Animals create implicit memories of the time of day that significant events occur then anticipate the recurrence of those conditions at the same time on subsequent days. We tested the hypothesis that implicit time memory for daily encounters relies on the setting of the canonical circadian clockwork in brain areas involved in the formation or expression of context memories. We conditioned mice to avoid locations paired with a mild foot shock at one of two Zeitgeber times set 8 hours apart. Place avoidance was exhibited only when testing time matched the prior training time. The suprachiasmatic nucleus, dorsal striatum, nucleus accumbens, cingulate cortex, hippocampal complex, and amygdala were assessed for clock gene expression. Baseline phase dependent differences in clock gene expression were found in most tissues. Evidence for conditioned resetting of a molecular circadian oscillation was found only in the striatum (dorsal striatum and nucleus accumbens shell), and specifically for Per2 expression. There was no evidence of glucocorticoid stress response in any tissue. The results are consistent with a model where temporal conditioning promotes a selective Per2 response in dopamine-targeted brain regions responsible for sensorimotor integration, without resetting the entire circadian clockwork.

Department of Cell and Systems Biology University of Toronto Toronto Ontario Canada

Department of Neurohumoral Regulations Institute of Physiology of the Czech Academy of Sciences Prague Czech Republic

Department of Psychology University of Toronto Toronto Ontario Canada

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Pahl M, Zhu H, Pix W, Tautz J, Zhang S. Circadian timed episodic-like memory - a bee knows what to do when, and also where. Journal of Experimental Biology. 2007;210:3559–67. doi: 10.1242/jeb.005488. PubMed DOI

Moore D, Doherty P. Acquisition of a time-memory in forager honey bees. Journal of Comparative Physiology A. Neuroethol Sens Neural Behav Physiol. 2009;195:741–75. doi: 10.1007/s00359-009-0450-7. PubMed DOI

Moore D, Van Nest BN, Seier E. Diminishing returns: the influence of experience and environment on time-memory extinction in honey bee foragers. Journal of Comparative Physiology A. Neuroethol Sens Neural Behav Physiol. 2011;197:641–651. doi: 10.1007/s00359-011-0624-y. PubMed DOI

Barrett MC, Sherry DF. Consolidation and reconsolidation of memory in black-capped chickadees (Poecile atricapillus) Behavioral Neuroscience. 2012;126:809–818. doi: 10.1037/a0030408. PubMed DOI

Cain SW, Chou T, Ralph MR. Circadian modulation of performance on an aversion-based place learning task in hamsters. Behavioral Brain Research. 2004;150:201–205. doi: 10.1016/j.bbr.2003.07.001. PubMed DOI

Ralph MR, et al. The significance of circadian phase for performance on a reward-based learning task in hamsters. Behavioral Brain Research. 2002;136:179–184. doi: 10.1016/S0166-4328(02)00131-6. PubMed DOI

Ralph MR, Sam K, Rawashdeh OA, Cain SW, Ko CH. Memory for time of day (time memory) is encoded by a circadian oscillator and is distinct from other context memories. Chronobiology International. 2013;30:540–547. doi: 10.3109/07420528.2012.754449. PubMed DOI

Valentinuzzi VS, et al. Memory for time of training modulates performance on a place conditioning task in marmosets. Neurobiology of Learning and Memory. 2008;89:604–607. doi: 10.1016/j.nlm.2007.08.002. PubMed DOI

Cain SW, McDonald RJ, Ralph MR. Time stamp in conditioned place avoidance can be set to different circadian phases. Neurobiology of Learning and Memory. 2008;89:591–594. doi: 10.1016/j.nlm.2007.07.011. PubMed DOI

Kamin LJ. The retention of an incompletely learned avoidance response. Journal of Comparative Physiology and Psychology. 1957;50:457–460. doi: 10.1037/h0044226. PubMed DOI

Holloway FA, Wansley R. Multiphasic retention deficits at periodic intervals after passive-avoidance learning. Science. 1973;180:208–210. doi: 10.1126/science.180.4082.208. PubMed DOI

Holloway FA, Wansley R. Multiple retention deficits at periodic intervals after active and passive avoidance learning. Behavioral Biology. 1973;9:1–14. doi: 10.1016/S0091-6773(73)80164-6. PubMed DOI

Wansley R, Holloway FA. “Multiple retention deficits following one-trial appetitive training. Behavioral Biology. 1975;14:135–149. doi: 10.1016/S0091-6773(75)90135-2. PubMed DOI

