Abstract
Background
Substance use disorders are associated with disruptions in circadian rhythms. Both
human and animal work have shown the integral role for circadian clocks in the modulation
of reward behaviors. Astrocytes have emerged as key regulators of circadian rhythmicity.
However, no studies to date have identified the role of circadian astrocyte function
in the nucleus accumbens (NAc), a hub for reward regulation, or determined the importance
of these rhythms for reward-related behavior.
Methods
Using astrocyte-specific RNA sequencing across time of day, we first characterized
diurnal variation of the NAc astrocyte transcriptome. We then investigated the functional
significance of this circadian regulation through viral-mediated disruption of molecular
clock function in NAc astrocytes, followed by assessment of reward-related behaviors,
metabolic-related molecular assays, and whole-cell electrophysiology in the NAc.
Results
Strikingly, approximately 43% of the astrocyte transcriptome has a diurnal rhythm,
and key metabolic pathways were enriched among the top rhythmic genes. Moreover, mice
with a viral-mediated loss of molecular clock function in NAc astrocytes show a significant
increase in locomotor response to novelty, exploratory drive, operant food self-administration,
and motivation. At the molecular level, these animals also show disrupted metabolic
gene expression, along with significant downregulation of both lactate and glutathione
levels in the NAc. Loss of NAc astrocyte clock function also significantly altered
glutamatergic signaling onto neighboring medium spiny neurons, alongside upregulated
glutamate-related gene expression.
Conclusions
Taken together, these findings demonstrate a novel role for astrocyte circadian molecular
clock function in the regulation of the NAc and reward-related behaviors.
Keywords
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References
- Drug overdose deaths in the United States, 1999–2018.NCHS Data Brief. 2020; : 1-8
- Costs of substance abuse.(Available at:)https://www.drugabuse.gov/drug-topics/trends-statistics/costs-substance-abuseDate accessed: October 20, 2021
- Drugs, brains, and behavior: The science of addiction. Treatment and recovery.(Available at:)https://www.drugabuse.gov/publications/drugs-brains-behavior-science-addiction/treatment-recoveryDate accessed: October 20, 2021
- Circadian rhythms, sleep, and substance abuse.Sleep Med Rev. 2012; 16: 67-81
- Sleep abnormalities associated with alcohol, cannabis, cocaine, and opiate use: A comprehensive review.Addict Sci Clin Pract. 2016; 11: 9
- Circadian rhythms and addiction: Mechanistic insights and future directions.Behav Neurosci. 2014; 128: 387-412
- Coordination of circadian timing in mammals.Nature. 2002; 418: 935-941
- Molecular architecture of the mammalian circadian clock.Trends Cell Biol. 2014; 24: 90-99
- Transcriptional architecture of the mammalian circadian clock.Nat Rev Genet. 2017; 18: 164-179
- The clock gene Per2 influences the glutamatergic system and modulates alcohol consumption [published correction appears in Nat Med 2005; 11:233].Nat Med. 2005; 11: 35-242
- The clock gene PER2 and sleep problems: Association with alcohol consumption among Swedish adolescents.Ups J Med Sci. 2010; 115: 41-48
- Circadian clock gene polymorphisms in alcohol use disorders and alcohol consumption.Alcohol Alcohol. 2010; 45: 303-311
- CLOCK is suggested to associate with comorbid alcohol use and depressive disorders.J Circadian Rhythms. 2010; 8: 1
- Effects of the circadian rhythm gene period 1 (per1) on psychosocial stress-induced alcohol drinking.Am J Psychiatry. 2011; 168: 1090-1098
