24 results on '"Rachel N. Arey"'
Search Results
2. Uncovering novel regulators of memory using C. elegans genetic and genomic analysis
- Author
-
Katie L. Brandel-Ankrapp and Rachel N. Arey
- Subjects
Biochemistry - Abstract
How organisms learn and encode memory is an outstanding question in neuroscience research. Specifically, how memories are acquired and consolidated at the level of molecular and gene pathways remains unclear. In addition, memory is disrupted in a wide variety of neurological disorders; therefore, discovering molecular regulators of memory may reveal therapeutic targets for these disorders. C. elegans are an excellent model to uncover molecular and genetic regulators of memory. Indeed, the nematode's invariant neuronal lineage, fully mapped genome, and conserved associative behaviors have allowed the development of a breadth of genetic and genomic tools to examine learning and memory. In this mini-review, we discuss novel and exciting genetic and genomic techniques used to examine molecular and genetic underpinnings of memory from the level of the whole-worm to tissue-specific and cell-type specific approaches with high spatiotemporal resolution.
- Published
- 2023
3. A systems biology-based identification and in vivo functional screening of Alzheimer's disease risk genes reveals modulators of memory function
- Author
-
Adam D Hudgins, Shiyi Zhou, Rachel N. Arey, Coleen T. Murphy, and Yousin Suh
- Abstract
Genome-wide association studies (GWAS) have uncovered over 40 genomic loci associated with risk for late-onset Alzheimer's Disease (LOAD), but identification of the underlying causal genes remains challenging. While the role of glial biology in the mediation of LOAD genetic risk has been increasingly recognized, recent studies of induced pluripotent stem cell (iPSC)-derived neurons from LOAD patients have demonstrated the existence of neuronal cell-intrinsic functional defects, absent interactions with other brain cell types or exposure to neurotoxic insults. Here, we searched for genetic contributions to neuronal dysfunction in LOAD pathobiology, using an integrative systems approach that incorporated multi-evidence-based gene-mapping and network analysis-based prioritization. We found widespread dysfunction in neuronal gene co-expression networks in the LOAD brain and identified synaptic and endolysosomal function as being specifically impacted by LOAD-associated genetic variation. A systematic perturbation screening of candidate risk genes in C. elegans revealed that neuronal knockdown of the LOAD risk gene orthologs vha-10 (ATP6V1G2), cmd-1 (CALM3), amph-1 (BIN1), ephx-1 (NGEF), and pho-5 (ACP2) significantly alters short/intermediate-term memory function, the cognitive domain affected earliest during LOAD progression. These results highlight the impact of LOAD risk genes on evolutionarily conserved memory function, as mediated through neuronal endosomal dysfunction, and identify new targets for further mechanistic interrogation.
- Published
- 2022
4. A lysosomal surveillance response (LySR) that reduces proteotoxicity and extends healthspan
- Author
-
Terytty Yang Li, Arwen W. Gao, Xiaoxu Li, Yasmine J. Liu, Rachel N. Arey, Kimberly Morales, Amélia Lalou, Qi Wang, Tanes Lima, and Johan Auwerx
- Abstract
SUMMARYLysosomes are cytoplasmic organelles central for the degradation of macromolecules to maintain cellular homeostasis and health. Here, we discovered an adaptive lysosomal transcriptional response that we termed the Lysosomal Surveillance Response (LySR). Typified by the induction of a large group of transcripts involved in lysosomal function and proteolysis, the LySR can be triggered by silencing of specific vacuolar H+-ATPase subunits in Caenorhabditis elegans. Notably, LySR activation enhances the clearance of protein aggregates in worm models of Alzheimer’s and Huntington’s disease and amyotrophic lateral sclerosis, thereby boosting fitness and extending lifespan. The GATA transcription factor, ELT-2, regulates the LySR program as well as its associated beneficial effects. In mammalian cells, overexpression of GATA4/GATA6, the mammalian orthologs of ELT-2, is sufficient to induce the expression of multiple lysosome-specific proteases and alleviate proteotoxicity. Activating the LySR pathway may therefore represent an attractive mechanism to reduce proteotoxicity and, as such, potentially extend healthspan.HighlightsRNAi of specific v-ATPase subunits extends C. elegans lifespan and activates LySRGATA transcription factor ELT-2 regulates LySR and LySR-associated lifespan extensionLySR activation reduces protein aggregates and extends worm healthspanOverexpression of GATA4/GATA6 alleviates amyloid-β proteotoxicity in mammalian cells
- Published
- 2022
5. Valproate reverses mania-like behaviors in mice via preferential targeting of HDAC2
- Author
-
Evan Y. Snyder, Angela R. Ozburn, Colleen A. McClung, Mariah A. Hildebrand, George C. Tseng, Jeffrey Oliver-Smith, Matthew B Jarpe, Alicia M. Winquist, Hui Zhang, Wei Zong, Puja K. Parekh, Darius Becker-Krail, Zhiguang Huo, Ethan Fitzgerald, Rachel N. Arey, Xiyu Zhu, Lauren M. DePoy, Andrew Crain, Kyle D. Ketchesin, Brian T. D. Tobe, Xiangning Xue, and Ryan W. Logan
- Subjects
0301 basic medicine ,Induced Pluripotent Stem Cells ,Histone Deacetylase 2 ,Pharmacology ,Article ,Treatment of bipolar disorder ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Mice ,0302 clinical medicine ,RNA interference ,mental disorders ,Medicine ,Animals ,Humans ,Induced pluripotent stem cell ,Molecular Biology ,business.industry ,Histone deacetylase 2 ,Valproic Acid ,HDAC1 ,Ventral tegmental area ,Histone Deacetylase Inhibitors ,Psychiatry and Mental health ,Mania ,030104 developmental biology ,medicine.anatomical_structure ,lipids (amino acids, peptides, and proteins) ,Histone deacetylase ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
Valproate (VPA) has been used in the treatment of bipolar disorder since the 1990s. However, the therapeutic targets of VPA have remained elusive. Here we employ a preclinical model to identify the therapeutic targets of VPA. We find compounds that inhibit histone deacetylase proteins (HDACs) are effective in normalizing manic-like behavior, and that class I HDACs (e.g., HDAC1 and HDAC2) are most important in this response. Using an RNAi approach, we find that HDAC2, but not HDAC1, inhibition in the ventral tegmental area (VTA) is sufficient to normalize behavior. Furthermore, HDAC2 overexpression in the VTA prevents the actions of VPA. We used RNA sequencing in both mice and human induced pluripotent stem cells (iPSCs) derived from bipolar patients to further identify important molecular targets. Together, these studies identify HDAC2 and downstream targets for the development of novel therapeutics for bipolar mania.