Cain SW, Ralph MR. Circadian modulation of conditioned place avoidance in hamsters does not require the suprachiasmatic nucleus. Neurobiology of Learning and Memory. 2009;91:81–84. doi: 10.1016/j.nlm.2008.10.005. PubMed DOI

Ko CH, McDonald RJ, Ralph MR. The suprachiasmatic nucleus is not required for temporal gating of performance on a reward-based learning and memory task. Biological Rhythm Research. 2003;34:177–192. doi: 10.1076/brhm.34.2.177.14493. DOI

Cain SW, Chalmers JA, Ralph MR. Circadian modulation of passive avoidance is not eliminated in arrhythmic hamsters with suprachiasmatic nucleus lesions. Behavioral Brain Research. 2012;230:288–290. doi: 10.1016/j.bbr.2012.02.022. PubMed DOI

Cain SW, Yoon J, Shrestha TC, Ralph MR. Retention of a 24-hour time memory in Syrian hamsters carrying the 20-hour short circadian period mutation in casein kiNASe-1ε (ck1εtau/tau) Neurobiology of Learning and Memory. 2014;114:171–77. doi: 10.1016/j.nlm.2014.06.004. PubMed DOI

Lukoyanov NV, Pereira PA, Mesquita RM, Andrade JP. Restricted feeding facilitates time-place learning in adult rats. Behavioral Brain Research. 2002;134:283–90. doi: 10.1016/S0166-4328(02)00036-0. PubMed DOI

Wise RADA. learning and motivation. Nature Reviews Neuroscience. 2004;5:483–494. doi: 10.1038/nrn1406. PubMed DOI

Abercrombie ED, Keefe KA, DiFrischia DS, Zigmond MJ. Differential effect of stress on in vivo DA release in striatum, nucleus accumbens, and medial frontal cortex. Journal of Neurochemistry. 1989;52:1655–1658. doi: 10.1111/j.1471-4159.1989.tb09224.x. PubMed DOI

Thierry AM, Tassin JP, Blanc G, Glowinski J. Selective activation of the mesocortical dopaminergic system by stress. Nature (London) 1976;263:242–244. doi: 10.1038/263242a0. PubMed DOI

Fadda F, Melis MR, Argiolas A. Effect of electric foot shock on DA and 3,4-dihydroxyphenylacetic acid (DOPAC) in different brain areas of rats. Bollettino. - Societa Italiana Biologia Sperimentale. 1978;54:1747–1750. PubMed

Lavielle S, et al. Blockade by benzodiazepines of the selective high increase in DA turnover induced by stress in mesocortical DAergic neurons of the rat. Brain Research. 1979;168:585–594. doi: 10.1016/0006-8993(79)90311-1. PubMed DOI

Robinson TE, Becker JB, Young EA, Akil H, Castaneda E. The effects of footshock stress on regional brain DA metabolism and pituitary beta-endorphin release in rats previously sensitized to amphetamine. Neuropharmacology. 1987;26:679–691. doi: 10.1016/0028-3908(87)90228-0. PubMed DOI

Shanks N, Zalcman S, Zacharko RM, Anisman H. Alterations of central norepinephrine, DA and serotonin in several strains of mice following acute stressor exposure. Pharmacology, Biochemistry and Behavior. 1991;38:69–75. doi: 10.1016/0091-3057(91)90591-O. PubMed DOI

Mistlberger RE. Neurobiology of food anticipatory circadian rhythms. Physiology and Behavior. 2011;104:535–545. doi: 10.1016/j.physbeh.2011.04.015. PubMed DOI

Mistlberger RE, Mumby DG. The limbic system and food-anticipatory circadian rhythms in the rat: ablation and DA blocking studies. Behavioral Brain Research. 1992;47:159–168. doi: 10.1016/S0166-4328(05)80122-6. PubMed DOI

Spyraki C, Fibiger HC, Phillips AG. DAergic substrates of amphetamine -induced place preference conditioning. Brain Research. 1982;253:185–193. doi: 10.1016/0006-8993(82)90685-0. PubMed DOI

Carr GD, White NM. Conditioned place preference from intra-accumbens but not intra-caudate amphetamine injections. Life Sciences. 1983;33:2551–2557. doi: 10.1016/0024-3205(83)90165-0. PubMed DOI

Cain SW, Rawashdeh OA, Siu M, Kim SC, Ralph MR. Dopamine dependent setting of a circadian oscillator underlying the memory for time of day. Neurobiology of Learning and Memory. 2017;141:78–83. doi: 10.1016/j.nlm.2017.03.015. PubMed DOI

