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Article ; Online: Circuit-wide gene network analysis reveals sex-specific roles for phosphodiesterase 1b in cocaine addiction.

The Journal of neuroscience : the official journal of the Society for Neuroscience

2024

Abstract: Cocaine use disorder is a significant public health issue without an effective pharmacological treatment. Successful treatments are hindered in part by an incomplete understanding of the molecular mechanisms that underlie long-lasting maladaptive ... ...

Abstract	Cocaine use disorder is a significant public health issue without an effective pharmacological treatment. Successful treatments are hindered in part by an incomplete understanding of the molecular mechanisms that underlie long-lasting maladaptive plasticity and addiction-like behaviors. Here, we leverage a large RNA-sequencing dataset to generate gene co-expression networks across 6 interconnected regions of the brain's reward circuitry from mice that underwent saline or cocaine self-administration. We identify phosphodiesterase 1b (
Language	English
Publishing date	2024-04-18
Publishing country	United States
Document type	Journal Article
ZDB-ID	604637-x
ISSN	1529-2401 ; 0270-6474
ISSN (online)	1529-2401
ISSN	0270-6474
DOI	10.1523/JNEUROSCI.1327-23.2024
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Article: Sex-Specific Regulation of Stress Susceptibility by the Astrocytic Gene

Parise, Eric M / Gyles, Trevonn M / Godino, Arthur / Sial, Omar K / Browne, Caleb J / Parise, Lyonna F / Torres-Berrío, Angélica / Salery, Marine / Durand-de Cuttoli, Romain / Rivera, Matthew T / Cardona-Acosta, Astrid M / Holt, Leanne / Markovic, Tamara / van der Zee, Yentl Y / Lorsch, Zachary S / Cathomas, Flurin / Garon, Juliet B / Teague, Collin / Issler, Orna /

Hamilton, Peter J / Bolaños-Guzmán, Carlos A / Russo, Scott J / Nestler, Eric J

bioRxiv : the preprint server for biology

2024

Abstract: Major depressive disorder (MDD) is linked to impaired structural and synaptic plasticity in limbic brain regions. Astrocytes, which regulate synapses and are influenced by chronic stress, likely contribute to these changes. We analyzed astrocyte gene ... ...

Abstract	Major depressive disorder (MDD) is linked to impaired structural and synaptic plasticity in limbic brain regions. Astrocytes, which regulate synapses and are influenced by chronic stress, likely contribute to these changes. We analyzed astrocyte gene profiles in the nucleus accumbens (NAc) of humans with MDD and mice exposed to chronic stress.
Language	English
Publishing date	2024-04-15
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.04.12.588724
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Article ; Online: The long noncoding RNA FEDORA is a cell type- and sex-specific regulator of depression.

Science advances

2022 Volume 8, Issue 48, Page(s) eabn9494

Abstract: Women suffer from depression at twice the rate of men, but the underlying molecular mechanisms are poorly understood. Here, we identify marked baseline sex differences in the expression of long noncoding RNAs (lncRNAs), a class of regulatory transcripts, ...

Abstract	Women suffer from depression at twice the rate of men, but the underlying molecular mechanisms are poorly understood. Here, we identify marked baseline sex differences in the expression of long noncoding RNAs (lncRNAs), a class of regulatory transcripts, in human postmortem brain tissue that are profoundly lost in depression. One such human lncRNA, RP11-298D21.1 (which we termed FEDORA), is enriched in oligodendrocytes and neurons and up-regulated in the prefrontal cortex (PFC) of depressed females only. We found that virally expressing FEDORA selectively either in neurons or in oligodendrocytes of PFC promoted depression-like behavioral abnormalities in female mice only, changes associated with cell type-specific regulation of synaptic properties, myelin thickness, and gene expression. We also found that blood FEDORA levels have diagnostic implications for depressed women and are associated with clinical response to ketamine. These findings demonstrate the important role played by lncRNAs, and FEDORA in particular, in shaping the sex-specific landscape of the brain and contributing to sex differences in depression.
Language	English
Publishing date	2022-11-30
Publishing country	United States
Document type	Journal Article
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.abn9494
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Article ; Online: Blood miR-144-3p: a novel diagnostic and therapeutic tool for depression.