- Published
- 2020
6. Invited review: Unearthing the mechanisms of age-related neurodegenerative disease using Caenorhabditis elegans
- Author
-
Ashley N. Hayden, Emily J. Leptich, and Rachel N. Arey
- Subjects
Physiology ,Longevity ,Animals ,Neurodegenerative Diseases ,Caenorhabditis elegans ,Molecular Biology ,Biochemistry - Abstract
As human life expectancy increases, neurodegenerative diseases present a growing public health threat, for which there are currently few effective treatments. There is an urgent need to understand the molecular and genetic underpinnings of these disorders so new therapeutic targets can be identified. Here we present the argument that the simple nematode worm Caenorhabditis elegans is a powerful tool to rapidly study neurodegenerative disorders due to their short lifespan and vast array of genetic tools, which can be combined with characterization of conserved neuronal processes and behavior orthologous to those disrupted in human disease. We review how pre-existing C. elegans models provide insight into human neurological disease as well as an overview of current tools available to study neurodegenerative diseases in the worm, with an emphasis on genetics and behavior. We also discuss open questions that C. elegans may be particularly well suited for in future studies and how worms will be a valuable preclinical model to better understand these devastating neurological disorders.
- Published
- 2021
7. Decision letter: C. elegans orthologs MUT-7/CeWRN-1 of Werner syndrome protein regulate neuronal plasticity
- Author
-
Rachel N. Arey
- Subjects
Werner Syndrome Protein ,Neuroplasticity ,Biology ,Cell biology - Published
- 2020
8. Nervous system-wide profiling of presynaptic mRNAs reveals regulators of associative memory
- Author
-
Coleen T. Murphy, Rachel N. Arey, and Rachel Kaletsky
- Subjects
Central Nervous System ,0301 basic medicine ,Nervous system ,Somatic cell ,Population ,Central nervous system ,Presynaptic Terminals ,Fluorescent Antibody Technique ,lcsh:Medicine ,In situ hybridization ,Biology ,Article ,Deep sequencing ,Learning and memory ,Genomic analysis ,Transcriptome ,03 medical and health sciences ,0302 clinical medicine ,Memory ,medicine ,Animals ,RNA, Messenger ,Caenorhabditis elegans ,lcsh:Science ,education ,3' Untranslated Regions ,Gene ,Mammals ,Neurons ,education.field_of_study ,Binding Sites ,Multidisciplinary ,Gene Expression Profiling ,lcsh:R ,RNA-Binding Proteins ,Genomics ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,Gene Expression Regulation ,Protein Biosynthesis ,Synapses ,lcsh:Q ,030217 neurology & neurosurgery ,Genome-Wide Association Study ,Protein Binding - Abstract
Presynaptic protein synthesis is important in the adult central nervous system; however, the nervous system-wide set of mRNAs localized to presynaptic areas has yet to be identified in any organism. Here we differentially labeled somatic and synaptic compartments in adult C. elegans with fluorescent proteins, and isolated synaptic and somatic regions from the same population of animals. We used this technique to determine the nervous system-wide presynaptic transcriptome by deep sequencing. Analysis of the synaptic transcriptome reveals that synaptic transcripts are predicted to have specialized functions in neurons. Differential expression analysis identified 542 genes enriched in synaptic regions relative to somatic regions, with synaptic functions conserved in higher organisms. We find that mRNAs for pumilio RNA-binding proteins are abundant in synaptic regions, which we confirmed through high-sensitivity in situ hybridization. Presynaptic PUMILIOs regulate associative memory. Our approach enables the identification of new mechanisms that regulate synaptic function and behavior.
