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1.
Cell Mol Life Sci ; 78(6): 3045-3055, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33313982

RESUMO

Excess maternal fat intake and obesity increase offspring susceptibility to conditions such as chronic anxiety and substance abuse. We hypothesised that environmentally modulated DNA methylation changes (5mC/5hmC) in regulatory regions of the genome that modulate mood and consumptive behaviours could contribute to susceptibility to these conditions. We explored the effects of environmental factors on 5mC/5hmC levels within the GAL5.1 enhancer that controls anxiety-related behaviours and alcohol intake. We first observed that 5mC/5hmC levels within the GAL5.1 enhancer differed significantly in different parts of the brain. Moreover, we noted that early life stress had no significant effect of 5mC/5hmC levels within GAL5.1. In contrast, we identified that allowing access of pregnant mothers to high-fat diet (> 60% calories from fat) had a significant effect on 5mC/5hmC levels within GAL5.1 in hypothalamus and amygdala of resulting male offspring. Cell transfection-based studies using GAL5.1 reporter plasmids showed that 5mC has a significant repressive effect on GAL5.1 activity and its response to known stimuli, such as EGR1 transcription factor expression and PKC agonism. Intriguingly, CRISPR-driven disruption of GAL5.1 from the mouse genome, although having negligible effects on metabolism or general appetite, significantly decreased intake of high-fat diet suggesting that GAL5.1, in addition to being epigenetically modulated by high-fat diet, also actively contributes to the consumption of high-fat diet suggesting its involvement in an environmentally influenced regulatory loop. Furthermore, considering that GAL5.1 also controls alcohol preference and anxiety these studies may provide a first glimpse into an epigenetically controlled mechanism that links maternal high-fat diet with transgenerational susceptibility to alcohol abuse and anxiety.


Assuntos
Alcoolismo/patologia , Ansiedade/patologia , Dieta Hiperlipídica , Elementos Facilitadores Genéticos/genética , 5-Metilcitosina/metabolismo , Alcoolismo/genética , Tonsila do Cerebelo/metabolismo , Animais , Ansiedade/genética , Linhagem Celular Tumoral , Metilação de DNA , Modelos Animais de Doenças , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Epigênese Genética , Feminino , Humanos , Hipotálamo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína Quinase C/química , Proteína Quinase C/metabolismo
2.
Subst Use Misuse ; 55(14): 2438-2442, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32957797

RESUMO

BACKGROUND: The overwhelming fatalities of the global COVID-19 Pandemic will have daunting epigenetic sequala that can translate into an array of mental health issues, including panic, phobia, health anxiety, sleep disturbances to dissociative like symptoms including suicide. Method: We searched PUBMED for articles listed using the search terms "COVID 19 Pandemic", COVID19 and genes," "stress and COVID 19", Stress and Social distancing: Results: Long-term social distancing may be neurologically harmful, the consequence of epigenetic insults to the gene encoding the primary receptor for SARS-CoV2, and COVID 19. The gene is Angiotensin I Converting-Enzyme 2 (ACE2). According to the multi-experiment matrix (MEM), the gene exhibiting the most statistically significant co-expression link to ACE2 is Dopa Decarboxylase (DDC). DDC is a crucial enzyme that participates in the synthesis of both dopamine and serotonin. SARS-CoV2-induced downregulation of ACE2 expression might reduce dopamine and serotonin synthesis, causing hypodopaminergia. Discussion: Indeed, added to the known reduced dopamine function during periods of stress, including social distancing the consequence being both genetic and epigenetic vulnerability to all Reward Deficiency Syndrome (RDS) addictive behaviors. Stress seen in PTSD can generate downstream alterations in immune functions by reducing methylation levels of immune-related genes. Conclusion: Mitigation of these effects by identifying subjects at risk and promoting dopaminergic homeostasis to help regulate stress-relative hypodopaminergia, attenuate fears, and prevent subsequent unwanted drug and non-drug RDS type addictive behaviors seems prudent.


