and XML versions will be made available after technical processing, editing, and proofing. Stay current on the latest in life science and biomedical research from eLife. Sign up for alerts at elife.elifesciences.org Misaligned feeding impairs memories 1 2 Dawn H Loh1,5*, Shekib A Jami2,5, Richard E Flores1, Danny Truong1, Cristina A Ghiani1,3, 3 Thomas J O’Dell4,5, Christopher S Colwell1,5*. 4 5 6 7 8 9 10 11 12 13 14 1 Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA. 2 Molecular, Cellular, and Integrative Physiology Ph.D. Program, University of California Los Angeles, Los Angeles, CA 90095, USA. 3 Department of Pathology & Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA. 4 Department of Physiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA. 5 UCLA Integrative Center for Learning and Memory, University of California Los Angeles, Los Angeles, CA 90095, USA. 15 16 *Correspondence to: , . 1 17 Abstract 18 Robust sleep/wake rhythms are important for health and cognitive function. Unfortunately, many 19 people are living in an environment where their circadian system is challenged by inappropriate 20 meal- or work-times. Here we scheduled food access to the sleep time and examined the impact 21 on learning and memory in mice. Under these conditions, we demonstrate that the molecular 22 clock in the master pacemaker, the suprachiasmatic nucleus (SCN), is unaltered while the 23 molecular clock in the hippocampus is synchronized by the timing of food availability. This 24 chronic circadian misalignment causes reduced hippocampal long term potentiation and total 25 CREB expression. Importantly this mis-timed feeding resulted in dramatic deficits in 26 hippocampal-dependent learning and memory. Our findings suggest that the timing of meals 27 have far-reaching effects on hippocampal physiology and learned behaviour. 2 28 Introduction 29 The circadian system is a finely tuned network of central and peripheral oscillators 30 headed by a master pacemaker, the suprachiasmatic nucleus (SCN), which governs daily rhythms 31 in physiology and behaviour, including cognition. This network regulates cognitive processes (1, 32 2), and the neural circuits involved in learning and memory also exhibit circadian rhythms in 33 gene expression and synaptic plasticity (3-6). Genetic disruption of these molecular oscillations 34 has severe consequences on cognition (7-9). Environmental perturbations also have the capacity 35 to disrupt synchrony and misalign this clock network (10-19) and are problematic as many 36 people in our modern society extend their work and recreation into the night hours. 37 There has been mounting evidence that the timing of when we eat is critical for our 38 metabolic health (20, 21). At this point, timing of food intake is well-established to have a major 39 impact on the phase of the molecular oscillations in peripheral organs such as the liver and 40 pancreas (22, 23). Mis-timed meals during the sleep phase accelerates weight gain compared 41 with animals fed during their wake phase (24, 25), whereas wake-phase feeding has a protective 42 effect against the cardiac and metabolic dysfunction caused by high fat diets (26, 27). Similar 43 disruptive effects are seen in humans, where misaligned mealtimes produce cardiac and 44 metabolic deficits, leading to a pre-diabetic state (28). We thus became interested in the 45 possibility that these ill consequences of eating at inappropriate phases of the daily cycle may 46 also be maladaptive for cognitive function. In this study, we sought to determine the effects of 47 chronic but stable misalignment of the circadian network by scheduling access to food at an 48 inappropriate phase of the daily cycle. We demonstrate that this simple manipulation has far- 49 reaching consequences for learning and memory. 3 50 Results 51 Misaligned feeding alters diurnal rhythms of activity and sleep. 52 Mice were allotted a six hour window in which food was made available either during the 53 middle of their active (aligned) or inactive (misaligned) phase (Figure 1). Mice adapted to the 54 feeding protocol within 6 days (P = 0.9, Figure 2A) and there were no significant differences in 55 body weight between the two groups at the time of testing (P = 0.5, Figure 2B). Daytime activity 56 was increased in mice subjected to misaligned feeding (P < 0.001; Figure 3A, B), and the 57 strength of daily rhythms of activity was reduced by misaligned feeding (P = 0.003; Figure 3C). 58 Similarly, the temporal pattern of sleep was altered by misaligned feeding (Figure 3D). 59 Immobility-defined video monitoring of sleep behaviour of misaligned mice showed decreased 60 time spent asleep during the day (P < 0.001) and a corresponding increase in sleep during the 61 night (P < 0.001; Figure 3E). Misaligned mice no longer exhibit a day vs night difference in 62 sleep, sleeping equally during the day and night (P = 0.5). Crucially, the total time spent asleep 63 over a 24 hr day was not reduced by misaligned feeding (P = 0.2). The change in temporal 64 pattern of sleep quantity is also reflected in sleep fragmentation, where misaligned mice exhibit a 65 greater number of sleep bouts (P < 0.05) with a corresponding decrease in average sleep bout 66 duration (P < 0.001) during the day compared to aligned mice (Figure3-figure supplement 1). 67 This increased day-time sleep fragmentation is compensated by fewer (P < 0.05) and longer (P < 68 0.001) night sleep bouts in the misaligned animals, resulting in no significant change in the total 69 number (P = 0.9) and average duration (P = 0.6) of sleep bouts over a 24 hr period. 70 Misaligned feeding alters phase of hippocampus without shifting the SCN. 4 71 Using ex vivo organotypic cultures of explants from PER2::LUC reporter mice subjected 72 to aligned or misaligned feeding, we confirmed that daytime feeding shifts the phase of the liver 73 oscillator (P < 0.001) without altering the phase of the SCN oscillator (P = 0.07; Figure 4A,C,D 74 ). Importantly, we demonstrate that daytime feeding significantly misaligns the hippocampal 75 oscillator by 14.1 hr (P < 0.001; Figure 4B, D), with small but si (...truncated)