- Published
- 2019
9. Profiling of presynaptic mRNAs reveals a role for axonal PUMILIOs in associative memory formation
- Author
-
Coleen T. Murphy, Rachel N. Arey, and Rachel Kaletsky
- Subjects
0303 health sciences ,Somatic cell ,Regulator ,Repressor ,In situ hybridization ,Biology ,Deep sequencing ,Cell biology ,Transcriptome ,03 medical and health sciences ,0302 clinical medicine ,Protein biosynthesis ,Gene ,030217 neurology & neurosurgery ,030304 developmental biology - Abstract
Presynaptic protein synthesis is important in the adult central nervous system; however, the set of mRNAs localized to presynaptic areas has yet to be identified in any organism. We differentially labeled somatic and synaptic compartments nervous system-wide in adult C. elegans and isolated synaptic regions for deep sequencing. Analysis of the synaptic transcriptome reveals that synaptic transcripts are predicted to have specialized functions in neurons. Differential expression analysis identified 543 genes enriched in synaptic regions relative to somatic regions, with synaptic functions conserved in higher organisms. We find that mRNAs for pumilio RNA-binding proteins are abundant in synaptic regions, which we confirmed through high-sensitivity in situ hybridization. We identified a new role for the PUM2 orthologs puf-7/8 as repressors of memory formation through regulation of the mitochondrial dynamics regulator, mff-1. Identification of presynaptic mRNAs provides insight into mechanisms that regulate synaptic function and behavior.
- Published
- 2019
- Full Text
- View/download PDF
10. The Neuronal Kinesin UNC-104/KIF1A Is a Key Regulator of Synaptic Aging and Insulin Signaling-Regulated Memory
- Author
-
Haoyun Lei, Pengpeng Li, Kang Shen, Rachel N. Arey, X.Z. Shawn Xu, Jianfeng Liu, Ling Bo Li, and Coleen T. Murphy
- Subjects
0301 basic medicine ,Aging ,Regulator ,Nerve Tissue Proteins ,Biology ,Neurotransmission ,General Biochemistry, Genetics and Molecular Biology ,Article ,Synapse ,03 medical and health sciences ,Downregulation and upregulation ,Memory ,Animals ,Insulin ,Caenorhabditis elegans ,Caenorhabditis elegans Proteins ,KIF1A ,Agricultural and Biological Sciences(all) ,Biochemistry, Genetics and Molecular Biology(all) ,fungi ,Anatomy ,Associative learning ,030104 developmental biology ,Synapses ,Axoplasmic transport ,Kinesin ,General Agricultural and Biological Sciences ,Neuroscience ,Signal Transduction - Abstract
Aging is the greatest risk factor for a number of neurodegenerative diseases, such as Alzheimer's and Parkinson's disease. Furthermore, normal aging is associated with a decline in sensory, motor, and cognitive functions. Emerging evidence suggests that synapse alterations, rather than neuronal cell death, are the causes of neuronal dysfunctions in normal aging and in early stages of neurodegenerative diseases. However, little is known about the mechanisms underlying age-related synaptic decline. Here, we uncover a surprising role of the anterograde molecular motor UNC-104/KIF1A as a key regulator of neural circuit deterioration in aging C. elegans. Through analyses of synapse protein localization, synaptic transmission, and animal behaviors, we find that reduced function of UNC-104 accelerates motor circuit dysfunction with age, whereas upregulation of UNC-104 significantly improves motor function at advanced ages and also mildly extends lifespan. In addition, UNC-104-overexpressing animals outperform wild-type controls in associative learning and memory tests. Further genetic analyses suggest that UNC-104 functions downstream of the DAF-2-signaling pathway and is regulated by the FOXO transcription factor DAF-16, which contributes to the effects of DAF-2 in neuronal aging. Together, our cellular, electrophysiological, and behavioral analyses highlight the importance of axonal transport in the maintenance of synaptic structural integrity and function during aging and raise the possibility of targeting kinesins to slow age-related neural circuit dysfunction.
- Published
- 2016
- Full Text
- View/download PDF
11. The C. elegans adult neuronal IIS/FOXO transcriptome reveals adult phenotype regulators
- Author
-
Coleen T. Murphy, Rachel N. Arey, Jessica N. Landis, April E. Williams, Vanisha Lakhina, Jasmine Ashraf, and Rachel Kaletsky
- Subjects
0301 basic medicine ,Aging ,media_common.quotation_subject ,Longevity ,Mutant ,Cell Separation ,Biology ,Mechanotransduction, Cellular ,Transcriptome ,03 medical and health sciences ,Forkhead Transcription Factors ,Memory ,Somatomedins ,Animals ,Insulin ,Regeneration ,Caenorhabditis elegans ,Caenorhabditis elegans Proteins ,Transcription factor ,media_common ,Neurons ,Genetics ,Multidisciplinary ,fungi ,biology.organism_classification ,Phenotype ,Axons ,030104 developmental biology ,nervous system ,Mutation ,Signal transduction ,Signal Transduction - Abstract
Insulin/insulin-like growth factor signalling (IIS) is a critical regulator of an organism's most important biological decisions from growth, development, and metabolism to reproduction and longevity. It primarily does so through the activity of the DAF-16 transcription factor (forkhead box O (FOXO) homologue), whose global targets were identified in Caenorhabditis elegans using whole-worm transcriptional analyses more than a decade ago. IIS and FOXO also regulate important neuronal and adult behavioural phenotypes, such as the maintenance of memory and axon regeneration with age, in both mammals and C. elegans, but the neuron-specific IIS/FOXO targets that regulate these functions are still unknown. By isolating adult C. elegans neurons for transcriptional profiling, we identified both the wild-type and IIS/FOXO mutant adult neuronal transcriptomes for the first time. IIS/FOXO neuron-specific targets are distinct from canonical IIS/FOXO-regulated longevity and metabolism targets, and are required for extended memory in IIS daf-2 mutants. The activity of the forkhead transcription factor FKH-9 in neurons is required for the ability of daf-2 mutants to regenerate axons with age, and its activity in non-neuronal tissues is required for the long lifespan of daf-2 mutants. Together, neuron-specific and canonical IIS/FOXO-regulated targets enable the coordinated extension of neuronal activities, metabolism, and longevity under low-insulin signalling conditions.