Assuntos
Comportamento Aditivo/genética , Infecções por Coronavirus/metabolismo , Dopamina/metabolismo , Pneumonia Viral/metabolismo , Ansiedade/genética , Ansiedade/metabolismo , Comportamento Aditivo/metabolismo , Comportamento Aditivo/psicologia , Betacoronavirus , Infecções por Coronavirus/psicologia , Dopa Descarboxilase/genética , Dopa Descarboxilase/metabolismo , Regulação para Baixo , Epigênese Genética , Humanos , Pandemias , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/psicologia , Recompensa , Estresse Psicológico/genética , Estresse Psicológico/metabolismo , Estresse Psicológico/psicologia , Transtornos Relacionados ao Uso de Substâncias/genética , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Transtornos Relacionados ao Uso de Substâncias/psicologia , Suicídio , Síndrome
3.
J Stroke Cerebrovasc Dis ; 29(9): 105040, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32807452

RESUMO

BACKGROUND: Emotional disturbances, such as anxiety and depression are common after acute ischemic stroke (AIS). Individual variation in emotional outcome is strongly influenced by genetic factors. One of pituitary axis, is the hypothalamic-pituitary-thyroid axis, a critical regulator of post-stroke recovery, suggesting that allelic variants in thyroid hormone (TH) signaling regulation can influence stroke outcome. AIM: To determine associations between AIS emotional outcome and allelic variants of the TH metabolizing enzymes 1-3 type deiodinase (DIO1-3) and the membrane transporting organic anion polypeptide 1C1 (OATP1C1). METHODS: Eligible AIS patients from Lithuania (n=168) were genotyped for ten DIO1-3 and OATP1C1 single nucleotide polymorphisms (SNP): DIO1 rs12095080-A/G, rs11206244-C/T, and rs2235544-A/C; DIO2 rs225014-T/C and rs225015-G/A; DIO3 rs945006-T/G; OATP1C1 rs974453-G/A, rs10444412-T/C, rs10770704-C/T, and rs1515777-A/G. Emotional outcome was evaluated using the Hospital Anxiety and Depression Scale at discharge from the neurology department after experienced index AIS. RESULTS: After adjustment for potential confounders, the major allelic (wild-type) DIO1-rs12095080 genotype (AA) was associated with higher odds ratio of anxiety symptoms (OR = 5.16; 95% CI: 1.04-25.58; p = 0.045), conversely, DIO1-rs11206244 wild-type genotype (CC) and wild-type OATP1C1-rs1515777 allele containing the genotypes (AA + AG) were associated with lower odds ratio of symptoms of anxiety (OR = 0.37; 95% CI: 0.14-0.96; p = 0.041 and OR = 0.30; 95% CI: 0.12-0.76; p = 0.011, respectively). Wild-type OATP1C1-rs974453 genotype (GG) was associated with higher odds ratio of symptoms of depression (OR = 2.73; 95% CI: 1.04-7.12; p = 0.041). CONCLUSION: Allelic variants in thyroid axis genes may predict emotional outcomes of AIS.


Assuntos
Afeto , Ansiedade/genética , Proteínas de Ligação a DNA/genética , Depressão/genética , Transportadores de Ânions Orgânicos/genética , Polimorfismo de Nucleotídeo Único , Acidente Vascular Cerebral/genética , Idoso , Ansiedade/diagnóstico , Ansiedade/epidemiologia , Ansiedade/psicologia , Depressão/diagnóstico , Depressão/epidemiologia , Depressão/psicologia , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Iodeto Peroxidase/genética , Lituânia/epidemiologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/psicologia
4.
PLoS Biol ; 18(4): e3000717, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32353004

