38 results on '"Gerstner, Jason R."'
Search Results
2. FABP7: a glial integrator of sleep, circadian rhythms, plasticity, and metabolic function.
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Gerstner, Jason R., Flores, Carlos C., Lefton, Micah, Rogers, Brooke, and Davis, Christopher J.
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CIRCADIAN rhythms ,SLEEP interruptions ,SLOW wave sleep ,CELL physiology ,SLEEP ,SLEEP spindles ,MOLECULAR chaperones - Abstract
Sleep and circadian rhythms are observed broadly throughout animal phyla and influence neural plasticity and cognitive function. However, the few phylogenetically conserved cellular and molecular pathways that are implicated in these processes are largely focused on neuronal cells. Research on these topics has traditionally segregated sleep homeostatic behavior from circadian restactivity rhythms. Here we posit an alternative perspective, whereby mechanisms underlying the integration of sleep and circadian rhythms that affect behavioral state, plasticity, and cognition reside within glial cells. The brain-type fatty acid binding protein, FABP7, is part of a larger family of lipid chaperone proteins that regulate the subcellular trafficking of fatty acids for a wide range of cellular functions, including gene expression, growth, survival, inflammation, and metabolism. FABP7 is enriched in glial cells of the central nervous system and has been shown to be a clock-controlled gene implicated in sleep/wake regulation and cognitive processing. FABP7 is known to affect gene transcription, cellular outgrowth, and its subcellular localization in the fine perisynaptic astrocytic processes (PAPs) varies based on time-of-day. Future studies determining the effects of FABP7 on behavioral state- and circadian-dependent plasticity and cognitive processes, in addition to functional consequences on cellular and molecular mechanisms related to neural-glial interactions, lipid storage, and blood brain barrier integrity will be important for our knowledge of basic sleep function. Given the comorbidity of sleep disturbance with neurological disorders, these studies will also be important for our understanding of the etiology and pathophysiology of how these diseases affect or are affected by sleep. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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3. Dietary nutrients associated with short and long sleep duration. Data from a nationally representative sample
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Grandner, Michael A., Jackson, Nicholas, Gerstner, Jason R., and Knutson, Kristen L.
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- 2013
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4. Sleep symptoms associated with intake of specific dietary nutrients
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GRANDNER, MICHAEL A., JACKSON, NICHOLAS, GERSTNER, JASON R., and KNUTSON, KRISTEN L.
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- 2014
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5. Editorial: Sleep and circadian rhythms in plasticity and memory, volume II.
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Gerstner, Jason R., Heller, H. Craig, and Aton, Sara J.
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CIRCADIAN rhythms ,SLEEP ,HAZARDOUS wastes ,MEMORY ,CLASSICAL conditioning - Published
- 2024
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6. A Dichotomous Role for FABP7 in Sleep and Alzheimer’s Disease Pathogenesis: A Hypothesis.
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Needham, Hope, Torpey, Grace, Flores, Carlos C., Davis, Christopher J., Vanderheyden, William M., and Gerstner, Jason R.
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ALZHEIMER'S disease ,AMYOTROPHIC lateral sclerosis ,FATTY acids ,SLEEP ,PARKINSON'S disease ,CATAPLEXY - Abstract
Fatty acid binding proteins (FABPs) are a family of intracellular lipid chaperone proteins known to play critical roles in the regulation of fatty acid uptake and transport as well as gene expression. Brain-type fatty acid binding protein (FABP7) is enriched in astrocytes and has been implicated in sleep/wake regulation and neurodegenerative diseases; however, the precise mechanisms underlying the role of FABP7 in these biological processes remain unclear. FABP7 binds to both arachidonic acid (AA) and docosahexaenoic acid (DHA), resulting in discrete physiological responses. Here, we propose a dichotomous role for FABP7 in which ligand type determines the subcellular translocation of fatty acids, either promoting wakefulness aligned with Alzheimer’s pathogenesis or promoting sleep with concomitant activation of anti-inflammatory pathways and neuroprotection. We hypothesize that FABP7-mediated translocation of AA to the endoplasmic reticulum of astrocytes increases astrogliosis, impedes glutamatergic uptake, and enhances wakefulness and inflammatory pathways via COX- 2 dependent generation of pro-inflammatory prostaglandins. Conversely, we propose that FABP7-mediated translocation of DHA to the nucleus stabilizes astrocyte-neuron lactate shuttle dynamics, preserves glutamatergic uptake, and promotes sleep by activating anti-inflammatory pathways through the peroxisome proliferator-activated receptor-g transcriptional cascade. Importantly, this model generates several testable hypotheses applicable to other neurodegenerative diseases, including amyotrophic lateral sclerosis and Parkinson’s disease. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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7. The Zinc-Binding Protein Chordc1 Undergoes Complex Diurnal Changes in mRNA Expression During Mouse Brain Development
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Gerstner, Jason R. and Landry, Charles F.
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- 2007
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8. Single prolonged stress blocks sleep homeostasis and pre-trauma sleep deprivation does not exacerbate the severity of trauma-induced fear-associated memory impairments.
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Davis, Christopher J., Gerstner, Jason R., and Vanderheyden, William M.