- Repeat variation in the human PER2 gene as a new genetic marker associated with cocaine addiction and brain dopamine D2 receptor availability.Transl Psychiatry. 2012; 2: e86
- The CLOCK C3111T polymorphism is associated with reward dependence in healthy Japanese subjects.Neuropsychobiology. 2013; 67: 1-5
- Comparing the utility of homogeneous subtypes of cocaine use and related behaviors with DSM-IV cocaine dependence as traits for genetic association analysis.Am J Med Genet B Neuropsychiatr Genet. 2014; 165B: 148-156
- Cocaine sensitization and reward are under the influence of circadian genes and rhythm.Proc Natl Acad Sci U S A. 2002; 99: 9026-9030
- Regulation of dopaminergic transmission and cocaine reward by the Clock gene.Proc Natl Acad Sci U S A. 2005; 102: 9377-9381
- Circadian transcription factor NPAS2 and the NAD+-dependent deacetylase SIRT1 interact in the mouse nucleus accumbens and regulate reward.Eur J Neurosci. 2022; 55: 675-693
- Mania-like behavior induced by disruption of CLOCK.Proc Natl Acad Sci U S A. 2007; 104: 6406-6411
- Cocaine self-administration behaviors in ClockΔ19 mice.Psychopharmacology (Berl). 2012; 223: 169-177
- The role of clock in ethanol-related behaviors.Neuropsychopharmacology. 2013; 38: 2393-2400
- Cocaine-related behaviors in mice with deficient gliotransmission.Psychopharmacology (Berl). 2013; 226: 167-176
- Direct regulation of diurnal Drd3 expression and cocaine reward by NPAS2.Biol Psychiatry. 2015; 77: 425-433
- NPAS2 regulation of anxiety-like behavior and GABAA receptors.Front Mol Neurosci. 2017; 10: 360
- Cell-type-specific regulation of nucleus accumbens synaptic plasticity and cocaine reward sensitivity by the circadian protein, NPAS2.J Neurosci. 2019; 39: 4657-4667
- Circadian- and sex-dependent increases in intravenous cocaine self-administration in Npas2 mutant mice.J Neurosci. 2021; 41: 1046-1058
- How might circadian rhythms control mood? Let me count the ways.Biol Psychiatry. 2013; 74: 242-249
- Rhythms of life: Circadian disruption and brain disorders across the lifespan.Nat Rev Neurosci. 2019; 20: 49-65
- Mood-related central and peripheral clocks.Eur J Neurosci. 2020; 51: 326-345
- Circadian rhythm disruption and mental health.Transl Psychiatry. 2020; 10: 28
- The nucleus accumbens as a nexus between values and goals in goal-directed behavior: A review and a new hypothesis.Front Behav Neurosci. 2013; 7: 135
- The nucleus accumbens: Mechanisms of addiction across drug classes reflect the importance of glutamate homeostasis.Pharmacol Rev. 2016; 68: 816-871
- Astrocytic dysfunction and addiction: Consequences of impaired glutamate homeostasis.Neuroscientist. 2014; 20: 610-622
- Astroglial correlates of neuropsychiatric disease: From astrocytopathy to astrogliosis.Prog Neuropsychopharmacol Biol Psychiatry. 2018; 87: 126-146
- Astrocytes: Biology and pathology.Acta Neuropathol. 2010; 119: 7-35
- Glutamate uptake.Prog Neurobiol. 2001; 65: 1-105
- Mechanisms of glutamate release from astrocytes.Neurochem Int. 2008; 52: 142-154
- Bioenergetics and redox adaptations of astrocytes to neuronal activity.J Neurochem. 2016; 139: 115-125
- Glycolysis-derived compounds from astrocytes that modulate synaptic communication.Front Neurosci. 2019; 12: 1035
- Circadian rhythm generation and entrainment in astrocytes.J Neurosci. 2005; 25: 404-408
- Real-time monitoring of circadian clock oscillations in primary cultures of mammalian cells using Tol2 transposon-mediated gene transfer strategy.BMC Biotechnol. 2010; 10: 3
- Clock genes in glia cells: A rhythmic history.ASN Neuro. 2016; 8 (1759091416670766)
- Spinal AMPA receptor inhibition attenuates mechanical allodynia and neuronal hyperexcitability following spinal cord injury in rats.J Neurosci Res. 2007; 85: 2352-2359