Molecular psychiatry

2022 Volume 27, Issue 11, Page(s) 4536–4549

Abstract: Major depressive disorder (MDD) is the leading cause of disability worldwide. There is an urgent need for objective biomarkers to diagnose this highly heterogeneous syndrome, assign treatment, and evaluate treatment response and prognosis. MicroRNAs ( ... ...

Abstract	Major depressive disorder (MDD) is the leading cause of disability worldwide. There is an urgent need for objective biomarkers to diagnose this highly heterogeneous syndrome, assign treatment, and evaluate treatment response and prognosis. MicroRNAs (miRNAs) are short non-coding RNAs, which are detected in body fluids that have emerged as potential biomarkers of many disease conditions. The present study explored the potential use of miRNAs as biomarkers for MDD and its treatment. We profiled the expression levels of circulating blood miRNAs from mice that were collected before and after exposure to chronic social defeat stress (CSDS), an extensively validated mouse model used to study depression, as well as after either repeated imipramine or single-dose ketamine treatment. We observed robust differences in blood miRNA signatures between stress-resilient and stress-susceptible mice after an incubation period, but not immediately after exposure to the stress. Furthermore, ketamine treatment was more effective than imipramine at re-establishing baseline miRNA expression levels, but only in mice that responded behaviorally to the drug. We identified the red blood cell-specific miR-144-3p as a candidate biomarker to aid depression diagnosis and predict ketamine treatment response in stress-susceptible mice and MDD patients. Lastly, we demonstrate that systemic knockdown of miR-144-3p, via subcutaneous administration of a specific antagomir, is sufficient to reduce the depression-related phenotype in stress-susceptible mice. RNA-sequencing analysis of blood after such miR-144-3p knockdown revealed a blunted transcriptional stress signature as well. These findings identify miR-144-3p as a novel target for diagnosis of MDD as well as for antidepressant treatment, and enhance our understanding of epigenetic processes associated with depression.
MeSH term(s)	Mice ; Animals ; Depressive Disorder, Major/diagnosis ; Depressive Disorder, Major/drug therapy ; Depressive Disorder, Major/genetics ; MicroRNAs/metabolism ; Biomarkers ; Epigenesis, Genetic ; Antidepressive Agents/pharmacology ; Antidepressive Agents/therapeutic use ; Ketamine/pharmacology ; Ketamine/therapeutic use
Chemical Substances	MicroRNAs ; Biomarkers ; Antidepressive Agents ; Ketamine (690G0D6V8H)
Language	English
Publishing date	2022-07-28
Publishing country	England
Document type	Journal Article
ZDB-ID	1330655-8
ISSN	1476-5578 ; 1359-4184
ISSN (online)	1476-5578
ISSN	1359-4184
DOI	10.1038/s41380-022-01712-6
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Zs.A 4812: Show issues

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Article ; Online: Long-term behavioral and cell-type-specific molecular effects of early life stress are mediated by H3K79me2 dynamics in medium spiny neurons.

Kronman, Hope / Torres-Berrío, Angélica / Sidoli, Simone / Issler, Orna / Godino, Arthur / Ramakrishnan, Aarthi / Mews, Philipp / Lardner, Casey K / Parise, Eric M / Walker, Deena M / van der Zee, Yentl Y / Browne, Caleb J / Boyce, Brittany F / Neve, Rachael / Garcia, Benjamin A / Shen, Li / Peña, Catherine J / Nestler, Eric J

Nature neuroscience

2021 Volume 24, Issue 5, Page(s) 667–676

Abstract: Animals susceptible to chronic social defeat stress (CSDS) exhibit depression-related behaviors, with aberrant transcription across several limbic brain regions, most notably in the nucleus accumbens (NAc). Early life stress (ELS) promotes susceptibility ...