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SLEEP deprivation , *NON-REM sleep , *POST-traumatic stress disorder , *HOMEOSTASIS , *SLEEP , *MEMORY - Abstract
Sleep is intimately linked to cognitive performance and exposure to traumatic stress that leads to post-traumatic stress disorder (PTSD) impairs both sleep and cognitive function. However, the contribution of pre-trauma sleep loss to subsequent trauma-dependent fear-associated memory impairment remains unstudied. We hypothesized that sleep deprivation (SD) prior to trauma exposure may increase the severity of a PTSD-like phenotype in rats exposed to single prolonged stress (SPS), a rodent model of PTSD. Rats were exposed to SPS alone, SD alone, or a combination of SPS+SD and measures of fear-associated memory impairments and vigilance state changes were compared to a group of control animals not exposed to SPS or SD. We found that SPS, and SPS+SD animals showed impaired fear-associated memory processing and that the addition of SD to SPS did not further exaggerate the effect of SPS alone. Additionally, the combination of SPS with SD results in a unique homeostatic sleep duration phenotype when compared to SD, SPS, or control animals. SPS exposure following SD represses homeostatic rebound and eliminates sleep-deprivation-induced increases in NREM sleep delta power. This work identifies a unique time frame where trauma exposure and sleep interact and identifies this window of time as a potential therapeutic treatment window for staving off the negative consequences of trauma exposure. [ABSTRACT FROM AUTHOR]
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- 2021
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9. The Molecular Genetic Interaction Between Circadian Rhythms and Susceptibility to Seizures and Epilepsy.
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Re, Christopher J., Batterman, Alexander I., Gerstner, Jason R., Buono, Russell J., and Ferraro, Thomas N.
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SEIZURES (Medicine) ,CIRCADIAN rhythms ,EPILEPSY ,MOLECULAR interactions ,CLOCK genes ,SLEEP spindles - Abstract
Seizure patterns observed in patients with epilepsy suggest that circadian rhythms and sleep/wake mechanisms play some role in the disease. This review addresses key topics in the relationship between circadian rhythms and seizures in epilepsy. We present basic information on circadian biology, but focus on research studying the influence of both the time of day and the sleep/wake cycle as independent but related factors on the expression of seizures in epilepsy. We review studies investigating how seizures and epilepsy disrupt expression of core clock genes, and how disruption of clock mechanisms impacts seizures and the development of epilepsy. We focus on the overlap between mechanisms of circadian-associated changes in SCN neuronal excitability and mechanisms of epileptogenesis as a means of identifying key pathways and molecules that could represent new targets or strategies for epilepsy therapy. Finally, we review the concept of chronotherapy and provide a perspective regarding its application to patients with epilepsy based on their individual characteristics (i.e., being a "morning person" or a "night owl"). We conclude that better understanding of the relationship between circadian rhythms, neuronal excitability, and seizures will allow both the identification of new therapeutic targets for treating epilepsy as well as more effective treatment regimens using currently available pharmacological and non-pharmacological strategies. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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10. Astrocyte expression of the Drosophila TNF-alpha homologue, Eiger, regulates sleep in flies.
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Vanderheyden, William M., Goodman, Alan G., Taylor, Rebecca H., Frank, Marcos G., Van Dongen, Hans P. A., and Gerstner, Jason R.
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EFFECT of sleep on cognition ,COGNITIVE ability ,TUMOR necrosis factor receptors ,ASTROCYTES ,TUMOR necrosis factors ,HOMEOSTASIS - Abstract
Sleep contributes to cognitive functioning and is sufficient to alter brain morphology and function. However, mechanisms underlying sleep regulation remain poorly understood. In mammals, tumor necrosis factor-alpha (TNFα) is known to regulate sleep, and cytokine expression may represent an evolutionarily ancient mechanism in sleep regulation. Here we show that the Drosophila TNFα homologue, Eiger, mediates sleep in flies. We show that knockdown of Eiger in astrocytes, but not in neurons, significantly reduces sleep duration, and total loss-of-function reduces the homeostatic response to sleep loss. In addition, we show that neuronal, but not astrocyte, expression of the TNFα receptor superfamily member, Wengen, is necessary for sleep deprivation-induced homeostatic response and for mediating increases in sleep in response to human TNFα. These data identify a novel astrocyte-to-neuron signaling mechanism in the regulation of sleep homeostasis and show that the Drosophila cytokine, Eiger, represents an evolutionarily conserved mechanism of sleep regulation across phylogeny. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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11. Alzheimer's Disease and Sleep--Wake Disturbances: Amyloid, Astrocytes, and Animal Models.
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Vanderheyden, William M., Gerstner, Jason R., M. Lim, Miranda, and Musiek, Erik S.
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ALZHEIMER'S disease , *SLEEP interruptions , *AMYLOID , *ASTROCYTES , *NEURODEGENERATION - Abstract
Sleep-wake abnormalities are common in patients with Alzheimer's disease, andean be a major reason for institutionalization. However, an emerging concept is that these sleep-wake disturbances are part of the causal pathway accelerating the neurodegenerative process. Recently, new findings have provided intriguing evidence for a positive feedback loop between sleep-wake dysfunction and β-amyloid (Aβ) aggregation. Studies in both humans and animal models have shown that extended periods of wakefulness increase Aβ levels and aggregation, and accumulation of Aβ causes fragmentation of sleep. This perspective is aimed at presenting evidence supporting causal links between sleep-wake dysfunction and aggregation of Aβ peptide in Alzheimer's disease, and explores the role of astrocytes, a specialized type of glial cell, in this context underlying Alzheimer's disease pathology. The utility of current animal models and the unexplored potential of alternative animal models for testing mechanisms involved in the reciprocal relationship between sleep disruption and Aβ are also discussed. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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12. Amyloid-β induces sleep fragmentation that is rescued by fatty acid binding proteins in Drosophila.
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Gerstner, Jason R., Lenz, Olivia, Vanderheyden, William M., Chan, May T., Pfeiffenberger, Cory, and Pack, Allan I.
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- 2017
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13. Removal of unwanted variation reveals novel patterns of gene expression linked to sleep homeostasis in murine cortex.