- Published
- 2015
12. Direct Regulation of Diurnal Drd3 Expression and Cocaine Reward by NPAS2
- Author
-
Rachel N. Arey, Edgardo Falcon, Alexandria L. Nugent, Sade Spencer, Alan Twaddle, Colleen A. McClung, Shibani Mukherjee, Andrea G. Gillman, David W. Self, Angela R. Ozburn, and James Lyons-Weiler
- Subjects
medicine.medical_specialty ,CLOCK Proteins ,Mice, Transgenic ,Nerve Tissue Proteins ,Biology ,Nucleus accumbens ,Nucleus Accumbens ,Article ,Small hairpin RNA ,Cocaine ,Dopamine Uptake Inhibitors ,Reward ,Internal medicine ,Conditioning, Psychological ,Basic Helix-Loop-Helix Transcription Factors ,medicine ,Animals ,Circadian rhythm ,Biological Psychiatry ,Neurons ,Gene knockdown ,NPAS2 ,Receptors, Dopamine D1 ,Receptors, Dopamine D3 ,Circadian Rhythm ,Cell biology ,Mice, Inbred C57BL ,Endocrinology ,Dopamine receptor ,Space Perception ,Chromatin immunoprecipitation - Abstract
Background Circadian gene disruptions are associated with the development of psychiatric disorders, including addiction. However, the mechanisms by which circadian genes regulate reward remain poorly understood. Methods We used mice with a mutation in Npas2 and adeno-associated virus-short hairpin RNA mediated knockdown of Npas2 and Clock in the nucleus accumbens (NAc). We performed conditioned place preference assays. We utilized cell sorting quantitative real-time polymerase chain reaction, and chromatin immunoprecipitation followed by deep sequencing. Results Npas2 mutants exhibit decreased sensitivity to cocaine reward, which is recapitulated with a knockdown of neuronal PAS domain protein 2 (NPAS2) specifically in the NAc, demonstrating the importance of NPAS2 in this region. Interestingly, reducing circadian locomotor output cycles kaput (CLOCK) (a homologue of NPAS2) in the NAc had no effect, suggesting an important distinction in NPAS2 and CLOCK function. Furthermore, we found that NPAS2 expression is restricted to Drd1 expressing neurons while CLOCK is ubiquitous. Moreover, NPAS2 and CLOCK have distinct temporal patterns of DNA binding, and we identified novel and unique binding sites for each protein. We identified the Drd3 dopamine receptor as a direct transcriptional target of NPAS2 and found that NPAS2 knockdown in the NAc disrupts its diurnal rhythm in expression. Chronic cocaine treatment likewise disrupts the normal rhythm in Npas2 and Drd3 expression in the NAc, which may underlie behavioral plasticity in response to cocaine. Conclusions Together, these findings identify an important role for the circadian protein, NPAS2, in the NAc in the regulation of dopamine receptor expression and drug reward.