RESUMO

Extensive evidence links Glutamate receptor, ionotropic, NMDA2B (GRIN2B), encoding the GluN2B/NR2B subunit of N-methyl-D-aspartate receptors (NMDARs), with various neurodevelopmental disorders, including autism spectrum disorders (ASDs), but the underlying mechanisms remain unclear. In addition, it remains unknown whether mutations in GluN2B, which starts to be expressed early in development, induces early pathophysiology that can be corrected by early treatments for long-lasting effects. We generated and characterized Grin2b-mutant mice that carry a heterozygous, ASD-risk C456Y mutation (Grin2b+/C456Y). In Grin2b+/C456Y mice, GluN2B protein levels were strongly reduced in association with decreased hippocampal NMDAR currents and NMDAR-dependent long-term depression (LTD) but unaltered long-term potentiation, indicative of mutation-induced protein degradation and LTD sensitivity. Behaviorally, Grin2b+/C456Y mice showed normal social interaction but exhibited abnormal anxiolytic-like behavior. Importantly, early, but not late, treatment of young Grin2b+/C456Y mice with the NMDAR agonist D-cycloserine rescued NMDAR currents and LTD in juvenile mice and improved anxiolytic-like behavior in adult mice. Therefore, GluN2B-C456Y haploinsufficiency decreases GluN2B protein levels, NMDAR-dependent LTD, and anxiety-like behavior, and early activation of NMDAR function has long-lasting effects on adult mouse behavior.


Assuntos
Ansiedade/genética , Hipocampo/fisiologia , Depressão Sináptica de Longo Prazo/fisiologia , Receptores de N-Metil-D-Aspartato/genética , Animais , Ansiedade/fisiopatologia , Comportamento Animal/efeitos dos fármacos , Ciclosserina/farmacologia , Potenciais Pós-Sinápticos Excitadores/genética , Técnicas de Introdução de Genes , Haploinsuficiência/genética , Heterozigoto , Hipocampo/metabolismo , Depressão Sináptica de Longo Prazo/efeitos dos fármacos , Camundongos Mutantes , Mutação , Proteínas do Tecido Nervoso/metabolismo , Receptores de N-Metil-D-Aspartato/agonistas , Receptores de N-Metil-D-Aspartato/metabolismo
5.
N Z Med J ; 133(1515): 70-78, 2020 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-32438378

RESUMO

AIMS: To describe health conditions in New Zealand nuclear veterans and their offspring, and examine the utility of tests to assess their heritability. METHOD: An online survey, open to all veterans and offspring, with questions on health conditions, the GHQ12 to measure psychological distress, the Euroquol-5D visual analogue scale (EQ5D VAS) to measure health state, and free text items on veteran support. RESULTS: Eighty-three responses (56%) were from veterans, 65 (44%) from offspring. Anxiety and depression were prevalent in both groups, with cancers (n=31, 37%) and joint conditions common in veterans (n=26, 31%). Few offspring reported cancer, rather problems with fertility (n=18, 40%). The free text themes fell into four domains, official commitment, health, emotional and information support; however, little support had been sought. CONCLUSION: Cancers have utility in assessing heritability, but a low prevalence and lack of diagnostic data rules this out. Psychological conditions may be heritable, but the techniques to assess this are still developing. Chromosomal damage in veterans and offspring can be detected, but with present knowledge cannot explain health outcomes. Future work should assemble a veteran and family register with linkage to routine data-sets. Veterans and offspring should be encouraged to seek support.