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Gerstner, Jason R., Koberstein, John N., Watson, Adam J., Zapero, Nikolai, Risso, Davide, Speed, Terence P., Frank, Marcos G., and Peixoto, Lucia
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GENE expression , *HOMEOSTASIS , *SLEEP , *BRAIN function localization , *SLEEP deprivation , *GENETIC regulation - Abstract
Background: Why we sleep is still one of the most perplexing mysteries in biology. Strong evidence indicates that sleep is necessary for normal brain function and that sleep need is a tightly regulated process. Surprisingly, molecular mechanisms that determine sleep need are incompletely described. Moreover, very little is known about transcriptional changes that specifically accompany the accumulation and discharge of sleep need. Several studies have characterized differential gene expression changes following sleep deprivation. Much less is known, however, about changes in gene expression during the compensatory response to sleep deprivation (i.e. recovery sleep). Results: In this study we present a comprehensive analysis of the effects of sleep deprivation and subsequent recovery sleep on gene expression in the mouse cortex. We used a non-traditional analytical method for normalization of genome-wide gene expression data, Removal of Unwanted Variation (RUV). RUV improves detection of differential gene expression following sleep deprivation. We also show that RUV normalization is crucial to the discovery of differentially expressed genes associated with recovery sleep. Our analysis indicates that the majority of transcripts upregulated by sleep deprivation require 6 h of recovery sleep to return to baseline levels, while the majority of downregulated transcripts return to baseline levels within 1-3 h. We also find that transcripts that change rapidly during recovery (i.e. within 3 h) do so on average with a time constant that is similar to the time constant for the discharge of sleep need. Conclusions: We demonstrate that proper data normalization is essential to identify changes in gene expression that are specifically linked to sleep deprivation and recovery sleep. Our results provide the first evidence that recovery sleep is comprised of two waves of transcriptional regulation that occur at different times and affect functionally distinct classes of genes. [ABSTRACT FROM AUTHOR]
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- 2016
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14. The sleep-wake cycle and Alzheimer's disease: what do we know?
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Lim, Miranda M, Gerstner, Jason R, and Holtzman, David M
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- 2014
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15. BMAL1 controls the diurnal rhythm and set point for electrical seizure threshold in mice.
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Gerstner, Jason R., Smith, George G., Lenz, Olivia, Perron, Isaac J., Buono, Russell J., and Ferraro, Thomas N.
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SPASMS ,LABORATORY mice ,HUMAN genes ,TRANSCRIPTION factors ,CIRCADIAN rhythms ,EPILEPSY ,EYE movements - Abstract
The epilepsies are a heterogeneous group of neurological diseases defined by the occurrence of unprovoked seizures which, in many cases, are correlated with diurnal rhythms. In order to gain insight into the biological mechanisms controlling this phenomenon, we characterized time-of-day effects on electrical seizure threshold in mice. Male C57BL/6J wild-type mice were maintained on a 14/10 h light/dark cycle, from birth until 6 weeks of age for seizure testing. Seizure thresholds were measured using a step-wise paradigm involving a single daily electrical stimulus. Results showed that the current required to elicit both generalized and maximal seizures was significantly higher in mice tested during the dark phase of the diurnal cycle compared to mice tested during the light phase. This rhythm was absent in BMAL1 knockout (KO) mice. BMAL1 KO also exhibited significantly reduced seizure thresholds at all times tested, compared to C57BL/6J mice. Results document a significant influence of time-of-day on electrical seizure threshold in mice and suggest that this effect is under the control of genes that are known to regulate circadian behaviors. Furthermore, low seizure thresholds in BMAL1 KO mice suggest that BMAL1 itself is directly involved in controlling neuronal excitability. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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16. dCREB2-Mediated Enhancement of Memory Formation.
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Tubon Jr., Thomas C., Jiabin Zhang, Friedman, Eugenia L., Haining Jin, Gonzales, Erin D., Hong Zhou, Drier, Diana, Gerstner, Jason R., Paulson, Emily A., Fropf, Robin, and Yin, Jerry C. P.
- Subjects
CREB protein ,GENETIC transcription ,LONG-term memory ,DROSOPHILA as laboratory animals ,GENETIC translation ,BEHAVIORAL assessment - Abstract
CREB-responsive transcription has an important role in adaptive responses in all cells and tissue. In the nervous system, it has an essential and well established role in long-term memory formation throughout a diverse set of organisms. Activation of this transcription factor correlates with long-term memory formation and disruption of its activity interferes with this process. Most convincingly, aug-menting CREB activity in a number of different systems enhances memory formation. In Drosophila, a sequence rearrangement in the original transgene used to enhance memory formation has been a source of confusion. This rearrangement prematurely terminates translation of the full-length protein, leaving the identity of the "enhancing molecule" unclear. In this report, we show that a naturally occurring, downstream, in-frame initiation codon is used to make a dCREB2 protein off of both transgenic and chromosomal substrates. This protein is a transcriptional activator and is responsible for memory enhancement. A number of parameters can affect enhancement, including the short-lived activity of the activator protein, and the time-of-day when induction and behavioral training occur. Our results reaffirm that overexpression of a dCREB2 activator can enhance memory formation and illustrate the complexity of this behavioral enhancement. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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17. Time of Day Regulates Subcellular Trafficking, Tripartite Synaptic Localization, and Polyadenylation of the Astrocytic Fabp7 mRNA.
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Gerstner, Jason R., Vanderheyden, William M., LaVaute, Timothy, Westmark, Cara J., Rouhana, Labib, Pack, Allan I., Wickens, Marv, and Landry, Charles F.