- Published
- 2015
13. Daytime spikes in dopaminergic activity drive rapid mood-cycling in mice
- Author
-
Michelle M. Sidor, Marc G. Caron, John F. Enwright, Karl Deisseroth, Puja K. Parekh, Kafui Dzirasa, Kay M. Tye, Sade Spencer, Erin M Remillard, Melissa R. Warden, Rachel N. Arey, Colleen A. McClung, Sunil Kumar, Jacob P. R. Jacobsen, Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences, Picower Institute for Learning and Memory, and Tye, Kay
- Subjects
Male ,Time Factors ,Dopamine Agents ,Action Potentials ,CLOCK Proteins ,Mice ,Premovement neuronal activity ,Cell Line, Transformed ,bipolar disorder ,Dopaminergic ,anxiety ,Circadian Rhythm ,3. Good health ,Ventral tegmental area ,Psychiatry and Mental health ,medicine.anatomical_structure ,depression ,Psychopharmacology ,dopamine ,Psychology ,medicine.drug ,Tyrosine 3-Monooxygenase ,ventral tegmental area ,Mice, Transgenic ,Motor Activity ,behavioral disciplines and activities ,Article ,Food Preferences ,Cellular and Molecular Neuroscience ,Dopamine ,mental disorders ,medicine ,Animals ,Bipolar disorder ,Circadian rhythm ,Maze Learning ,optogenetics ,Molecular Biology ,Swimming ,Tyrosine hydroxylase ,Adaptation, Ocular ,Dopaminergic Neurons ,medicine.disease ,Rats ,Mice, Inbred C57BL ,Affect ,Gene Expression Regulation ,circadian rhythms ,Mutation ,Neuroscience - Abstract
Disruptions in circadian rhythms and dopaminergic activity are involved in the pathophysiology of bipolar disorder, though their interaction remains unclear. Moreover, a lack of animal models that display spontaneous cycling between mood states has hindered our mechanistic understanding of mood switching. Here, we find that mice with a mutation in the circadian Clock gene (ClockΔ19) exhibit rapid mood-cycling, with a profound manic-like phenotype emerging during the day following a period of euthymia at night. Mood-cycling coincides with abnormal daytime spikes in ventral tegmental area (VTA) dopaminergic activity, tyrosine hydroxylase (TH) levels and dopamine synthesis. To determine the significance of daytime increases in VTA dopamine activity to manic behaviors, we developed a novel optogenetic stimulation paradigm that produces a sustained increase in dopamine neuronal activity and find that this induces a manic-like behavioral state. Time-dependent dampening of TH activity during the day reverses manic-related behaviors in ClockΔ19 mice. Finally, we show that CLOCK acts as a negative regulator of TH transcription, revealing a novel molecular mechanism underlying cyclic changes in mood-related behavior. Taken together, these studies have identified a mechanistic connection between circadian gene disruption and the precipitation of manic episodes in bipolar disorder., McKnight Foundation, Brain & Behavior Research Foundation, National Institute of Mental Health (U.S.) (MH082876), National Institute on Drug Abuse (DA023988), National Institute of Neurological Disorders and Stroke (U.S.) (NS058339)
- Published
- 2015
14. Activation of G
- Author
-
Rachel N, Arey, Geneva M, Stein, Rachel, Kaletsky, Amanda, Kauffman, and Coleen T, Murphy
- Subjects
Animals, Genetically Modified ,Animals ,GTP-Binding Protein alpha Subunits, Gq-G11 ,Cognitive Dysfunction ,Caenorhabditis elegans ,Cyclic AMP Response Element-Binding Protein ,Article ,Memory Consolidation ,Signal Transduction - Abstract
Perhaps the most devastating decline with age is the loss of memory. Therefore, identifying mechanisms to restore memory function with age is critical. Using C. elegans associative learning and memory assays, we identified a gain-of-function G(αq) signaling pathway mutant that forms a long-term (CREB-dependent) memory following one Conditioned Stimulus-Unconditioned Stimulus (CS-US) pairing, which usually requires seven CS-US pairings. Increased CREB activity in AIM interneurons reduces the threshold for memory consolidation through transcription of a set of previously-identified “long-term memory” genes. Enhanced G(αq) signaling in the AWC sensory neuron is both necessary and sufficient for improved memory and increased AIM CREB activity, and activation of G(αq) specifically in aged animals rescues the ability to form memory. Activation of G(αq) in AWC sensory neurons cell-non-autonomously induces consolidation after one CS-US pairing, enabling both cognitive function maintenance with age and restoration of memory function in animals with impaired memory performance, without decreased longevity.
- Published
- 2017
15. RNA surveillance via nonsense-mediated mRNA decay is crucial forlongevity in daf-2/insulin/IGF-1 mutant C. elegans
- Author
-
Tae-Young Roh, Seokjin Ham, Murat Artan, Wooseon Hwang, Chang Man Ha, Yoon Ki Kim, Mihwa Seo, Rachel N. Arey, Seon Woo A. An, Rachel Kaletsky, Heehwa G. Son, Coleen T. Murphy, Seung-Jae Lee, Hong Gil Nam, Youngjae Ryu, Keunhee Seo, and Dongyeop Lee
- Subjects
0301 basic medicine ,media_common.quotation_subject ,Science ,Longevity ,Nonsense-mediated decay ,Mutant ,General Physics and Astronomy ,medicine.disease_cause ,Article ,General Biochemistry, Genetics and Molecular Biology ,Animals, Genetically Modified ,03 medical and health sciences ,Downregulation and upregulation ,medicine ,Animals ,Insulin ,RNA, Messenger ,Insulin-Like Growth Factor I ,Caenorhabditis elegans ,Caenorhabditis elegans Proteins ,media_common ,Genetics ,Mutation ,Multidisciplinary ,biology ,Gene Expression Profiling ,RNA ,General Chemistry ,biology.organism_classification ,Receptor, Insulin ,Nonsense Mediated mRNA Decay ,3. Good health ,Luminescent Proteins ,030104 developmental biology ,Daf-2 - Abstract
Long-lived organisms often feature more stringent protein and DNA quality control. However, whether RNA quality control mechanisms, such as nonsense-mediated mRNA decay (NMD), which degrades both abnormal as well as some normal transcripts, have a role in organismal aging remains unexplored. Here we show that NMD mediates longevity in C. elegans strains with mutations in daf-2/insulin/insulin-like growth factor 1 receptor. We find that daf-2 mutants display enhanced NMD activity and reduced levels of potentially aberrant transcripts. NMD components, including smg-2/UPF1, are required to achieve the longevity of several long-lived mutants, including daf-2 mutant worms. NMD in the nervous system of the animals is particularly important for RNA quality control to promote longevity. Furthermore, we find that downregulation of yars-2/tyrosyl-tRNA synthetase, an NMD target transcript, by daf-2 mutations contributes to longevity. We propose that NMD-mediated RNA surveillance is a crucial quality control process that contributes to longevity conferred by daf-2 mutations., The decline of DNA and protein quality control contributes to organismal ageing. Here, Son et al. report that nonsense-mediated mRNA decay, a RNA quality control mechanism, is enhanced in long-lived daf-2 mutant worms and contributes to their longevity by regulating expression of the yars-2/tyrosyl tRNA synthetase.