Assuntos
Ansiedade/epidemiologia , Depressão/epidemiologia , Neoplasias/epidemiologia , Armas Nucleares , Exposição Ocupacional , Veteranos/estatística & dados numéricos , Adolescente , Adulto , Idoso , Ansiedade/genética , Depressão/genética , Família , Testes Genéticos , Inquéritos Epidemiológicos , Humanos , Infertilidade/epidemiologia , Infertilidade/genética , Artropatias/epidemiologia , Artropatias/genética , Pessoa de Meia-Idade , Neoplasias/genética , Nova Zelândia/epidemiologia , Exposição Ocupacional/efeitos adversos , Prevalência , Radiação Ionizante , Apoio Social , Adulto Jovem
6.
PLoS One ; 15(5): e0232789, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32407325

RESUMO

BAHD1 is a heterochomatinization factor recently described as a component of a multiprotein complex associated with histone deacetylases HDAC1/2. The physiological and patho-physiological functions of BAHD1 are not yet well characterized. Here, we examined the consequences of BAHD1 deficiency in the brains of male mice. While Bahd1 knockout mice had no detectable defects in brain anatomy, RNA sequencing profiling revealed about 2500 deregulated genes in Bahd1-/- brains compared to Bahd1+/+ brains. A majority of these genes were involved in nervous system development and function, behavior, metabolism and immunity. Exploration of the Allen Brain Atlas and Dropviz databases, assessing gene expression in the brain, revealed that expression of the Bahd1 gene was limited to a few territories and cell subtypes, particularly in the hippocampal formation, the isocortex and the olfactory regions. The effect of partial BAHD1 deficiency on behavior was then evaluated on Bahd1 heterozygous male mice, which have no lethal or metabolic phenotypes. Bahd1+/- mice showed anxiety-like behavior and reduced prepulse inhibition (PPI) of the startle response. Altogether, these results suggest that BAHD1 plays a role in chromatin-dependent gene regulation in a subset of brain cells and support recent evidence linking genetic alteration of BAHD1 to psychiatric disorders in a human patient.


Assuntos
Ansiedade/genética , Encéfalo/metabolismo , Proteínas Cromossômicas não Histona/genética , Reflexo de Sobressalto/genética , Animais , Ansiedade/fisiopatologia , Encéfalo/patologia , Cromatina/genética , Regulação da Expressão Gênica/genética , Haploinsuficiência/genética , Histona Desacetilase 1/genética , Histona Desacetilase 2/genética , Humanos , Camundongos , Camundongos Knockout , Fenótipo , Análise de Sequência de RNA
7.
J Neurosci ; 40(24): 4739-4749, 2020 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-32393533

RESUMO

High trait anxiety is associated with altered activity across emotion regulation circuitry and a higher risk of developing anxiety disorders and depression. This circuitry is extensively modulated by serotonin. Here, to understand why some people may be more vulnerable to developing affective disorders, we investigated whether serotonin-related gene expression across the brain's emotion regulation circuitry may underlie individual differences in trait anxiety using the common marmoset (Callithrix jacchus, mixed sexes) as a model. First, we assessed the association of region-specific expression of the serotonin transporter (SLC6A4) and serotonin receptor (HTR1A, HTR2A, HTR2C) genes with anxiety-like behavior; and second, we investigated their causal role in two key features of the high trait anxious phenotype: high responsivity to anxiety-provoking stimuli and an exaggerated conditioned threat response. While the expression of the serotonin receptors did not show a significant relationship with anxiety-like behavior in any of the targeted brain regions, serotonin transporter expression, specifically within the right ventrolateral prefrontal cortex (vlPFC) and most strongly in the right amygdala, was associated positively with anxiety-like behavior. The causal relationship between amygdala serotonin levels and an animal's sensitivity to threat was confirmed via direct amygdala infusions of a selective serotonin reuptake inhibitor (SSRI), citalopram. Both anxiety-like behaviors, and conditioned threat-induced responses were reduced by the blockade of serotonin reuptake in the amygdala. Together, these findings provide evidence that high amygdala serotonin transporter expression contributes to the high trait anxious phenotype and suggest that reduction of threat reactivity by SSRIs may be mediated by their actions in the amygdala.SIGNIFICANCE STATEMENT Findings here contribute to our understanding of how the serotonin system underlies an individual's expression of threat-elicited negative emotions such as anxiety and fear within nonhuman primates. Exploration of serotonergic gene expression across brain regions implicated in emotion regulation revealed that serotonin transporter gene expression in the ventrolateral prefrontal cortex (vlPFC) and most strongly in the amygdala, but none of the serotonin receptor genes, were predictive of interindividual differences in anxiety-like behavior. Targeting of amygdala serotonin reuptake with selective serotonin reuptake inhibitors (SSRIs) confirmed the causal relationship between amygdala serotonin transporter and an animal's sensitivity to threat by reversing expression of two key features of the high trait-like anxiety phenotype: high responsivity to anxiety-provoking uncertain threat and responsivity to certain conditioned threat.