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MESSENGER RNA , *ADENYLATION (Biochemistry) , *FATTY acid-binding proteins , *BRAIN physiology , *ASTROCYTES , *GENE expression , *LABORATORY mice - Abstract
The astrocyte brain fatty acid binding protein (Fabp7) has previously been shown to have a coordinated diurnal regulation ofmRNAand protein throughout mouse brain, and an age-dependent decline in protein expression within synaptoneurosomal fractions. Mechanisms that control time-of-day changes in expression and trafficking Fabp7 to the perisynaptic process are not known. In this study, we confirmed an enrichment of Fabp7mRNAand protein in the astrocytic perisynaptic compartment, and observed a diurnal change in the intracellular distribution of Fabp7 mRNA in molecular layers of hippocampus. Northern blotting revealed a coordinated time-of-daydependent oscillation for the Fabp7mRNApoly(A) tail throughout murine brain. Cytoplasmic polyadenylation element-binding protein 1 (CPEB1) regulates subcellular trafficking and translation of synaptic plasticity-related mRNAs. Here we show that Fabp7 mRNA coimmunoprecipitated with CPEB1 from primary mouse astrocyte extracts, and its 3'UTRcontains phylogenetically conserved cytoplasmic polyadenylation elements (CPEs) capable of regulating translation of reportermRNAsduring Xenopus oocyte maturation. Given that Fabp7 expression is confined to astrocytes and neural progenitors in adult mouse brain, the synchronized cycling pattern of Fabp7mRNA is a novel discovery among known CPE-regulated transcripts. These results implicate circadian, sleep, and/or metabolic control of CPEB-mediated subcellular trafficking and localized translation of Fabp7 mRNA in the tripartite synapse of mammalian brain. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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18. Cytoplasmic to nuclear localization of fatty-acid binding protein correlates with specific forms of long-term memory in Drosophila.
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Gerstner, Jason R., Vanderheyden, William M., Shaw, Paul J., Landry, Charles F., and Yin, Jerry C.P.
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- 2011
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19. Fatty-Acid Binding Proteins Modulate Sleep and Enhance Long-Term Memory Consolidation in Drosophila.
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Gerstner, Jason R., Vanderheyden, William M., Shaw, Paul J., Landry, Charles F., and Yin, Jerry C. P.
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MEMORY , *CARRIER proteins , *SLEEP deprivation , *FATTY acids , *CARBOXYLIC acids , *DROSOPHILA melanogaster , *PHARMACOLOGY , *HUMAN behavior , *DRUG therapy - Abstract
Sleep is thought to be important for memory consolidation, since sleep deprivation has been shown to interfere with memory processing. However, the effects of augmenting sleep on memory formation are not well known, and testing the role of sleep in memory enhancement has been limited to pharmacological and behavioral approaches. Here we test the effect of overexpressing the brain-type fatty acid binding protein (Fabp7) on sleep and long-term memory (LTM) formation in Drosophila melanogaster. Transgenic flies carrying the murine Fabp7 or the Drosophila homologue dFabp had reduced baseline sleep but normal LTM, while Fabp induction produced increases in both net sleep and LTM. We also define a posttraining consolidation "window" that is sufficient for the observed Fabp-mediated memory enhancement. Since Fabp overexpression increases consolidated daytime sleep bouts, these data support a role for longer naps in improving memory and provide a novel role for lipid-binding proteins in regulating memory consolidation concurrently with changes in behavioral state. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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20. Circadian rhythms and memory formation.
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Gerstner, Jason R. and Yin, Jerry C. P.
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LONG-term memory , *NEUROPHYSIOLOGY , *VERTEBRATES , *MEMORY , *INVERTEBRATES as laboratory animals , *INVERTEBRATES , *ANIMALS , *CIRCADIAN rhythms , *COMPUTER simulation , *NEUROPLASTICITY , *RESEARCH funding - Abstract
There has been considerable progress in elucidating the molecular mechanisms that contribute to memory formation and the generation of circadian rhythms. However, it is not well understood how these two processes interact to generate long-term memory. Recent studies in both vertebrate and invertebrate models have shown time-of-day effects on neurophysiology and memory formation, and have revealed a possible role for cycling molecules in memory persistence. Together, these studies suggest that common mechanisms underlie circadian rhythmicity and long-term memory formation. [ABSTRACT FROM AUTHOR]
- Published
- 2010
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21. Cycling Behavior and Memory Formation.
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Gerstner, Jason R., Lyons, Lisa C., Wright Jr., Kenneth P., Loh, Dawn H., Rawashdeh, Oliver, Eckel-Mahan, Kristin L., and Roman, Gregg W.
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BEHAVIOR , *MEMORY , *NEUROSCIENCE conferences , *HOMEOSTASIS - Abstract
Circadian research has spent considerable effort in the determining clock output pathways, including identifying both physiological and behavioral processes that demonstrate significant time-of-day variation. Memory formation and consolidation represent notable processes shaped by endogenous circadian oscillators. To date, very few studies on memory mechanisms have considered potential confounding effects of time-of-day and the organism's innate activity cycles (e.g., nocturnal, diurnal, or crepuscular). The following studies highlight recent work describing this interactive role of circadian rhythms and memory formation, and were presented at a mini-symposium at the 2009 annual meeting of the Society for Neuroscience. The studies illustrate these time-of-day observations in a variety of behavioral paradigms and model organisms, including olfactory avoidance conditioning in Drosophila, long-term sensitization in Aplysia, active-avoidance conditioning in Zebrafish, and classical fear conditioning in rodents, suggesting that the circadian influence on memory behavior is highly conserved across species. Evidence also exists for a conserved mechanistic relationship between specific cycling molecules and memory formation, and the extent to which proper circadian cycling of these molecules is necessary for optimal cognitive performance. Studies describe the involvement of the core clock gene period, as well as vasoactive intestinal peptide, melatonin, and the cAMP/MAPK (cAMP/mitogen-activated protein kinase) cascade. Finally, studies in humans describe evidence for alterations in cognitive performance based on an interaction between sleep-wake homeostasis and the internal circadian clock. Conservation of a functional relationship between circadian rhythms with learning and memory formation across species provides a critical framework for future analysis of molecular mechanisms underlying complex behavior. [ABSTRACT FROM AUTHOR]
- Published
- 2009
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22. Regulation of Neural Specification from Human Embryonic Stem Cells by BMP and FGF.