Harbour VL, et al. Comprehensive mapping of regional expression of the clock protein PERIOD2 in rat forebrain across the 24-h day. PLoS One. 2013;8:e76391. doi: 10.1371/journal.pone.0076391. PubMed DOI PMC

Chun LE, Morton S, Hinds LR, Spencer RL. Variations in Phase and Amplitude of rhythmic clock gene expression across prefrontal cortex, hippocampus, amygdala, and hypothalamic paraventricular and suprachiasmatic nuclei of male and female rats. Journal of Biological Rhythms. 2015;30:417–36. doi: 10.1177/0748730415598608. PubMed DOI PMC

Al-Safadi S, et al. Stress-Induced Changes in the Expression of the Clock Protein PERIOD1 in the Rat Limbic Forebrain and Hypothalamus: Role of Stress Type, Time of Day, and Predictability. PLoS One. 2014;9:e111166. doi: 10.1371/journal.pone.0111166. PubMed DOI PMC

Pantazopoulos H, Dolatshad H, Davis FC. A fear-inducing odor alters PER2 and c-Fos expression in brain regions involved in fear memory. PLoS One. 2011;6:e20658. doi: 10.1371/journal.pone.0020658. PubMed DOI PMC

Wakamatsu H, et al. Restricted-feeding-induced anticipatory activity rhythm is associated with a phase-shift of the expression of mPer1 and mPer2 mRNA in the cerebral cortex and hippocampus but not in the suprachiasmatic nucleus of mice. European Journal of Neuroscience. 2001;13:1190–1196. doi: 10.1046/j.0953-816x.2001.01483.x. PubMed DOI

Ángeles-Castellanos M, Mendoza J, Escobar C. Restricted feeding schedules phase shift daily rhythms of c-Fos and protein Per1 immunoreactivity in corticolimbic regions in rats. Neuroscience. 2007;144:344–355. doi: 10.1016/j.neuroscience.2006.08.064. PubMed DOI

Verwey M, Amir S. Variable restricted feeding disrupts the daily oscillations of Period2 expression in the limbic forebrain and dorsal striatum in rats. Journal of Molecular Neuroscience. 2012;46:258–264. doi: 10.1007/s12031-011-9529-z. PubMed DOI

Radonić A, et al. Guideline to reference gene selection for quantitative real-time PCR. Biochemical and Biophysical Research Communications. 2004;313:856–862. doi: 10.1016/j.bbrc.2003.11.177. PubMed DOI

Chapman JR, Waldenström J. With reference to reference Genes: A Systematic Review of Endogenous Controls in Gene Expression Studies. PLoS One. 2015;10:e0141853. doi: 10.1371/journal.pone.0141853. PubMed DOI PMC

Kozera B, Rapacz M. Reference genes in real-time PCR. Journal of Applied Genetics. 2013;54:391–406. doi: 10.1007/s13353-013-0173-x. PubMed DOI PMC

Lee KS, et al. Validation of commonly used reference genes for sleep-related gene expression studies. BMC Molecular Biology. 2009;10:45. doi: 10.1186/1471-2199-10-45. PubMed DOI PMC

Cleal JK, Shepherd JN, Shearer JL, Bruce KD, Cagampang FR. Sensitivity of housekeeping genes in the suprachiasmatic nucleus of the mouse brain to diet and the daily light–dark cycle. Brain Research. 2014;1575:72–77. doi: 10.1016/j.brainres.2014.05.031. PubMed DOI

Jain N, Vergish S, Khurana JP. Validation of house-keeping genes for normalization of gene expression data during diurnal/circadian studies in rice by qRT-PCR. Scientific Reports. 2018;8:3203. doi: 10.1038/s41598-018-21374-1. PubMed DOI PMC

Shepard JD, Barron KW, Myers DA. Corticosterone delivery to the amygdala increases corticotropin-releasing factor mRNA in the central amygdaloid nucleus and anxiety-like behavior. Brain Research. 2000;861:288–295. doi: 10.1016/S0006-8993(00)02019-9. PubMed DOI

Myers B, Greenwood-Van Meerveld B. Elevated corticosterone in the amygdala leads to persistant increases in anxiety-like behavior and pain sensitivity. Behavioral Brain Research. 2010;214:465–469. doi: 10.1016/j.bbr.2010.05.049. PubMed DOI

Tran L, Greenwood-Van Meerveld B. Altered expression of glucocorticoid receptor and corticotropin-releasing factor in the central amygdala in response to elevated corticosterone. Behavioral Brain Research. 2012;234:380–385. doi: 10.1016/j.bbr.2012.07.010. PubMed DOI