- Published
- 2017
16. An important role for Cholecystokinin, a CLOCK target gene, in the development and treatment of manic-like behaviors
- Author
-
Colleen A. McClung, John F. Enwright, Rachel N. Arey, Angela R. Ozburn, Carol A. Tamminga, Edgardo Falcon, Subroto Ghose, and Sade Spencer
- Subjects
Male ,medicine.medical_specialty ,Bipolar Disorder ,Lithium (medication) ,medicine.drug_class ,CLOCK Proteins ,Biology ,digestive system ,Article ,Mice ,Cellular and Molecular Neuroscience ,Internal medicine ,mental disorders ,Gene expression ,medicine ,Animals ,Humans ,Molecular Biology ,Cholecystokinin ,chromatin structure ,Gene knockdown ,Behavior, Animal ,Ventral Tegmental Area ,digestive, oral, and skin physiology ,Mood stabilizer ,Histone-Lysine N-Methyltransferase ,Ventral tegmental area ,CLOCK ,Psychiatry and Mental health ,medicine.anatomical_structure ,Endocrinology ,lithium ,Gene Knockdown Techniques ,Histone methyltransferase ,Mutation ,gene expression ,dopamine ,Lithium Chloride ,Myeloid-Lymphoid Leukemia Protein ,hormones, hormone substitutes, and hormone antagonists ,medicine.drug - Abstract
Mice with a mutation in the Clock gene (ClockΔ19) have been identified as a model of mania, however, the mechanisms that underlie this phenotype, and the changes in the brain that are necessary for lithium’s effectiveness on these mice remain unclear. Here we find that Cholecystokinin(Cck) is a direct transcriptional target of CLOCK and levels of Cck are reduced in the ventral tegmental area (VTA) of ClockΔ19 mice. Selective knock-down of Cck expression via RNA interference (RNAi) in the VTA of wild type mice produces a manic-like phenotype. Moreover, chronic treatment with lithium restores Cck expression to near wild type and this increase is necessary for the therapeutic actions of lithium. The decrease in Cck expression in the ClockΔ19 mice appears to be due to a lack of interaction with the histone methyltransferase, MLL1, resulting in decreased histone H3K4me3 and gene transcription, an effect reversed by lithium. Human postmortem tissue from bipolar subjects reveals a similar increase in Cck expression in the VTA with mood stabilizer treatment. These studies identify a key role for Cck in the development and treatment of mania, and describe some of the molecular mechanisms by which lithium may act as an effective anti-manic agent.
- Published
- 2013
17. Conserved regulators of cognitive aging: From worms to humans
- Author
-
Coleen T. Murphy and Rachel N. Arey
- Subjects
0301 basic medicine ,Cognitive aging ,biology ,ved/biology ,media_common.quotation_subject ,ved/biology.organism_classification_rank.species ,Longevity ,biology.organism_classification ,Article ,03 medical and health sciences ,Behavioral Neuroscience ,030104 developmental biology ,0302 clinical medicine ,Cognitive Aging ,Models, Animal ,Animals ,Humans ,Cognitive decline ,Model organism ,Caenorhabditis elegans ,Neuroscience ,030217 neurology & neurosurgery ,media_common - Abstract
Cognitive decline is a major deficit that arises with age in humans. While some research on the underlying causes of these problems can be done in humans, harnessing the strengths of small model systems, particularly those with well-studied longevity mutants, such as the nematode C. elegans, will accelerate progress. Here we review the approaches being used to study cognitive decline in model organisms and show how simple model systems allow the rapid discovery of conserved molecular mechanisms, which will eventually enable the development of therapeutics to slow cognitive aging.