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Lavaute, Timothy M., Young Dong Yoo, Pankratz, Matthew T., Weick, Jason P., Gerstner, Jason R., and Su-Chun Zhang
- Subjects
EMBRYONIC stem cells ,BONE morphogenetic proteins ,FIBROBLAST growth factors ,PHOSPHORYLATION ,FUNCTIONAL analysis - Abstract
Inhibition of bone morphogenetic protein (BMP) signaling is required for vertebrate neural induction, and fibroblast growth factors (FGFs) may affect neural induction through phosphorylation at the linker region of Smad1, thus regulating BMP signaling. Here we show that human embryonic stem cells efficiently convert to neuroepithelial cells in the absence of BMP antagonists, or even when exposed to high concentrations of exogenous BMP4. Molecular and functional analyses revealed multiple levels of endogenous BMP signaling inhibition that may account for the efficient neural differentiation. Blocking FGF signaling inhibited neural induction, but did not alter the phosphorylation of the linker region of Smad1, suggesting that FGF enhances human neural specification independently of BMP signaling. [ABSTRACT FROM AUTHOR]
- Published
- 2009
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23. Glitazone Treatment Rescues Phenotypic Deficits in a Fly Model of Gaucher/Parkinson's Disease.
- Author
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Shola-Dare, Oluwanifemi, Bailess, Shelby, Flores, Carlos C., Vanderheyden, William M., and Gerstner, Jason R.
- Subjects
PHENOTYPES ,THERAPEUTICS ,GAUCHER'S disease ,PARKINSON'S disease ,TYPE 2 diabetes ,LYSOSOMES ,1-Methylcyclopropene - Abstract
Parkinson's Disease (PD) is the most common movement disorder, and the strongest genetic risk factor for PD is mutations in the glucocerebrosidase gene (GBA). Mutations in GBA also lead to the development of Gaucher Disease (GD), the most common type of lysosomal storage disorder. Current therapeutic approaches fail to address neurological GD symptoms. Therefore, identifying therapeutic strategies that improve the phenotypic traits associated with GD/PD in animal models may provide an opportunity for treating neurological manifestations of GD/PD. Thiazolidinediones (TZDs, also called glitazones) are a class of compounds targeted for the treatment of type 2 diabetes, and have also shown promise for the treatment of neurodegenerative disease, including PD. Here, we tested the efficacy of glitazone administration during development in a fly GD model with deletions in the GBA homolog, dGBA1b (GBA1
ΔTT/ΔTT ). We observed an optimal dose of pioglitazone (PGZ) at a concentration of 1 μM that reduced sleep deficits, locomotor impairments, climbing defects, and restoration of normal protein levels of Ref(2)P, a marker of autophagic flux, in GBA1ΔTT/ΔTT mutant flies, compared to GBA1+/+ control flies. These data suggest that PGZ may represent a potential compound with which to treat GD/PD by improving function of lysosomal-autophagy pathways, a cellular process that removes misfolded or aggregated proteins. [ABSTRACT FROM AUTHOR]- Published
- 2021
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24. Brain Fatty Acid Binding Protein (Fabp7) Is Diurnally Regulated in Astrocytes and Hippocampal Granule Cell Precursors in Adult Rodent Brain.
- Author
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Gerstner, Jason R., Bremer, Quentin Z., Vander Heyden, William M., LaVaute, Timothy M., Yin, Jerry C., and Landry, Charles F.
- Subjects
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DIETARY fats , *BRAIN research , *HIPPOCAMPUS (Brain) , *NERVOUS system development , *MESSENGER RNA , *RNA , *IMMUNOBLOTTING , *IN situ hybridization , *NEUROSCIENCES - Abstract
Brain fatty acid binding protein (Fabp7), which is important in early nervous system development, is expressed in astrocytes and neuronal cell precursors in mature brain. We report here that levels of Fabp7 mRNA in adult murine brain change over a 24 hour period. Unlike Fabp5, a fatty acid binding protein that is expressed widely in various cell types within brain, RNA analysis revealed that Fabp7 mRNA levels were elevated during the light period and lower during dark in brain regions involved in sleep and activity mechanisms. This pattern of Fabp7 mRNA expression was confirmed using in situ hybridization and found to occur throughout the entire brain. Changes in the intracellular distribution of Fabp7 mRNA were also evident over a 24 hour period. Diurnal changes in Fabp7, however, were not found in postnatal day 6 brain, when astrocytes are not yet mature. In contrast, granule cell precursors of the subgranular zone of adult hippocampus did undergo diurnal changes in Fabp7 expression. These changes paralleled oscillations in Fabp7 mRNA throughout the brain suggesting that cell-coordinated signals likely control brain-wide Fabp7 mRNA expression. Immunoblots revealed that Fabp7 protein levels also underwent diurnal changes in abundance, with peak levels occurring in the dark period. Of clock or clock-regulated genes, the synchronized, global cycling pattern of Fabp7 expression is unique and implicates glial cells in the response or modulation of activity and/or circadian rhythms. [ABSTRACT FROM AUTHOR]
- Published
- 2008
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25. Expression of the Transcriptional Coactivator CITED1 in the Adult and Developing Murine Brain.
- Author
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Gerstner, Jason R. and Landry, Charles F.
