Regulation of olfactory associative memory by the circadian clock output signal Pigment-dispersing factor (PDF)

ABSTRACTDissociation between the output of the circadian clock and external environmental cues is a major cause of human cognitive dysfunction. While the effects of ablation of the molecular clock on memory have been studied in many systems, little has been done to test the role of specific clock circuit output signals. To address this gap, we examined the effects of mutation of Pigment-dispersing factor (Pdf) and its receptor, Pdfr on associative memory in male and female Drosophila. Loss of PDF signaling significantly decreases the ability to form associative memory. Appetitive short-term memory (STM), which in wildtype is time-of-day (TOD)-independent, is decreased across the day by mutation of Pdf or Pdfr, but more substantially in the morning than in the evening. This defect is due to PDFR expression in adult neurons outside the core clock circuit and the mushroom body Kenyon cells. The acquisition of a TOD difference in mutants implies the existence of multiple oscillators that act to normalize memory formation across the day for appetitive processes. Interestingly, aversive STM requires PDF but not PDFR, suggesting that there are valence-specific pathways downstream of PDF that regulate memory formation. These data argue that the circadian clock uses circuit-specific and molecularly diverse output pathways to enhance the ability of animals to optimize responses to changing conditions.SIGNIFICANCE STATEMENTFrom humans to invertebrates, cognitive processes are influenced by organisms’ internal circadian clocks, the pace of which is linked to the solar cycle. Disruption of this link is increasingly common (e.g. jetlag, social jetlag disorders) and causes cognitive impairments that are costly and long-lasting. A detailed understanding of how the internal clock regulates cognition is critical for the development of therapeutic methods. Here, we show for the first time that olfactory associative memory in Drosophila requires signaling by Pigment-dispersing factor (PDF), a neuromodulatory signaling peptide produced only by circadian clock circuit neurons. We also find a novel role for the clock circuit in stabilizing appetitive sucrose/odor memory across the day.

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Regulation of Olfactory Associative Memory by the Circadian Clock Output Signal Pigment-Dispersing Factor (PDF)

Journal of Neuroscience ◽

10.1523/jneurosci.0782-20.2020 ◽

2020 ◽

Vol 40 (47) ◽

pp. 9066-9077

Author(s):

Johanna G. Flyer-Adams ◽

Emmanuel J. Rivera-Rodriguez ◽

Junwei Yu ◽

Jacob D. Mardovin ◽

Martha L. Reed ◽

...

Keyword(s):

Circadian Clock ◽

Associative Memory ◽

Output Signal ◽

Pigment Dispersing Factor ◽

Circadian Clock Output

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Role of MicroRNA Genes miR-1000 and miR-375 in Forming Olfactory Conditional Memory in Drosophila melanogaster

MicroRNA ◽

10.2174/2211536609666200204113403 ◽

2020 ◽

Vol 09 ◽

Author(s):

Sadniman Rahman ◽

Chaity Modak ◽

Mousumi Akter ◽

Mohammad Shamimul Alam

Keyword(s):

Learning And Memory ◽

Short Term Memory ◽

Memory Loss ◽

Memory Formation ◽

Neural Integration ◽

Significant Difference ◽

Locomotion Speed ◽

Microrna Genes ◽

With Memory

Background: Learning and memory is basic aspects in neurogenetics as most of the neurological disorders start with dementia or memory loss. Several genes associated with memory formation have been discovered. MicroRNA genes miR-1000 and miR-375 were reported to be associated with neural integration and glucose homeostasis in some insects and vertebrates. However, neuronal function of these genes is yet to be established in D. melanogaster. Objective: Possible role of miR-1000 and miR-375 in learning and memory formation in this fly has been explored in the present study. Methods: Both appetitive and aversive olfactory conditional learning were tested in the miR-1000 and miR-375 knockout (KO) strains and compared with wild one. Five days old third instar larvae were trained by allowing them to be associated with an odor with reward (fructose) or punishment (salt). Then, the larvae were tested to calculate their preferences to the odor trained with. Learning index (LI) values and larval locomotion speed were calculated for all strains. Results: No significant difference was observed for larval locomotion speed in mutant strains. Knockout strain of miR-1000 showed significant deficiency in both appetitive and aversive memory formation whereas miR-375 KO strain showed a significantly lower response only in appetitive one. Conclusion: The results of the present study indicate important role played by these two genes in forming short-term memory in D. melanogaster.

