Publications by authors named "Rachel N Arey"

8 Publications

  • Page 1 of 1

Valproate reverses mania-like behaviors in mice via preferential targeting of HDAC2.

Mol Psychiatry 2020 Nov 24. Epub 2020 Nov 24.

Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA.

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.
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http://dx.doi.org/10.1038/s41380-020-00958-2DOI Listing
November 2020

Nervous system-wide profiling of presynaptic mRNAs reveals regulators of associative memory.

Sci Rep 2019 12 30;9(1):20314. Epub 2019 Dec 30.

Department of Molecular Biology & LSI Genomics, Princeton University, Princeton, NJ, 08544, USA.

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.
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http://dx.doi.org/10.1038/s41598-019-56908-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937282PMC
December 2019

Activation of G Signaling Enhances Memory Consolidation and Slows Cognitive Decline.

Neuron 2018 05 12;98(3):562-574.e5. Epub 2018 Apr 12.

Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA; Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA. Electronic address:

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 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 G signaling in the AWC sensory neuron is both necessary and sufficient for improved memory and increased AIM CREB activity, and activation of G specifically in aged animals rescues the ability to form memory. Activation of G 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.
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http://dx.doi.org/10.1016/j.neuron.2018.03.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5934306PMC
May 2018

RNA surveillance via nonsense-mediated mRNA decay is crucial for longevity in daf-2/insulin/IGF-1 mutant C. elegans.

Nat Commun 2017 03 9;8:14749. Epub 2017 Mar 9.

Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk 37673, South Korea.

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.
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http://dx.doi.org/10.1038/ncomms14749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5347137PMC
March 2017

Conserved regulators of cognitive aging: From worms to humans.

Behav Brain Res 2017 03 18;322(Pt B):299-310. Epub 2016 Jun 18.

Department of Molecular Biology & LSI Genomics, Princeton University, Princeton, NJ 08544, United States. Electronic address:

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.
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http://dx.doi.org/10.1016/j.bbr.2016.06.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5164975PMC
March 2017

The Neuronal Kinesin UNC-104/KIF1A Is a Key Regulator of Synaptic Aging and Insulin Signaling-Regulated Memory.

Curr Biol 2016 Mar 11;26(5):605-15. Epub 2016 Feb 11.

Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA; Department of Biology, Stanford University, Stanford, CA 94305, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.cub.2015.12.068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4783184PMC
March 2016

Genome-wide functional analysis of CREB/long-term memory-dependent transcription reveals distinct basal and memory gene expression programs.

Neuron 2015 Jan;85(2):330-45

Department of Molecular Biology & LSI Genomics, Princeton University, Princeton, NJ 08544, USA. Electronic address:

Induced CREB activity is a hallmark of long-term memory, but the full repertoire of CREB transcriptional targets required specifically for memory is not known in any system. To obtain a more complete picture of the mechanisms involved in memory, we combined memory training with genome-wide transcriptional analysis of C. elegans CREB mutants. This approach identified 757 significant CREB/memory-induced targets and confirmed the involvement of known memory genes from other organisms, but also suggested new mechanisms and novel components that may be conserved through mammals. CREB mediates distinct basal and memory transcriptional programs at least partially through spatial restriction of CREB activity: basal targets are regulated primarily in nonneuronal tissues, while memory targets are enriched for neuronal expression, emanating from CREB activity in AIM neurons. This suite of novel memory-associated genes will provide a platform for the discovery of orthologous mammalian long-term memory components.
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http://dx.doi.org/10.1016/j.neuron.2014.12.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4340687PMC
January 2015

Direct regulation of diurnal Drd3 expression and cocaine reward by NPAS2.

Biol Psychiatry 2015 Mar 13;77(5):425-433. Epub 2014 Aug 13.

Department of Psychiatry and Translational Neuroscience Program, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219.

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.
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http://dx.doi.org/10.1016/j.biopsych.2014.07.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4315729PMC
March 2015