Abstract	Animals susceptible to chronic social defeat stress (CSDS) exhibit depression-related behaviors, with aberrant transcription across several limbic brain regions, most notably in the nucleus accumbens (NAc). Early life stress (ELS) promotes susceptibility to CSDS in adulthood, but associated enduring changes in transcriptional control mechanisms in the NAc have not yet been investigated. In this study, we examined long-lasting changes to histone modifications in the NAc of male and female mice exposed to ELS. Dimethylation of lysine 79 of histone H3 (H3K79me2) and the enzymes (DOT1L and KDM2B) that control this modification are enriched in D2-type medium spiny neurons and are shown to be crucial for the expression of ELS-induced stress susceptibility. We mapped the site-specific regulation of this histone mark genome wide to reveal the transcriptional networks it modulates. Finally, systemic delivery of a small molecule inhibitor of DOT1L reversed ELS-induced behavioral deficits, indicating the clinical relevance of this epigenetic mechanism.
MeSH term(s)	Animals ; F-Box Proteins/metabolism ; Gene Expression Regulation ; Histone Demethylases/metabolism ; Histone-Lysine N-Methyltransferase/metabolism ; Histones/metabolism ; Jumonji Domain-Containing Histone Demethylases/metabolism ; Male ; Mice ; Neurons/metabolism ; Nucleus Accumbens/metabolism ; Receptors, Dopamine D1/metabolism ; Receptors, Dopamine D2/metabolism ; Stress, Psychological/metabolism
Chemical Substances	F-Box Proteins ; Histones ; Receptors, Dopamine D1 ; Receptors, Dopamine D2 ; Histone Demethylases (EC 1.14.11.-) ; Jumonji Domain-Containing Histone Demethylases (EC 1.14.11.-) ; KDM2A protein, human (EC 1.14.11.27) ; Dot1l protein, mouse (EC 2.1.1.-) ; Histone-Lysine N-Methyltransferase (EC 2.1.1.43)
Language	English
Publishing date	2021-03-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1420596-8
ISSN	1546-1726 ; 1097-6256
ISSN (online)	1546-1726
ISSN	1097-6256
DOI	10.1038/s41593-021-00814-8
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Zs.A 4891: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Author Correction: Long-term behavioral and cell-type-specific molecular effects of early life stress are mediated by H3K79me2 dynamics in medium spiny neurons.

Nature neuroscience

2021 Volume 24, Issue 5, Page(s) 753–754

Language	English
Publishing date	2021-04-08
Publishing country	United States
Document type	Published Erratum
ZDB-ID	1420596-8
ISSN	1546-1726 ; 1097-6256
ISSN (online)	1546-1726
ISSN	1097-6256
DOI	10.1038/s41593-021-00848-y
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Zs.A 4891: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Sex-Specific Role for SLIT1 in Regulating Stress Susceptibility.

Biological psychiatry

2021 Volume 91, Issue 1, Page(s) 81–91

Abstract: Background: Major depressive disorder is a pervasive and debilitating syndrome characterized by mood disturbances, anhedonia, and alterations in cognition. While the prevalence of major depressive disorder is twice as high for women as men, little is ... ...