Sumová A, Trávnícková Z, Mikkelsen JD, Illnerová H. Spontaneous rhythm in c-Fos immunoreactivity in the dorsomedial part of the rat suprachiasmatic nucleus. Brain Research. 1998;801:254–258. doi: 10.1016/S0006-8993(98)00619-2. PubMed DOI

Hood S, et al. Endogenous dopamine regulates the rhythm of expression of the clock protein PER2 in the rat dorsal striatum via daily activation of D2 dopamine receptors. Journal of Neuroscience. 2010;30:14046–14058. doi: 10.1523/JNEUROSCI.2128-10.2010. PubMed DOI PMC

Mulder C, Van Der Zee EA, Hut RA, Gerkema MP. Time-place learning and memory persist in mice lacking functional Per1 and Per2 clock genes. Journal of Biological Rhythms. 2013;28:367–379. doi: 10.1177/0748730413512958. PubMed DOI

Pitts S, Perone E, Silver R. Food-entrained circadian rhythms are sustained in arrhythmic Clk/Clk mutant mice. American Journal of Physiology, Regulatory and Integrative Comparative Physiology. 2003;285:R57–R67. doi: 10.1152/ajpregu.00023.2003. PubMed DOI PMC

Iijima M, et al. Altered food-anticipatory activity rhythm in Cryptochrome deficient mice. Neuroscience Research. 2005;52:166–173. doi: 10.1016/j.neures.2005.03.003. PubMed DOI

Pendergast JS, et al. Robust food anticipatory activity in BMAL1-deficient mice. PLoS One. 2009;4:e4860. doi: 10.1371/journal.pone.0004860. PubMed DOI PMC

Storch KF, Weitz CJ. Daily rhythms of food-anticipatory behavioral activity do not require the known circadian clock. Proceedings of the National Academy of Science, USA. 2009;106:6808–6813. doi: 10.1073/pnas.0902063106. PubMed DOI PMC

Takasu NN, et al. Circadian regulation of food-anticipatory activity in molecular clock deficient mice. PLoS One. 2012;7:e48892. doi: 10.1371/journal.pone.0048892. PubMed DOI PMC

Laing EE, Möller-Levet CS, Poh N, Santhi N, Archer SN. Derk-Jan Dijk. Blood transcriptome based biomarkers for human circadian phase. eLife. 2017;6:e20214. doi: 10.7554/eLife.20214. PubMed DOI PMC

Anafi RC, Francey LJ, Hogenesch JB, Kim J. CYCLOPS reveals human transcriptional rhythms in health and disease. Proceedings of the National Academy of Science, USA. 2017;114:5312–5317. doi: 10.1073/pnas.1619320114. PubMed DOI PMC

Balleine BW, O’Doherty JP. Human and rodent homologies in action control: corticostriatal determinants of goal-directed and habitual action. Neuropsychopharmacology. 2010;35:48–69. doi: 10.1038/npp.2009.131. PubMed DOI PMC

van der Meer MA, Johnson A, Schmitzer-Torbert NC, Redish AD. Triple dissociation of information processing in dorsal striatum, ventral striatum, and hippocampus on a learned spatial decision task. Neuron. 2010;67:5–32. doi: 10.1016/j.neuron.2010.06.025. PubMed DOI PMC

Gremel CM, Costa RM. Orbitofrontal and striatal circuits dynamically encode the shift between goal-directed and habitual actions. Nature Communications. 2013;4:2264. doi: 10.1038/ncomms3264. PubMed DOI PMC

Burton AC, Nakamura K, Roesch MR. From ventral-medial to dorsal-lateral striatum: Neural correlates of reward-guided decision making. Neurobiology of Learning and Memory. 2015;117:51–59. doi: 10.1016/j.nlm.2014.05.003. PubMed DOI PMC

Iijima M, Nikaido T, Akiyama M, Moriya T, Shibata S. Methamphetamine-induced, suprachiasmatic nucleus-independent circadian rhythms of activity and mPer gene expression in the striatum of the mouse. European Journal of Neuroscience. 2002;16:921–929. doi: 10.1046/j.1460-9568.2002.02140.x. PubMed DOI

Gallardo CM, et al. Dopamine receptor 1 neurons in the dorsal striatum regulate food anticipatory circadian activity rhythms in mice. eLife. 2014;3:e03781. doi: 10.7554/eLife.03781. PubMed DOI PMC