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Optimizing Subjective Cognitive Decline to Detect Early Cognitive Dysfunction

Journal of Alzheimer s Disease ◽

10.3233/jad-201322 ◽

2021 ◽

Vol 80 (3) ◽

pp. 1185-1196

Author(s):

Silvia Chapman ◽

Preeti Sunderaraman ◽

Jillian L. Joyce ◽

Martina Azar ◽

Leigh E. Colvin ◽

...

Keyword(s):

Cognitive Decline ◽

Cognitive Dysfunction ◽

Associative Memory ◽

Short Term Memory ◽

Subjective Cognitive Decline ◽

Short Term ◽

Term Memory ◽

Memory Binding ◽

Preclinical Ad ◽

List Learning

Background: The utility of subjective cognitive decline (SCD) as an indicator of preclinical AD is overshadowed by its inconsistent association with objective cognition. Objective: This study examines if manipulations of SCD measurement affect its association with early cognitive dysfunction characteristic of preclinical AD. Methods: Cognitively healthy older adults (n = 110) completed SCD questionnaires that elicited complaints in general, compared to 5 years ago (retrospective SCD) and compared to their peers (age-anchored SCD) in binary and Likert scales. Outcome cognitive tasks included an associative memory task (Face-Name Test), a visual short-term memory binding task (STMB test), and a clinical neuropsychological list learning test (Selective Reminder Test). Results: SCD complaints, when compared to age-matched peers (age-anchored SCD) were endorsed less frequently than complaints compared to 5 years ago (retrospective SCD) (p < 0.01). In demographically adjusted regressions, age-anchored ordinal-rated SCD was associated with short term memory binding (β= –0.22, p = 0.040, CI = –0.45, –0.01), associative memory (β= –0.26, p = 0.018, CI = –0.45, –0.06), and list learning (β= –0.31, p = 0.002, CI = –0.51, –0.12). Retrospective and general ordinal-rated SCD was associated with associative memory (β= –0.25, p = 0.012, CI = –0.44, –0.06; β= –0.29, p = 0.003, CI = –0.47, –0.10) and list learning only (β= –0.25, p = 0.014, CI = –0.45, –0.05; β= –0.28, p = 0.004, CI = –0.48, –0.09). Conclusion: Ordinal age-anchored SCD appears better suited than other SCD measurements to detect early cognitive dysfunction characteristic of preclinical AD.

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Inhibition of short-term memory formation in the chick by blockade of extracellular glutamate uptake

Neurobiology of Learning and Memory ◽

10.1016/j.nlm.2003.10.002 ◽

2004 ◽

Vol 81 (2) ◽

pp. 115-119 ◽

Cited By ~ 16

Author(s):

M.E Gibbs ◽

L Hertz ◽

K.T Ng

Keyword(s):

Short Term Memory ◽

Glutamate Uptake ◽

Memory Formation ◽

Short Term ◽

Extracellular Glutamate ◽

Term Memory

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Circadian clock protein Rev-erbα regulates neuroinflammation

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1812405116 ◽

2019 ◽

Vol 116 (11) ◽

pp. 5102-5107 ◽

Cited By ~ 36

Author(s):

Percy Griffin ◽

Julie M. Dimitry ◽

Patrick W. Sheehan ◽

Brian V. Lananna ◽

Chun Guo ◽

...

Keyword(s):