Abstract	Background: Major depressive disorder is a pervasive and debilitating syndrome characterized by mood disturbances, anhedonia, and alterations in cognition. While the prevalence of major depressive disorder is twice as high for women as men, little is known about the molecular mechanisms that drive sex differences in depression susceptibility. Methods: We discovered that SLIT1, a secreted protein essential for axonal navigation and molecular guidance during development, is downregulated in the adult ventromedial prefrontal cortex (vmPFC) of women with depression compared with healthy control subjects, but not in men with depression. This sex-specific downregulation of Slit1 was also observed in the vmPFC of mice exposed to chronic variable stress. To identify a causal, sex-specific role for SLIT1 in depression-related behavioral abnormalities, we performed knockdown (KD) of Slit1 expression in the vmPFC of male and female mice. Results: When combined with stress exposure, vmPFC Slit1 KD reflected the human condition by inducing a sex-specific increase in anxiety- and depression-related behaviors. Furthermore, we found that vmPFC Slit1 KD decreased the dendritic arborization of vmPFC pyramidal neurons and decreased the excitability of the neurons in female mice, effects not observed in males. RNA sequencing analysis of the vmPFC after Slit1 KD in female mice revealed an augmented transcriptional stress signature. Conclusions: Together, our findings establish a crucial role for SLIT1 in regulating neurophysiological and transcriptional responses to stress within the female vmPFC and provide mechanistic insight into novel signaling pathways and molecular factors influencing sex differences in depression susceptibility.
MeSH term(s)	Anhedonia ; Animals ; Anxiety ; Depressive Disorder, Major ; Female ; Male ; Mice ; Prefrontal Cortex ; Sex Characteristics
Language	English
Publishing date	2021-02-27
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	209434-4
ISSN	1873-2402 ; 0006-3223
ISSN (online)	1873-2402
ISSN	0006-3223
DOI	10.1016/j.biopsych.2021.01.019
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Zs.A 720: Show issues

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Article ; Online: Sex-Specific Role for the Long Non-coding RNA LINC00473 in Depression.

Issler, Orna / van der Zee, Yentl Y / Ramakrishnan, Aarthi / Wang, Junshi / Tan, Chunfeng / Loh, Yong-Hwee E / Purushothaman, Immanuel / Walker, Deena M / Lorsch, Zachary S / Hamilton, Peter J / Peña, Catherine J / Flaherty, Erin / Hartley, Brigham J / Torres-Berrío, Angélica / Parise, Eric M / Kronman, Hope / Duffy, Julia E / Estill, Molly S / Calipari, Erin S /

Labonté, Benoit / Neve, Rachael L / Tamminga, Carol A / Brennand, Kristen J / Dong, Yan / Shen, Li / Nestler, Eric J

Neuron

2020 Volume 106, Issue 6, Page(s) 912–926.e5

Abstract: Depression is a common disorder that affects women at twice the rate of men. Here, we report that long non-coding RNAs (lncRNAs), a recently discovered class of regulatory transcripts, represent about one-third of the differentially expressed genes in ... ...

Abstract	Depression is a common disorder that affects women at twice the rate of men. Here, we report that long non-coding RNAs (lncRNAs), a recently discovered class of regulatory transcripts, represent about one-third of the differentially expressed genes in the brains of depressed humans and display complex region- and sex-specific patterns of regulation. We identified the primate-specific, neuronal-enriched gene LINC00473 as downregulated in prefrontal cortex (PFC) of depressed females but not males. Using viral-mediated gene transfer to express LINC00473 in adult mouse PFC neurons, we mirrored the human sex-specific phenotype by inducing stress resilience solely in female mice. This sex-specific phenotype was accompanied by changes in synaptic function and gene expression selectively in female mice and, along with studies of human neuron-like cells in culture, implicates LINC00473 as a CREB effector. Together, our studies identify LINC00473 as a female-specific driver of stress resilience that is aberrant in female depression.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Animals ; Behavior, Animal ; Depression/genetics ; Depression/metabolism ; Depressive Disorder, Major/genetics ; Depressive Disorder, Major/metabolism ; Down-Regulation ; Female ; Humans ; Male ; Mice ; Mice, Transgenic ; Middle Aged ; Neurons/metabolism ; Prefrontal Cortex/metabolism ; RNA, Long Noncoding/genetics ; RNA, Long Noncoding/metabolism ; RNA-Seq ; Resilience, Psychological ; Sex Factors ; Stress, Psychological/genetics ; Stress, Psychological/metabolism ; Young Adult
Chemical Substances	LINC00473 RNA, human ; RNA, Long Noncoding
Language	English
Publishing date	2020-04-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	808167-0
ISSN	1097-4199 ; 0896-6273
ISSN (online)	1097-4199
ISSN	0896-6273
DOI	10.1016/j.neuron.2020.03.023
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Zs.A 2496: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 92: Show issues

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