Blum ID, et al. A highly tunable dopaminergic oscillator generates ultradian rhythms of behavioral arousal. eLife. 2014;3:e05105. doi: 10.7554/eLife.05105. PubMed DOI PMC

Wang Y, Zhou FM. Striatal But Not Extrastriatal Dopamine Receptors Are Critical to Dopaminergic Motor Stimulation. Frontiers in Pharmacology. 2017;8:935. doi: 10.3389/fphar.2017.00935. PubMed DOI PMC

de Lartigue G. & McDougle M. Dorsal striatum dopamine oscillations: setting the pace of food anticipatory activity. Acta Physiol (Oxf). Jun 19:e13152, 10.1111/apha.13152. [Epub ahead of print] (2018). PubMed PMC

O’Brien Kylie B., Sharrief Anjail Z., Nordstrom Eric J., Travanty Anthony J., Huynh Mailee, Romero Megan P., Bittner Katie C., Bowser Michael T., Burton Frank H. Biochemical markers of striatal desensitization in cortical-limbic hyperglutamatergic TS- & OCD-like transgenic mice. Journal of Chemical Neuroanatomy. 2018;89:11–20. doi: 10.1016/j.jchemneu.2018.02.007. PubMed DOI

Hendricks JC, et al. A non-circadian role for cAMP signaling and CREB activity in Drosophila rest homeostasis. Nature Neuroscience. 2001;4:1108–1115. doi: 10.1038/nn743. PubMed DOI

Franken P, Thomason R, Heller HC, O’Hara BF. A non-circadian role for clock-genes in sleep homeostasis:a strain comparison. BMC Neuroscience. 2007;8:87. doi: 10.1186/1471-2202-8-87. PubMed DOI PMC

Albrecht U, Bordon A, Schmutz I, Ripperger J. The multiple facets of Per2. Cold Spring Harbor Symposium on Quantitative Biology. 2007;72:95–104. doi: 10.1101/sqb.2007.72.001. PubMed DOI

Yelamanchili SV, et al. Differential sorting of the vesicular glutamate transporter 1 into a defined vesicular pool is regulated by light signaling involving the clock gene Period2. Journal of Biological Chemistry. 2006;281:15671. doi: 10.1074/jbc.M600378200. PubMed DOI

Sakai T, Tamura. T, Kitamoto T, Kidokoro Y. A clock gene, period, plays a key role in long-term memory formation in Drosophila. Proceedings of the National Academy of Science USA. 2004;101:16058–16063. doi: 10.1073/pnas.0401472101. PubMed DOI PMC

Kornmann B, Schaad O, Bujard H, Takahashi JS, Schibler U. System-driven and oscillator-dependent circadian transcription in mice with a conditionally active liver clock. PLoS Biology. 2007;5:e34. doi: 10.1371/journal.pbio.0050034. PubMed DOI PMC

Ramanathan C, et al. Cell Type-Specific Functions of Period Genes Revealed by Novel Adipocyte and Hepatocyte Circadian Clock Models. PLoS Genetics. 2014;10:e1004244. doi: 10.1371/journal.pgen.1004244. PubMed DOI PMC

Ogawa Y, et al. Positive autoregulation delays the expression phase of mammalian clock gene Per2. PLo.S One. 2011;6:e18663. doi: 10.1371/journal.pone.0018663. PubMed DOI PMC

Albrecht Urs, Sun Zhong Sheng, Eichele Gregor, Lee Cheng Chi. A Differential Response of Two Putative Mammalian Circadian Regulators, mper1and mper2, to Light. Cell. 1997;91(7):1055–1064. doi: 10.1016/S0092-8674(00)80495-X. PubMed DOI

Wijnen H, Young MW. Interplay of circadian clocks and metabolic rhythms. Annual Reviews Genetics. 2006;40:409. doi: 10.1146/annurev.genet.40.110405.090603. PubMed DOI

Houdek P, Sumova A. In vivo initiation of Clock gene expression rhythmicity in fetal rat suprachiasmatic nuclei. PLoS One. 2014;9:e107360. doi: 10.1371/journal.pone.0107360. PubMed DOI PMC

Sumova A, Jac M, Sladek M, Sauman I, Ilnerova H. Clock gene daily profiles and their phase relationship in the rat suprachiasmatic nucleus are affected by photoperiod. Journal of Biological Rhythms. 2003;18:134–144. doi: 10.1177/0748730403251801. PubMed DOI

Targeted modification of the Per2 clock gene alters circadian function in mPer2luciferase (mPer2Luc) mice