Circadian Clock ◽

Microglial Activation ◽

Time Of Day ◽

Resting State Functional Connectivity ◽

Promoter Regions ◽

Clock Component ◽

Glial Cultures ◽

Inflammatory Phenotype

Circadian dysfunction is a common attribute of many neurodegenerative diseases, most of which are associated with neuroinflammation. Circadian rhythm dysfunction has been associated with inflammation in the periphery, but the role of the core clock in neuroinflammation remains poorly understood. Here we demonstrate that Rev-erbα, a nuclear receptor and circadian clock component, is a mediator of microglial activation and neuroinflammation. We observed time-of-day oscillation in microglial immunoreactivity in the hippocampus, which was disrupted in Rev-erbα−/− mice. Rev-erbα deletion caused spontaneous microglial activation in the hippocampus and increased expression of proinflammatory transcripts, as well as secondary astrogliosis. Transcriptomic analysis of hippocampus from Rev-erbα−/− mice revealed a predominant inflammatory phenotype and suggested dysregulated NF-κB signaling. Primary Rev-erbα−/− microglia exhibited proinflammatory phenotypes and increased basal NF-κB activation. Chromatin immunoprecipitation revealed that Rev-erbα physically interacts with the promoter regions of several NF-κB–related genes in primary microglia. Loss of Rev-erbα in primary astrocytes had no effect on basal activation but did potentiate the inflammatory response to lipopolysaccharide (LPS). In vivo, Rev-erbα−/− mice exhibited enhanced hippocampal neuroinflammatory responses to peripheral LPS injection, while pharmacologic activation of Rev-erbs with the small molecule agonist SR9009 suppressed LPS-induced hippocampal neuroinflammation. Rev-erbα deletion influenced neuronal health, as conditioned media from Rev-erbα–deficient primary glial cultures exacerbated oxidative damage in cultured neurons. Rev-erbα−/− mice also exhibited significantly altered cortical resting-state functional connectivity, similar to that observed in neurodegenerative models. Our results reveal Rev-erbα as a pharmacologically accessible link between the circadian clock and neuroinflammation.

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A54 THE CIRCADIAN CLOCK INFLUENCES JAK/STAT SIGNALING AND GUT PERMEABILITY

Journal of the Canadian Association of Gastroenterology ◽

10.1093/jcag/gwab002.052 ◽

2021 ◽

Vol 4 (Supplement_1) ◽

pp. 11-12

Author(s):

K Parasram ◽

D Bachetti ◽

P Karpowicz

Keyword(s):

Circadian Clock ◽

Clock Cycle ◽

Intestinal Barrier ◽

Fruit Fly ◽

Cell Types ◽

Time Of Day ◽

Acute Injury ◽

Intestinal Barrier Function ◽

Intestinal Immunity ◽

Stat Signaling

Abstract Background The circadian clock is a 24-hour feedback loop that drives rhythms in behaviours and physiological processes. This molecular timekeeper consists of the transcription factors, Clock-Cycle, that drive expression of thousands of clock-controlled genes, with two of these, Period and Timeless, acting as negative regulators of Clock-Cycle. This fundamental mechanism was initially characterized in the fruit fly, Drosophila melanogaster (Nobel Prize in Physiology & Medicine, 2017), and is highly conserved in humans. The intestine, or midgut, of Drosophila, is also similar to the human small intestine consisting of similar cellular lineage, signaling pathways, and physiological functions. The lineage of the Drosophila intestine contains the same four cell types as humans: intestinal stem cells (ISCs), progenitors called enteroblasts, enterocytes and enteroendocrine cells. This simplified lineage as well as the genetic tools available, make Drosophila an ideal model for intestinal regeneration in health and disease. We have previously shown that the circadian clock is active in ISCs, EBs and ECs during both homeostatic and regenerating conditions. Furthermore, the circadian clock regulates the mitosis of ISCs under regenerating conditions. Aims We sought to uncover if Jak/STAT signaling, one of the key pathways involved in ISC proliferation in the Drosophila intestine, shows a circadian rhythm and if there is a time-of-day difference in the regenerative response. Methods To test whether the clock regulates Jak/STAT during acute injury, we developed an irradiation assay that does not affect survival but acutely disrupts intestinal barrier function. Results Using a dynamic reporter of Jak/STAT activity we show that Period circadian clock mutants have low Jak/STAT signaling and a leaky gut phenotype. Wildtype controls show time-dependent gut leakiness upon irradiation, which is higher and time-independent in Period mutants. The level of Jak/STAT response differs depending on the time of irradiation in the controls, but is higher at all times in the mutants. Conclusions The Jak/Stat pathway regulates intestinal immunity and epithelial cell proliferation in humans, thus playing a role in colorectal cancer and inflammatory bowel disease. Our results suggest Jak/Stat is controlled by the circadian clock, which has implications for intestinal recovery following medical treatments, including radiation therapy. Funding Agencies NRC

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Circadian Timekeeping in Anticancer Therapeutics: An Emerging Vista of Chronopharmacology Research

Current Drug Metabolism ◽

10.2174/1389200222666211119103422 ◽

2021 ◽

Vol 22 ◽

Author(s):

Alekhya Puppala ◽

Sourbh Rankawat ◽

Sandipan Ray

Keyword(s):