- Abstract
The transcription coactivator CITED1 is an important mediator of transcriptional events regulated by estrogen or TGF-β. We used in situ hybridization to delineate the distribution of CITED1 mRNA in the adult and developing murine brain and found robust CITED1 expression in ventral hypothalamus and midbrain raphe. The distribution of CITED1 in these regions overlapped the reported expression of estrogen receptors α and β. Less intense expression of CITED1 was also evident in medial preoptic area, subfornical organ, thalamus and cerebral cortex. CITED1 mRNA in the arcuate nucleus (an area of active transcriptional modulation by TGF-β) was evident in postmigratory neurons as early as embryonic day 16. Expression of CITED1 in arcuate continued throughout postnatal development. CITED1 in developing cerebellum was first evident in external granule cells and was transiently expressed in the Purkinje cell/granule cell layer in a temporal pattern similar to estrogen receptor-β. The spatial and temporal distribution of CITED1 mRNA reported here is consistent with a role for CITED1 in the modulation of transcriptional events mediated by steroid hormone and cytokine signaling pathways. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]
- Published
- 2007
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26. The Nexus of Aβ, Aging, and Sleep.
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Gerstner, Jason R., Perron, Isaac J., and Pack, Allan I.
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- 2012
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27. Waking up to the alarm: sleep, clocks, and making memory (s)tick.
- Author
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Gerstner, Jason R., Aton, Sara J., and Heller, H. Craig
- Subjects
SOMNOLOGY ,MEMORY ,NITRIC oxide ,MANDUCA ,HIPPOCAMPUS (Brain) - Abstract
The article taillights research papers on the influence of sleep and circadian rhythms on brain plasticity-related processes. The topics covered include the importance of using invertebrate model systems for examining relationships between sleep, clocks and memory, evidence for nitric oxide in the diurnal regulation of olfactory memory in the hawkmoth, Manduca sexta, and sleep-and wake-associated changes in CA1 hippocampal network activity during memory consolidation.
- Published
- 2015
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28. ERK Phosphorylation Regulates Sleep and Plasticity in Drosophila.
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Vanderheyden, William M., Gerstner, Jason R., Tanenhaus, Anne, Yin, Jerry C., and Shaw, Paul J.
- Subjects
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EXTRACELLULAR signal-regulated kinases , *SLEEP deprivation , *DROSOPHILA , *MATERIAL plasticity , *MITOGEN-activated protein kinases , *PHOSPHORYLATION , *TRANSGENIC insects , *FLIES - Abstract
Given the relationship between sleep and plasticity, we examined the role of Extracellular signal-regulated kinase (ERK) in regulating baseline sleep, and modulating the response to waking experience. Both sleep deprivation and social enrichment increase ERK phosphorylation in wild-type flies. The effects of both sleep deprivation and social enrichment on structural plasticity in the LNvs can be recapitulated by expressing an active version of ERK (UAS-ERKSEM) pan-neuronally in the adult fly using GeneSwitch (Gsw) Gsw-elav-GAL4. Conversely, disrupting ERK reduces sleep and prevents both the behavioral and structural plasticity normally induced by social enrichment. Finally, using transgenic flies carrying a cAMP response Element (CRE)-luciferase reporter we show that activating ERK enhances CRE-Luc activity while disrupting ERK reduces it. These data suggest that ERK phosphorylation is an important mediator in transducing waking experience into sleep. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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29. ERK Phosphorylation Regulates Sleep and Plasticity in Drosophila.
- Author
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Vanderheyden, William M., Gerstner, Jason R., Tanenhaus, Anne, Yin, Jerry C., and Shaw, Paul J.
- Subjects
EXTRACELLULAR signal-regulated kinases ,SLEEP deprivation ,DROSOPHILA ,MATERIAL plasticity ,MITOGEN-activated protein kinases ,PHOSPHORYLATION ,TRANSGENIC insects ,FLIES - Abstract
Given the relationship between sleep and plasticity, we examined the role of Extracellular signal-regulated kinase (ERK) in regulating baseline sleep, and modulating the response to waking experience. Both sleep deprivation and social enrichment increase ERK phosphorylation in wild-type flies. The effects of both sleep deprivation and social enrichment on structural plasticity in the LNvs can be recapitulated by expressing an active version of ERK (UAS-ERK
SEM ) pan-neuronally in the adult fly using GeneSwitch (Gsw) Gsw-elav-GAL4. Conversely, disrupting ERK reduces sleep and prevents both the behavioral and structural plasticity normally induced by social enrichment. Finally, using transgenic flies carrying a cAMP response Element (CRE)-luciferase reporter we show that activating ERK enhances CRE-Luc activity while disrupting ERK reduces it. These data suggest that ERK phosphorylation is an important mediator in transducing waking experience into sleep. [ABSTRACT FROM AUTHOR]- Published
- 2013
- Full Text
- View/download PDF
30. Sleep and diurnal alternative polyadenylation sites associated with human APA-linked brain disorders.
- Author
-
Flores CC, Pasetto NA, Wang H, Dimitrov AG, Davis JF, Jiang Z, Davis CJ, and Gerstner JR
- Abstract
Disruption of sleep and circadian rhythms are a comorbid feature of many pathologies, and can negatively influence many health conditions, including neurodegenerative disease, metabolic illness, cancer, and various neurological disorders. Genetic association studies linking sleep and circadian disturbances with disease susceptibility have mainly focused on changes in gene expression due to mutations, such as single-nucleotide polymorphisms. The interaction between sleep and/or circadian rhythms with the use of Alternative Polyadenylation (APA) has been largely undescribed, particularly in the context of other disorders. APA is a process that generates various transcript isoforms of the same gene affecting its mRNA translation, stability, localization, and subsequent function. Here we identified unique APAs expressed in rat brain over time-of-day, immediately following sleep deprivation, and the subsequent recovery period. From these data, we performed a secondary analysis of these sleep- or time-of-day associated PASs with recently described APA-linked human brain disorder susceptibility genes.
