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  1. Article ; Online: Targeting histone demethylase LSD1 for treatment of deficits in autism mouse models.

    Rapanelli, Maximiliano / Williams, Jamal B / Ma, Kaijie / Yang, Fengwei / Zhong, Ping / Patel, Rajvi / Kumar, Manasa / Qin, Luye / Rein, Benjamin / Wang, Zi-Jun / Kassim, Bibi / Javidfar, Behnam / Couto, Lizette / Akbarian, Schahram / Yan, Zhen

    Molecular psychiatry

    2022  Volume 27, Issue 8, Page(s) 3355–3366

    Abstract: Large-scale genetic studies have revealed that the most prominent genes disrupted in autism are chromatin regulators mediating histone methylation/demethylation, suggesting the central role of epigenetic dysfunction in this disorder. Here, we show that ... ...

    Abstract Large-scale genetic studies have revealed that the most prominent genes disrupted in autism are chromatin regulators mediating histone methylation/demethylation, suggesting the central role of epigenetic dysfunction in this disorder. Here, we show that histone lysine 4 dimethylation (H3K4me2), a histone mark linked to gene activation, is significantly decreased in the prefrontal cortex (PFC) of autistic human patients and mutant mice with the deficiency of top-ranking autism risk factor Shank3 or Cul3. A brief treatment of the autism models with highly potent and selective inhibitors of the H3K4me2 demethylase LSD1 (KDM1A) leads to the robust rescue of core symptoms of autism, including social deficits and repetitive behaviors. Concomitantly, LSD1 inhibition restores NMDA receptor function in PFC and AMPA receptor-mediated currents in striatum of Shank3-deficient mice. Genome-wide RNAseq and ChIPseq reveal that treatment of Shank3-deficient mice with the LSD1 inhibitor restores the expression and H3K4me2 occupancy of downregulated genes enriched in synaptic signaling and developmental processes. The immediate early gene tightly linked to neuronal plasticity, Egr1, is on the top list of rescued genes. The diminished transcription of Egr1 is recapitulated in PFC of autistic human patients. Overexpression of Egr1 in PFC of Shank3-deficient mice ameliorates social preference deficits. These results have for the first time revealed an important role of H3K4me2 abnormality in ASD pathophysiology, and the therapeutic potential of targeting H3K4me2 demethylase LSD1 or the downstream molecule Egr1 for ASD.
    MeSH term(s) Humans ; Mice ; Animals ; Histones/metabolism ; Autistic Disorder ; Histone Demethylases/genetics ; Histone Demethylases/metabolism ; Chromatin ; Disease Models, Animal ; Microfilament Proteins/genetics ; Nerve Tissue Proteins/metabolism
    Chemical Substances Histones ; Histone Demethylases (EC 1.14.11.-) ; Chromatin ; KDM1A protein, human (EC 1.5.-) ; Shank3 protein, mouse ; Microfilament Proteins ; Nerve Tissue Proteins
    Language English
    Publishing date 2022-03-16
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1330655-8
    ISSN 1476-5578 ; 1359-4184
    ISSN (online) 1476-5578
    ISSN 1359-4184
    DOI 10.1038/s41380-022-01508-8
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Glucocorticoid Regulation of Food-Choice Behavior in Humans: Evidence from Cushing's Syndrome.

    Moeller, Scott J / Couto, Lizette / Cohen, Vanessa / Lalazar, Yelena / Makotkine, Iouri / Williams, Nia / Yehuda, Rachel / Goldstein, Rita Z / Geer, Eliza B

    Frontiers in neuroscience

    2016  Volume 10, Page(s) 21

    Abstract: The mechanisms by which glucocorticoids regulate food intake and resulting body mass in humans are not well-understood. One potential mechanism could involve modulation of reward processing, but human stress models examining effects of glucocorticoids on ...

    Abstract The mechanisms by which glucocorticoids regulate food intake and resulting body mass in humans are not well-understood. One potential mechanism could involve modulation of reward processing, but human stress models examining effects of glucocorticoids on behavior contain important confounds. Here, we studied individuals with Cushing's syndrome, a rare endocrine disorder characterized by chronic excess endogenous glucocorticoids. Twenty-three patients with Cushing's syndrome (13 with active disease; 10 with disease in remission) and 15 controls with a comparably high body mass index (BMI) completed two simulated food-choice tasks (one with "explicit" task contingencies and one with "probabilistic" task contingencies), during which they indicated their objective preference for viewing high calorie food images vs. standardized pleasant, unpleasant, and neutral images. All participants also completed measures of food craving, and approximately half of the participants provided 24-h urine samples for assessment of cortisol and cortisone concentrations. Results showed that on the explicit task (but not the probabilistic task), participants with active Cushing's syndrome made fewer food-related choices than participants with Cushing's syndrome in remission, who in turn made fewer food-related choices than overweight controls. Corroborating this group effect, higher urine cortisone was negatively correlated with food-related choice in the subsample of all participants for whom these data were available. On the probabilistic task, despite a lack of group differences, higher food-related choice correlated with higher state and trait food craving in active Cushing's patients. Taken together, relative to overweight controls, Cushing's patients, particularly those with active disease, displayed a reduced vigor of responding for food rewards that was presumably attributable to glucocorticoid abnormalities. Beyond Cushing's, these results may have relevance for elucidating glucocorticoid contributions to food-seeking behavior, enhancing mechanistic understanding of weight fluctuations associated with oral glucocorticoid therapy and/or chronic stress, and informing the neurobiology of neuropsychiatric conditions marked by abnormal cortisol dynamics (e.g., major depression, Alzheimer's disease).
    Language English
    Publishing date 2016-02-05
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2411902-7
    ISSN 1662-453X ; 1662-4548
    ISSN (online) 1662-453X
    ISSN 1662-4548
    DOI 10.3389/fnins.2016.00021
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Chromatin domain alterations linked to 3D genome organization in a large cohort of schizophrenia and bipolar disorder brains.