Drug Metabolism ◽

Circadian Clock ◽

Cancer Cells ◽

Anticancer Drugs ◽

Cancer Biology ◽

Anticancer Therapy ◽

Time Of Day ◽

Circadian Regulation ◽

Cancer Management ◽

Anticancer Therapeutics

Background: Intrinsic rhythms in host and cancer cells play an imperative role in tumorigenesis and anticancer therapy. Circadian medicine in cancer is principally reliant on the control of growth and development of cancer cells or tissues by targeting the molecular clock and implementing time-of-day-based anticancer treatments for therapeutic improvements. In recent years, based on extensive high-throughput studies, we witnessed the arrival of several drugs and drug-like compounds that can modulate circadian timekeeping for therapeutic gain in cancer management. Objective: This perspective article intends to illustrate the current trends in circadian medicine in cancer, focusing on clock-modulating pharmacological compounds and circadian regulation of anticancer drug metabolism and efficacy. Scope and Approach: Considering the critical roles of the circadian clock in metabolism, cell signaling, and apoptosis, chronopharmacology research is exceedingly enlightening for understanding cancer biology and improving anticancer therapeutics. In addition to reviewing the relevant literature, we investigated the rhythmic expression of molecular targets for many anticancer drugs frequently used to treat different cancer types. Key Findings and Conclusion: There are adequate empirical pieces of evidence supporting circadian regulation of drug metabolism, transport, and detoxification. Administration of anticancer drugs at specific dosing times can improve their effectiveness and reduce the toxic effects. Moreover, pharmacological modulators of the circadian clock could be used for targeted anticancer therapeutics such as boosting circadian rhythms in the host can markedly reduce the growth and viability of tumors. All in all, precision chronomedicine can offer multiple advantages over conventional anticancer therapy.

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Time-of-Day Dependent Neuronal Injury After Ischemic Stroke: Implication of Circadian Clock Transcriptional Factor Bmal1 and Survival Kinase AKT

Molecular Neurobiology ◽

10.1007/s12035-017-0524-4 ◽

2017 ◽

Vol 55 (3) ◽

pp. 2565-2576 ◽

Cited By ~ 18

Author(s):

Mustafa Caglar Beker ◽

Berrak Caglayan ◽

Esra Yalcin ◽

Ahmet Burak Caglayan ◽

Seyma Turkseven ◽

...

Keyword(s):

Ischemic Stroke ◽

Circadian Clock ◽

Neuronal Injury ◽

Time Of Day ◽

Transcriptional Factor

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Time-of-day-dependent responses of cyanobacterial cellular viability against oxidative stress

10.1101/851774 ◽

2019 ◽

Author(s):

Kenya Tanaka ◽

Ginga Shimakawa ◽

Shuji Nakanishi

Keyword(s):

Oxidative Stress ◽

Circadian Rhythms ◽

Cell Viability ◽

Circadian Clock ◽

Stress Tolerance ◽

Time Of Day ◽

Circadian Oscillation ◽

Subjective Time ◽

Rhythmic Pattern ◽

Oxidative Stress Tolerance

AbstractAs an adaptation to periodic fluctuations of environmental light, photosynthetic organisms have evolved a circadian clock. Control by the circadian clock of many cellular physiological functions, including antioxidant enzymes, metabolism and the cell cycle, has attracted attention in the context of oxidative stress tolerance. However, since each physiological function works in an integrated manner to deal with oxidative stress, whether or not cell responses to oxidative stress are under circadian control remains an open question. In fact, circadian rhythms of oxidative stress tolerance have not yet been experimentally demonstrated. In the present work, we applied an assay using methyl viologen (MV), which generates reactive oxygen species (ROS) under light irradiation, and experimentally verified the circadian rhythms of oxidative stress tolerance in photosynthetic cells of the cyanobacterium Synechococcus elongatus PCC7942, a standard model species for investigation of the circadian clock. Here, we report that ROS generated by MV treatment causes damage to stroma components and not to the photosynthetic electron transportation chain, leading to reduced cell viability. The degree of decrease in cell viability was dependent on the subjective time at which oxidative stress was applied. Thus, oxidative stress tolerance was shown to exhibit circadian rhythms. In addition, the rhythmic pattern of oxidative stress tolerance disappeared in mutant cells lacking the essential clock genes. Notably, ROS levels changed periodically, independent of the MV treatment. Thus, we demonstrate for the first time that in cyanobacterial cells, oxidative stress tolerance shows circadian oscillation.

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