- Published
- 2024
- Full Text
- View/download PDF
31. Identification of sleep and circadian alternative polyadenylation sites associated with APA-linked human brain disorders.
- Author
-
Flores CC, Pasetto NA, Wang H, Dimitrov A, Davis JF, Jiang Z, Davis CJ, and Gerstner JR
- Abstract
Sleep and circadian rhythm disruptions are comorbid features of many pathologies and can negatively influence numerous health conditions, including degenerative diseases, metabolic illnesses, cancer, and various neurological disorders. Genetic association studies linking sleep and circadian disturbances with disease susceptibility have mainly focused on changes in gene expression due to mutations, such as single-nucleotide polymorphisms. Thus, associations between sleep and/or circadian rhythm and alternative polyadenylation (APA), particularly in the context of other health challenges, are largely undescribed. APA is a process that generates various transcript isoforms from the same gene, resulting in effects on mRNA translation, stability, localization, and subsequent function. Here, we have identified unique APAs in rat brain that exhibit time-of-day-dependent oscillations in expression as well as APAs that are altered by sleep deprivation and the subsequent recovery period. Genes affected by APA usage include Mapt/Tau, Ntrk2, Homer1A, Sin3b and Sorl . Sorl1 has two APAs which cycle with a 24 h period, one additional APA cycles with a 12 h period and one more that is reduced during recovery sleep. Finally, we compared sleep- or circadian-associated APAs with recently described APA-linked brain disorder susceptibility genes and found 46 genes in common., Competing Interests: Competing interests J.G. is the founder of Blood Brain Biotechnology, LLC. All other authors declare no competing interests.
- Published
- 2024
- Full Text
- View/download PDF
32. Fabp7 Is Required for Normal Sleep Suppression and Anxiety-Associated Phenotype following Single-Prolonged Stress in Mice.
- Author
-
Vanderheyden WM, Lefton M, Flores CC, Owada Y, and Gerstner JR
- Abstract
Humans with post-traumatic stress disorder (PTSD) exhibit sleep disturbances that include insomnia, nightmares, and enhanced daytime sleepiness. Sleep disturbances are considered a hallmark feature of PTSD; however, little is known about the cellular and molecular mechanisms regulating trauma-induced sleep disorders. Using a rodent model of PTSD called "Single Prolonged Stress" (SPS) we examined the requirement of the brain-type fatty acid binding protein Fabp7, an astrocyte expressed lipid-signaling molecule, in mediating trauma-induced sleep disturbances. We measured baseline sleep/wake parameters and then exposed Fabp7 knock-out (KO) and wild-type (WT) C57BL/6N genetic background control animals to SPS. Sleep and wake measurements were obtained immediately following the initial trauma exposure of SPS, and again 7 days later. We found that active-phase (dark period) wakefulness was similar in KO and WT at baseline and immediately following SPS; however, it was significantly increased after 7 days. These effects were opposite in the inactive-phase (light period), where KOs exhibited increased wake in baseline and following SPS, but returned to WT levels after 7 days. To examine the effects of Fabp7 on unconditioned anxiety following trauma, we exposed KO and WT mice to the light-dark box test before and after SPS. Prior to SPS, KO and WT mice spent similar amounts of time in the lit compartment. Following SPS, KO mice spent significantly more time in the lit compartment compared to WT mice. These results demonstrate that mutations in an astrocyte-expressed gene ( Fabp7 ) influence changes in stress-dependent sleep disturbances and associated anxiety behavior., Competing Interests: Conflicts of Interest: The authors declare no conflict of interest.
- Published
- 2022
- Full Text
- View/download PDF
33. The transcriptional repressor Rev-erbα regulates circadian expression of the astrocyte Fabp7 mRNA.
- Author
-
Vanderheyden WM, Fang B, Flores CC, Jager J, and Gerstner JR
- Abstract
The astrocyte brain-type fatty-acid binding protein (Fabp7) circadian gene expression is synchronized in the same temporal phase throughout mammalian brain. Cellular and molecular mechanisms that contribute to this coordinated expression are not completely understood, but likely involve the nuclear receptor Rev-erbα (NR1D1), a transcriptional repressor. We performed ChIP-seq on ventral tegmental area (VTA) and identified gene targets of Rev-erbα, including Fabp7 . We confirmed that Rev-erbα binds to the Fabp7 promoter in multiple brain areas, including hippocampus, hypothalamus, and VTA, and showed that Fabp7 gene expression is upregulated in Rev-erbα knock-out mice. Compared to Fabp7 mRNA levels, Fabp3 and Fabp5 mRNA were unaffected by Rev-erbα depletion in hippocampus, suggesting that these effects are specific to Fabp7 . To determine whether these effects of Rev-erbα depletion occur broadly throughout the brain, we also evaluated Fabp mRNA expression levels in multiple brain areas, including cerebellum, cortex, hypothalamus, striatum, and VTA in Rev-erbα knock-out mice. While small but significant changes in Fabp5 mRNA expression exist in some of these areas, the magnitude of these effects are minimal to that of Fabp7 mRNA expression, which was over 6-fold across all brain regions. These studies suggest that Rev-erbα is a transcriptional repressor of Fabp7 gene expression throughout mammalian brain.