- Published
- 2016
18. An inhibitor of casein kinase 1 ε/δ partially normalizes the manic-like behaviors of the ClockΔ19 mouse
- Author
-
Colleen A. McClung and Rachel N. Arey
- Subjects
Male ,medicine.medical_specialty ,Bipolar Disorder ,Casein Kinase 1 epsilon ,CLOCK Proteins ,Biology ,Article ,Drug Administration Schedule ,Treatment of bipolar disorder ,Mice ,Internal medicine ,medicine ,Animals ,Circadian rhythm ,Casein Kinase Idelta ,Bipolar disorder ,Pharmacology ,Mice, Inbred BALB C ,Behavior, Animal ,Casein Kinase Iepsilon ,medicine.disease ,Mice, Inbred C57BL ,Disease Models, Animal ,Psychiatry and Mental health ,Endocrinology ,Mutation ,Casein kinase 1 ,medicine.symptom ,Mania - Abstract
Bipolar disorder is a terrible and debilitating disease with limited treatment options. Circadian rhythm disruptions are prominent in bipolar subjects, and studies have shown that rhythm stabilization through psychosocial interventions can improve their symptoms. Furthermore, mice with a mutation in one of the central circadian proteins, CLOCK, have severely disrupted rhythms along with a behavioral profile that closely resembles human mania. A compound has been developed (CK01, similar to PF-670462) that inhibits the activity of casein kinase 1 (CK1), a critical protein involved in the timing of the molecular clock. Previous studies have shown that PF-670462 and other similar compounds are capable of entraining and stabilizing rhythms in arrhythmic animals. Here we show that chronic administration of CK01 leads to a reversal of the anxiety-related behavior, and partial reversal of the depression-related phenotypes of the Clock mutant mouse. This drug had no significant effects on the behavior of wild-type mice at the doses tested. These results suggest that CK1ε/δ inhibitors could be viable drugs for the treatment of bipolar disorder.
- Published
- 2012
19. A mutation in CLOCK leads to altered dopamine receptor function
- Author
-
Rachel N. Arey, Matthew S. Goldberg, Colleen A. McClung, James A. Bibb, Marian Marvin, Melissa I. Torres-Altoro, Edgardo Falcon, and Sade Spencer
- Subjects
medicine.medical_specialty ,Dopaminergic ,Striatum ,Biology ,Biochemistry ,CLOCK ,Cellular and Molecular Neuroscience ,Endocrinology ,Dopamine receptor ,Dopamine receptor D3 ,Dopamine ,Dopamine receptor D2 ,Internal medicine ,medicine ,Signal transduction ,Neuroscience ,medicine.drug - Abstract
Mice with a mutation in the Clock gene (ClockΔ19) have a number of behavioral phenotypes that suggest alterations in dopaminergic transmission. These include hyperactivity, increased exploratory behavior, and increased reward value for drugs of abuse. However, the complex changes in dopaminergic transmission that underlie the behavioral abnormalities in these mice remain unclear. Here we find that a loss of CLOCK function increases dopamine release and turnover in striatum as indicated by increased levels of metabolites HVA and DOPAC, and enhances sensitivity to dopamine receptor antagonists. Interestingly, this enlarged dopaminergic tone results in downstream changes in dopamine receptor (DR) levels with a surprising augmentation of both D1- and D2-type DR protein, but a significant shift in the ratio of D1 : D2 receptors in favor of D2 receptor signaling. These effects have functional consequences for both behavior and intracellular signaling, with alterations in locomotor responses to both D1-type and D2-type specific agonists and a blunted response to cAMP activation in the ClockΔ19 mutants. Taken together, these studies further elucidate the abnormalities in dopaminergic transmission that underlie mood, activity, and addictive behaviors.
- Published
- 2012
20. Activation of Gαq Signaling Enhances Memory Consolidation and Slows Cognitive Decline
- Author
-
Geneva M. Stein, Coleen T. Murphy, Rachel N. Arey, Rachel Kaletsky, and Amanda Kauffman
- Subjects
0301 basic medicine ,General Neuroscience ,Cognition ,Biology ,Stimulus (physiology) ,Impaired memory ,CREB ,Sensory neuron ,Associative learning ,03 medical and health sciences ,030104 developmental biology ,medicine.anatomical_structure ,medicine ,biology.protein ,Memory consolidation ,Cognitive decline ,Neuroscience - Abstract
Perhaps the most devastating decline with age is the loss of memory. Therefore, identifying mechanisms to restore memory function with age is critical. Using C. elegans associative learning and memory assays, we identified a gain-of-function Gαq signaling pathway mutant that forms a long-term (cAMP response element binding protein [CREB]-dependent) memory following one conditioned stimulus-unconditioned stimulus (CS-US) pairing, which usually requires seven CS-US pairings. Increased CREB activity in AIM interneurons reduces the threshold for memory consolidation through transcription of a set of previously identified "long-term memory" genes. Enhanced Gαq signaling in the AWC sensory neuron is both necessary and sufficient for improved memory and increased AIM CREB activity, and activation of Gαq specifically in aged animals rescues the ability to form memory. Activation of Gαq in AWC sensory neurons non-cell autonomously induces consolidation after one CS-US pairing, enabling both cognitive function maintenance with age and restoration of memory function in animals with impaired memory performance without decreased longevity.