- Circadian modulation of gene expression, but not glutamate uptake, in mouse and rat cortical astrocytes.PLoS One. 2009; 4e7476
- Circadian regulation of ATP release in astrocytes.J Neurosci. 2011; 31: 8342-8350
- Astrocytes control circadian timekeeping in the suprachiasmatic nucleus via glutamatergic signaling.Neuron. 2017; 93: 1420-1435.e5
- Astrocytes regulate daily rhythms in the suprachiasmatic nucleus and behavior.Curr Biol. 2017; 27: 1055-1061
- Cell-autonomous clock of astrocytes drives circadian behavior in mammals.Science. 2019; 363: 187-192
- The glutamate homeostasis hypothesis of addiction.Nat Rev Neurosci. 2009; 10: 561-572
- Glutamate transporter GLT-1 mediates N-acetylcysteine inhibition of cocaine reinstatement.Addict Biol. 2015; 20: 316-323
- Gq-DREADD selectively initiates glial glutamate release and inhibits cue-induced cocaine seeking.Biol Psychiatry. 2015; 78: 441-451
- A transcriptome database for astrocytes, neurons, and oligodendrocytes: A new resource for understanding brain development and function.J Neurosci. 2008; 28: 264-278
- Molecular comparison of GLT1+ and ALDH1L1+ astrocytes in vivo in astroglial reporter mice.Glia. 2011; 59: 200-207
- An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex [published correction appears in J Neurosci 2015; 35:846].J Neurosci. 2014; 34: 11929-11947
- Intrinsic circadian clock of the mammalian retina: Importance for retinal processing of visual information.Cell. 2007; 130: 730-741
- Cell-type-specific isolation of ribosome-associated mRNA from complex tissues.Proc Natl Acad Sci U S A. 2009; 106: 13939-13944
- Opposing role for Egr3 in nucleus accumbens cell subtypes in cocaine action.J Neurosci. 2015; 35: 7927-7937
- JTK_CYCLE: An efficient nonparametric algorithm for detecting rhythmic components in genome-scale data sets.J Biol Rhythms. 2010; 25: 372-380
- Evaluation of five methods for genome-wide circadian gene identification.J Biol Rhythms. 2014; 29: 231-242
- Causal analysis approaches in ingenuity pathway analysis.Bioinformatics. 2014; 30: 523-530
- Metascape provides a biologist-oriented resource for the analysis of systems-level datasets.Nat Commun. 2019; 10: 1523
- Controlled enzymatic production of astrocytic hydrogen peroxide protects neurons from oxidative stress via an Nrf2-independent pathway.Proc Natl Acad Sci U S A. 2010; 107: 17385-17390
- Synaptic NMDA receptor activity is coupled to the transcriptional control of the glutathione system [published correction appears in Nat Commun 2017; 8:16158].Nat Commun. 2015; 6: 6761
- NH4(+) triggers the release of astrocytic lactate via mitochondrial pyruvate shunting.Proc Natl Acad Sci U S A. 2015; 112: 11090-11095
- AMPK-regulated astrocytic lactate shuttle plays a non-cell-autonomous role in neuronal survival.Cell Rep. 2020; 32: 108092
- Chronic stress induces brain region-specific alterations of molecular rhythms that correlate with depression-like behavior in mice.Biol Psychiatry. 2015; 78: 249-258
- Cocaine-mediated circadian reprogramming in the striatum through dopamine D2R and PPARγ activation.Nat Commun. 2020; 11: 4448
- Application of a translational profiling approach for the comparative analysis of CNS cell types [published correction appears in Cell 2009; 139:1022].Cell. 2008; 135: 749-1762
- Astrocytes locally translate transcripts in their peripheral processes.Proc Natl Acad Sci U S A. 2017; 114: E3830-E3838
- Cell-type-specific profiling of alternative translation identifies regulated protein isoform variation in the mouse brain.Cell Rep. 2019; 26: 594-607.e7
- Normal aging induces A1-like astrocyte reactivity.Proc Natl Acad Sci U S A. 2018; 115: E1896-E1905