- Published
- 2021
- Full Text
- View/download PDF
34. Sleep pressure regulates mushroom body neural-glial interactions in Drosophila.
- Author
-
Vanderheyden WM, Van Dongen HPA, Frank MG, and Gerstner JR
- Abstract
Sleep is a behavior that exists broadly across animal phyla, from flies to humans, and is necessary for normal brain function. Recent studies in both vertebrates and invertebrates have suggested a role for glial cells in sleep regulatory processes. Changes in neural-glial interactions have been shown to be critical for synaptic plasticity and circuit function. Here, we wanted to test the hypothesis that changes in sleep pressure alters neural-glial interactions. In the fruit fly, Drosophila melanogaster , sleep is known to be regulated by mushroom body (MB) circuits. We used the technique GFP Reconstitution Across Synaptic Partners (GRASP) to test whether changes in sleep pressure affect neural-glial interactions between MB neurons and astrocytes, a specialized glial cell type known to regulate sleep in flies and mammals. The MB-astrocyte GRASP signal was reduced after 24 h of sleep deprivation, whereas the signal returned to baseline levels following 72 h of recovery. Social enrichment, which increases sleep drive, similarly reduced the MB-astrocyte GRASP signal. We did not observe any changes in the MB-astrocyte GRASP signal over time-of-day, or following paraquat exposure or starvation. These data suggest that changes in sleep pressure are linked to dynamic changes in neural-glial interactions between astrocytes and neuronal sleep circuits, which are not caused by normal rest-activity cycles or stressors.
- Published
- 2019
- Full Text
- View/download PDF
35. Normal sleep requires the astrocyte brain-type fatty acid binding protein FABP7.
- Author
-
Gerstner JR, Perron IJ, Riedy SM, Yoshikawa T, Kadotani H, Owada Y, Van Dongen HPA, Galante RJ, Dickinson K, Yin JCP, Pack AI, and Frank MG
- Subjects
- Animals, Astrocytes cytology, Biological Clocks physiology, Brain cytology, Drosophila melanogaster, Fatty Acid-Binding Protein 7 genetics, Female, Humans, Male, Mice, Mice, Knockout, Mutation, Missense, Tumor Suppressor Proteins genetics, Astrocytes metabolism, Brain metabolism, Fatty Acid-Binding Protein 7 biosynthesis, Signal Transduction physiology, Sleep physiology, Tumor Suppressor Proteins biosynthesis
- Abstract
Sleep is found widely in the animal kingdom. Despite this, few conserved molecular pathways that govern sleep across phyla have been described. The mammalian brain-type fatty acid binding protein (Fabp7) is expressed in astrocytes, and its mRNA oscillates in tandem with the sleep-wake cycle. However, the role of FABP7 in regulating sleep remains poorly understood. We found that the missense mutation FABP7.T61M is associated with fragmented sleep in humans. This phenotype was recapitulated in mice and fruitflies bearing similar mutations: Fabp7 -deficient mice and transgenic flies that express the FABP7.T61M missense mutation in astrocytes also show fragmented sleep. These results provide novel evidence for a distinct molecular pathway linking lipid-signaling cascades within astrocytes in sleep regulation among phylogenetically disparate species.
- Published
- 2017
- Full Text
- View/download PDF
36. ERK phosphorylation regulates sleep and plasticity in Drosophila.
- Author
-
Vanderheyden WM, Gerstner JR, Tanenhaus A, Yin JC, and Shaw PJ
- Subjects
- Animals, Animals, Genetically Modified, Drosophila metabolism, Drosophila Proteins genetics, Drosophila Proteins metabolism, Extracellular Signal-Regulated MAP Kinases genetics, Phosphorylation, Sleep physiology, Drosophila enzymology, Drosophila physiology, Extracellular Signal-Regulated MAP Kinases metabolism
- Abstract
Given the relationship between sleep and plasticity, we examined the role of Extracellular signal-regulated kinase (ERK) in regulating baseline sleep, and modulating the response to waking experience. Both sleep deprivation and social enrichment increase ERK phosphorylation in wild-type flies. The effects of both sleep deprivation and social enrichment on structural plasticity in the LNvs can be recapitulated by expressing an active version of ERK (UAS-ERK(SEM)) pan-neuronally in the adult fly using GeneSwitch (Gsw) Gsw-elav-GAL4. Conversely, disrupting ERK reduces sleep and prevents both the behavioral and structural plasticity normally induced by social enrichment. Finally, using transgenic flies carrying a cAMP response Element (CRE)-luciferase reporter we show that activating ERK enhances CRE-Luc activity while disrupting ERK reduces it. These data suggest that ERK phosphorylation is an important mediator in transducing waking experience into sleep.
- Published
- 2013
- Full Text
- View/download PDF
37. On the evolution of memory: a time for clocks.
- Author
-
Gerstner JR
- Abstract
Evolutionarily, what was the earliest engram? Biology has evolved to encode representations of past events, and in neuroscience, we are attempting to link experience-dependent changes in molecular signaling with cellular processes that ultimately lead to behavioral output. The theory of evolution has guided biological research for decades, and since phylogenetically conserved mechanisms drive circadian rhythms, these processes may serve as common predecessors underlying more complex behavioral phenotypes. For example, the cAMP/MAPK/CREB cascade is interwoven with the clock to trigger circadian output, and is also known to affect memory formation. Time-of-day dependent changes have been observed in long-term potentiation (LTP) within the suprachiasmatic nucleus and hippocampus, along with light-induced circadian phase resetting and fear conditioning behaviors. Together this suggests during evolution, similar processes underlying metaplasticity in more simple circuits may have been redeployed in higher-order brain regions. Therefore, this notion predicts a model that LTP and metaplasticity may exist in neural circuits of other species, through phylogenetically conserved pathways, leading to several testable hypotheses.
- Published
- 2012
- Full Text
- View/download PDF
38. The aging clock: to 'BMAL'icious toward learning and memory.
- Author
-
Gerstner JR
- Subjects
- ARNTL Transcription Factors metabolism, Aging physiology, Animals, Exploratory Behavior physiology, Habituation, Psychophysiologic genetics, Mice, Mice, Knockout, ARNTL Transcription Factors genetics, Memory physiology
- Published
- 2010
- Full Text
- View/download PDF
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