    Girdhar, Kiran / Hoffman, Gabriel E / Bendl, Jaroslav / Rahman, Samir / Dong, Pengfei / Liao, Will / Hauberg, Mads E / Sloofman, Laura / Brown, Leanne / Devillers, Olivia / Kassim, Bibi S / Wiseman, Jennifer R / Park, Royce / Zharovsky, Elizabeth / Jacobov, Rivky / Flatow, Elie / Kozlenkov, Alexey / Gilgenast, Thomas / Johnson, Jessica S /
    Couto, Lizette / Peters, Mette A / Phillips-Cremins, Jennifer E / Hahn, Chang-Gyu / Gur, Raquel E / Tamminga, Carol A / Lewis, David A / Haroutunian, Vahram / Dracheva, Stella / Lipska, Barbara K / Marenco, Stefano / Kundakovic, Marija / Fullard, John F / Jiang, Yan / Roussos, Panos / Akbarian, Schahram

    Nature neuroscience

    2022  Volume 25, Issue 4, Page(s) 474–483

    Abstract: Chromosomal organization, scaling from the 147-base pair (bp) nucleosome to megabase-ranging domains encompassing multiple transcriptional units, including heritability loci for psychiatric traits, remains largely unexplored in the human brain. In this ... ...

    Abstract Chromosomal organization, scaling from the 147-base pair (bp) nucleosome to megabase-ranging domains encompassing multiple transcriptional units, including heritability loci for psychiatric traits, remains largely unexplored in the human brain. In this study, we constructed promoter- and enhancer-enriched nucleosomal histone modification landscapes for adult prefrontal cortex from H3-lysine 27 acetylation and H3-lysine 4 trimethylation profiles, generated from 388 controls and 351 individuals diagnosed with schizophrenia (SCZ) or bipolar disorder (BD) (n = 739). We mapped thousands of cis-regulatory domains (CRDs), revealing fine-grained, 10
    MeSH term(s) Adult ; Bipolar Disorder/genetics ; Brain ; Chromatin ; Humans ; Lysine/genetics ; Schizophrenia/genetics
    Chemical Substances Chromatin ; Lysine (K3Z4F929H6)
    Language English
    Publishing date 2022-03-24
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural
    ZDB-ID 1420596-8
    ISSN 1546-1726 ; 1097-6256
    ISSN (online) 1546-1726
    ISSN 1097-6256
    DOI 10.1038/s41593-022-01032-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 4891: Show issues Location:
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  4. Article ; Online: A prospective study of appetite and food craving in 30 patients with Cushing's disease.

    Geer, Eliza B / Lalazar, Yelena / Couto, Lizette M / Cohen, Vanessa / Lipton, Lianna R / Shi, Wei / Bagiella, Emilia / Conwell, Irene / Bederson, Joshua / Kostadinov, Jane / Post, Kalmon D / Freda, Pamela U

    Pituitary

    2016  Volume 19, Issue 2, Page(s) 117–126

    Abstract: Context: Glucocorticoid (GC) exposure increases food intake, but the mechanisms in humans are not known. Investigation of appetite and food craving has not been done in patients with chronic GC exposure due to Cushing's disease (CD), either before or ... ...

    Abstract Context: Glucocorticoid (GC) exposure increases food intake, but the mechanisms in humans are not known. Investigation of appetite and food craving has not been done in patients with chronic GC exposure due to Cushing's disease (CD), either before or after treatment, and could provide insight into mechanisms of food intake and obesity in these patients.
    Purpose: To examine whether surgical remission of CD changes appetite (prospective consumption, hunger, satisfaction, and fullness) and food cravings (sweet, salty, fatty, and savory); and to identify predictors of appetite and craving in CD remission.
    Methods: 30 CD patients, mean age 40.0 years (range 17-70), mean BMI 32.3 ± 6.4, were prospectively studied before and at a mean of 17.4 mo. after remission. At each visit fasting and post-test meal (50% carbohydrate, 35% protein, 15% fat) appetite and craving scores were assessed.
    Results: Remission decreased prospective consumption, sweet and savory craving (p < 0.05), but did not change hunger, satisfaction, fullness, or fat craving, despite decreases in BMI and fat mass. In CD remission, serum cortisol predicted lower satisfaction and fullness, and masses of abdominal fat depots predicted higher hunger and consumption (p < 0.05).
    Conclusions: Chronic GC exposure in CD patients may stimulate the drive to eat by enhancing craving, rather than regulating the sensation of hunger. Continued alterations in appetite regulation due to abdominal fat mass and circulating cortisol could play a role in the cardiovascular and metabolic risk that has been reported in CD patients despite remission.
    MeSH term(s) Adolescent ; Adult ; Aged ; Appetite/physiology ; Body Composition/physiology ; Craving/physiology ; Eating/physiology ; Eating/psychology ; Female ; Food ; Food Preferences/physiology ; Humans ; Male ; Middle Aged ; Neurosurgical Procedures/methods ; Pituitary ACTH Hypersecretion/diagnosis ; Pituitary ACTH Hypersecretion/physiopathology ; Pituitary ACTH Hypersecretion/psychology ; Pituitary ACTH Hypersecretion/surgery ; Prognosis ; Young Adult
    Language English
    Publishing date 2016-04
    Publishing country United States
    Document type Clinical Trial ; Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1385151-2
    ISSN 1573-7403 ; 1386-341X
    ISSN (online) 1573-7403
    ISSN 1386-341X
    DOI 10.1007/s11102-015-0690-1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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