- Brain cell type specific gene expression and co-expression network architectures [published correction appears in Sci Rep 2021; 11:19430].Sci Rep. 2018; 8: 8868
- Transcriptomic profiling of microglia and astrocytes throughout aging.J Neuroinflammation. 2020; 17: 97
- Cell-autonomous regulation of astrocyte activation by the circadian clock protein BMAL1.Cell Rep. 2018; 25: 1-9.e5
- Selective breeding for divergence in novelty-seeking traits: Heritability and enrichment in spontaneous anxiety-related behaviors.Behav Genet. 2006; 36: 697-712
- An animal model of genetic vulnerability to behavioral disinhibition and responsiveness to reward-related cues: Implications for addiction.Neuropsychopharmacology. 2010; 35: 388-400
- Exploratory locomotion, a predictor of addiction vulnerability, is oligogenic in rats selected for this phenotype.Proc Natl Acad Sci U S A. 2019; 116: 13107-13115
- Individual differences in elevated plus-maze exploration predicted progressive-ratio cocaine self-administration break points in Wistar rats.Psychopharmacology (Berl). 2007; 194: 211-219
- Antecedents and consequences of drug abuse in rats selectively bred for high and low response to novelty.Neuropharmacology. 2014; 76 Pt B: 425-436
- Association of novelty-related behaviors and intravenous cocaine self-administration in diversity outbred mice.Psychopharmacology (Berl). 2015; 232: 1011-1024
- Novelty seeking and drug addiction in humans and animals: From behavior to molecules.J Neuroimmune Pharmacol. 2016; 11: 456-470
- Integrated behavioral z-scoring increases the sensitivity and reliability of behavioral phenotyping in mice: Relevance to emotionality and sex.J Neurosci Methods. 2011; 197: 21-31
- Sex differences in appetitive learning of mice.Physiol Behav. 1986; 37: 263-268
- Behavioral differences between male and female rats: Effects of gonadal hormones on learning and memory.Neurosci Biobehav Rev. 1990; 14: 23-33
- The effects of sex and chronic restraint on instrumental learning in rats.Neurosci J. 2013; 2013: 893126
- Reactive astrocytes: Production, function, and therapeutic potential.Immunity. 2017; 46: 957-967
- Nrf2, the master regulator of anti-oxidative responses.Int J Mol Sci. 2017; 18: 2772
- Brain energy metabolism: Focus on astrocyte-neuron metabolic cooperation.Cell Metab. 2011; 14: 724-738
- Astrocyte deletion of Bmal1 alters daily locomotor activity and cognitive functions via GABA signalling.Nat Commun. 2017; 8: 14336
- Astrocytes control neuronal excitability in the nucleus accumbens.ScientificWorldJournal. 2007; 7: 89-97
- Astrocytes revisited: Concise historic outlook on glutamate homeostasis and signaling.Croat Med J. 2012; 53: 518-528
- Altered GluA1 (Gria1) function and accumbal synaptic plasticity in the ClockΔ19 model of bipolar mania.Biol Psychiatry. 2018; 84: 817-826
- Glutamate uptake into astrocytes stimulates aerobic glycolysis: A mechanism coupling neuronal activity to glucose utilization.Proc Natl Acad Sci U S A. 1994; 91: 10625-10629
- Cellular bases of brain energy metabolism and their relevance to functional brain imaging: Evidence for a prominent role of astrocytes.Cereb Cortex. 1996; 6: 50-61
- Sweet sixteen for ANLS.J Cereb Blood Flow Metab. 2012; 32: 1152-1166
- Lactate in the brain: From metabolic end-product to signalling molecule.Nat Rev Neurosci. 2018; 19: 235-249
- Circadian rhythm of the lactate and pyruvate concentration in rat liver and blood.Physiol Bohemoslov. 1981; 30: 213-220
- Regulation of clock and NPAS2 DNA binding by the redox state of NAD cofactors.Science. 2001; 293: 510-514
- Lactate as a biomarker for sleep.Sleep. 2012; 35: 1209-1222
- The liver circadian clock modulates biochemical and physiological responses to metformin.J Biol Rhythms. 2017; 32: 345-358