- Published
- 2018
21. 163. Utility of the Clock Mutant Mouse Model of Mania as a Tool for Drug Discovery
- Author
-
Colleen A. McClung, Ethan Fitzgerald, Rachel N. Arey, Xiyu Zhu, Ryan W. Logan, and Angela R. Ozburn
- Subjects
Drug discovery ,Mutant ,medicine ,Computational biology ,Biology ,medicine.symptom ,Mania ,Biological Psychiatry - Published
- 2018
22. The role of clock in ethanol-related behaviors
- Author
-
Colleen A. McClung, Edgardo Falcon, Angela R. Ozburn, Andrea G. Gillman, Shibani Mukherjee, Rachel N. Arey, and Sade Spencer
- Subjects
Male ,medicine.medical_specialty ,Pentobarbital ,Alcohol Drinking ,CLOCK Proteins ,Choice Behavior ,Mice ,Dopamine ,Internal medicine ,medicine ,Animals ,Circadian rhythm ,Pharmacology ,Mice, Inbred BALB C ,Sex Characteristics ,Ethanol ,Dopaminergic ,Ventral Tegmental Area ,Mice, Mutant Strains ,Ventral tegmental area ,CLOCK ,Psychiatry and Mental health ,Endocrinology ,medicine.anatomical_structure ,Acamprosate ,Biochemistry ,Female ,Original Article ,Psychology ,medicine.drug - Abstract
Mice with a mutation in the Clock gene (ClockΔ19) exhibit increased preference for stimulant rewards and sucrose. They also have an increase in dopaminergic activity in the ventral tegmental area (VTA) and a general increase in glutamatergic tone that might underlie these behaviors. However, it is unclear if their phenotype would extend to a very different class of drug (ethanol), and if so, whether these systems might be involved in their response. Continuous access voluntary ethanol intake was evaluated in ClockΔ19 mutants and wild-type (WT) mice. We found that ClockΔ19 mice exhibited significantly increased ethanol intake in a two-bottle choice paradigm. Interestingly, this effect was more robust in female mice. Moreover, chronic ethanol experience resulted in a long-lasting decrease in VTA Clock expression. To determine the importance of VTA Clock expression in ethanol intake, we knocked down Clock expression in the VTA of WT mice via RNA interference. We found that reducing Clock expression in the VTA resulted in significantly increased ethanol intake similar to the ClockΔ19 mice. Interestingly, we also discovered that ClockΔ19 mice exhibit significantly augmented responses to the sedative effects of ethanol and ketamine, but not pentobarbital. However, their drinking behavior was not affected by acamprosate, an FDA-approved drug for the treatment of alcoholism, suggesting that their increased glutamatergic tone might underlie the increased sensitivity to the sedative/hypnotic properties of ethanol but not the rewarding properties of ethanol. Taken together, we have identified a significant role for Clock in the VTA as a negative regulator of ethanol intake and implicate the VTA dopamine system in this response.
- Published
- 2012
23. ΔFosB indirectly regulates Cck promoter activity
- Author
-
Madison Paddock, Scott Edwards, Elizabeth Hoffman, Megan Wald, John F. Enwright, Sade Spencer, Rachel N. Arey, Eric J. Nestler, and Colleen A. McClung
- Subjects
Male ,Time Factors ,media_common.quotation_subject ,Genetic Vectors ,Immunoblotting ,Gene Expression ,Mice, Transgenic ,Striatum ,Nucleus accumbens ,CREB ,PC12 Cells ,Polymerase Chain Reaction ,Article ,Mice ,Transcription (biology) ,Gene expression ,Animals ,Immunoprecipitation ,Cyclic AMP Response Element-Binding Protein ,Promoter Regions, Genetic ,Molecular Biology ,Transcription factor ,media_common ,biology ,General Neuroscience ,Addiction ,Promoter ,Molecular biology ,Corpus Striatum ,Rats ,Up-Regulation ,biology.protein ,Neurology (clinical) ,Cholecystokinin ,Proto-Oncogene Proteins c-fos ,Developmental Biology ,Plasmids - Abstract
Some of the important biochemical, structural, and behavioral changes induced by chronic exposure to drugs of abuse appear to be mediated by the highly stable transcription factor DeltaFosB. Previous work has shown that DeltaFosB overexpression in mice for 2weeks leads to an increase in the expression of numerous genes in striatum, most of which are later downregulated following 8weeks of FosB expression. Interestingly, a large number of these genes were also upregulated in mice overexpressing the transcription factor CREB. It was unclear from this study, however, whether short-term DeltaFosB regulates these genes via CREB. Here, we find that 2weeks of DeltaFosB overexpression increases CREB expression in striatum, an effect that dissipates by 8weeks. The early induction is associated with increased CREB binding to certain target gene promoters in this brain region. Surprisingly, one gene that was a suspected CREB target based on previous reports, cholecystokinin (Cck), was not controlled by CREB in striatum. To further investigate the regulation of Cck following DeltaFosB overexpression, we confirmed that short-term DeltaFosB overexpression increases both Cck promoter activity and gene expression. It also increases binding activity at a putative CREB binding site (CRE) in the Cck promoter. However, while the CRE site is necessary for normal basal expression of Cck, it is not required for DeltaFosB induction of Cck. Taken together, these results suggest that while short-term DeltaFosB induction increases CREB expression and activity at certain gene promoters, this is not the only mechanism by which genes are upregulated under these conditions.
- Published
- 2010
24. Erratum: An important role for Cholecystokinin, a CLOCK target gene, in the development and treatment of manic-like behaviors
- Author
-
Edgardo Falcon, Rachel N. Arey, Sade Spencer, Colleen A. McClung, Carol A. Tamminga, Angela R. Ozburn, Subroto Ghose, and John F. Enwright
- Subjects
Cellular and Molecular Neuroscience ,Psychiatry and Mental health ,medicine.medical_specialty ,medicine ,Target gene ,Psychology ,Psychiatry ,Molecular Biology ,Neuroscience ,Cholecystokinin - Published
- 2013
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.