- The circadian clock regulates RPE-mediated lactate transport via SLC16A1 (MCT1).Exp Eye Res. 2020; 190: 107861
- Effect of aging on daily rhythms of lactate metabolism in the medial prefrontal cortex of male mice.Neuroscience. 2020; 448: 300-310
- The intertwined roles of circadian rhythms and neuronal metabolism fueling drug reward and addiction.Curr Opin Physiol. 2018; 5: 80-89
- Disrupting astrocyte-neuron lactate transfer persistently reduces conditioned responses to cocaine.Mol Psychiatry. 2016; 21: 1070-1076
- Lactate release from astrocytes to neurons contributes to cocaine memory formation.Bioessays. 2016; 38: 1266-1273
- Inhibition of lactate transport erases drug memory and prevents drug relapse.Biol Psychiatry. 2016; 79: 928-939
- Astrocytes determine conditioned response to morphine via glucocorticoid receptor-dependent regulation of lactate release.Neuropsychopharmacology. 2020; 45: 404-415
- Clock genes × stress × reward interactions in alcohol and substance use disorders.Alcohol. 2015; 49: 351-357
- Implications of circadian rhythm and stress in addiction vulnerability.F1000Res. 2016; 5: 59
- Glucocorticoids modulate neurotransmitter-induced glycogen metabolism in cultured cortical astrocytes.J Neurochem. 2004; 88: 900-908
- Glucocorticoid receptor signaling represses the antioxidant response by inhibiting histone acetylation mediated by the transcriptional activator NRF2.J Biol Chem. 2017; 292: 7519-7530
- Neuronal activity regulates astrocytic Nrf2 signaling.Proc Natl Acad Sci U S A. 2013; 110: 18291-18296
- Astrocyte NMDA receptors’ activity sustains neuronal survival through a Cdk5-Nrf2 pathway.Cell Death Differ. 2015; 22: 1877-1889
- Neuronal activity induces glutathione metabolism gene expression in astrocytes.Glia. 2018; 66: 2024-2039
- Role of nrf2 in oxidative stress and toxicity.Annu Rev Pharmacol Toxicol. 2013; 53: 401-426
- Adaptive regulation of the brain’s antioxidant defences by neurons and astrocytes.Free Radic Biol Med. 2016; 100: 147-152
- The anti-inflammatory and anti-oxidant mechanisms of the Keap1/Nrf2/ARE signaling pathway in chronic diseases.Aging Dis. 2019; 10: 637-651
- ROS function in redox signaling and oxidative stress.Curr Biol. 2014; 24: R453-R462
- Oxidative stress and neuroinflammation as a pivot in drug abuse. A focus on the therapeutic potential of antioxidant and anti-inflammatory agents and biomolecules.Antioxidants (Basel). 2020; 9: 830
- The role of oxidative stress in toxicities due to drugs of abuse.Curr Opin Toxicol. 2020; 20: 29-35
- Impaired cued and contextual memory in NPAS2-deficient mice.Science. 2000; 288: 2226-2230
Article info
Publication history
Published online: February 18, 2022
Accepted:
February 11,
2022
Received in revised form:
January 25,
2022
Received:
September 30,
2021
Identification
Copyright
© 2022 Society of Biological Psychiatry.
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- The Role of Molecular Clock Genes in Astrocytes of the Nucleus Accumbens in Reward- and Mood-Related Behavior in MiceBiological PsychiatryVol. 93Issue 3
- PreviewAs an adaptation to life on Earth, mammalian physiology dramatically changes through the duration of the day, and these temporal programs are regulated by an internal timekeeping system (1). A recent publication by Becker-Krail et al. (1) explored the importance of the molecular clock gene Bmal1 in a brain region involved in reward- and mood-related behavior. However, the publication includes a bold claim. The authors falsely state that the described work is the first to explore the role of the circadian system in astrocytes of the nucleus accumbens (NAc).
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