Assuntos
Tonsila do Cerebelo/metabolismo , Ansiedade/metabolismo , Emoções/fisiologia , Comportamento Exploratório/fisiologia , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Tonsila do Cerebelo/efeitos dos fármacos , Animais , Ansiedade/genética , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Callithrix , Citalopram/farmacologia , Emoções/efeitos dos fármacos , Comportamento Exploratório/efeitos dos fármacos , Extinção Psicológica/efeitos dos fármacos , Extinção Psicológica/fisiologia , Medo/efeitos dos fármacos , Medo/fisiologia , Feminino , Humanos , Masculino , Receptores de Serotonina/genética , Receptores de Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Inibidores de Captação de Serotonina/farmacologia
8.
Cell Mol Life Sci ; 77(21): 4347-4364, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32409861

RESUMO

Neuropsychiatric disorders, including autism spectrum disorders (ASD) and anxiety disorders are characterized by a complex range of symptoms, including social behaviour and cognitive deficits, depression and repetitive behaviours. Although the mechanisms driving pathophysiology are complex and remain largely unknown, advances in the understanding of gene association and gene networks are providing significant clues to their aetiology. In recent years, small noncoding RNA molecules known as microRNA (miRNA) have emerged as a new gene regulatory layer in the pathophysiology of mental illness. These small RNAs can bind to the 3'-UTR of mRNA thereby negatively regulating gene expression at the post-transcriptional level. Their ability to regulate hundreds of target mRNAs simultaneously predestines them to control the activity of entire cellular pathways, with obvious implications for the regulation of complex processes such as animal behaviour. There is growing evidence to suggest that numerous miRNAs are dysregulated in pathophysiology of neuropsychiatric disorders, and there is strong genetic support for the association of miRNA genes and their targets with several of these conditions. This review attempts to cover the most relevant microRNAs for which an important contribution to the control of social and anxiety-related behaviour has been demonstrated by functional studies in animal models. In addition, it provides an overview of recent expression profiling and genetic association studies in human patient-derived samples in an attempt to highlight the most promising candidates for biomarker discovery and therapeutic intervention.


Assuntos
Transtornos de Ansiedade/genética , Ansiedade/genética , Transtorno do Espectro Autista/genética , Regulação da Expressão Gênica , MicroRNAs/genética , Animais , Redes Reguladoras de Genes , Humanos , RNA Mensageiro/genética
9.
Psychiatry Res ; 288: 112984, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32315880

RESUMO

Cytochrome P450 C19 (CYP2C19) metabolizes exogenous and endogenous compounds. Although CYP2C19 is highly expressed in the liver, it is also expressed in the brain during early life. Previous human and animal studies have linked CYP2C19 genotype-predicted enzyme activity to hippocampal volumes, depressive symptoms, and anxiety-like behaviors. We examined these promising associations in a general community sample comprising 386 Caucasian adults with no history of psychiatric or neurological illnesses. Contrary to previous findings, CYP2C19 genotype-predicted enzyme activity was not associated with hippocampal volumes, nor depressive and anxiety symptoms. Interstudy differences in CYP2C19 frequencies and/or study methodology may explain this discrepancy.


Assuntos
Ansiedade/diagnóstico por imagem , Citocromo P-450 CYP2C19/metabolismo , Depressão/diagnóstico por imagem , Genótipo , Hipocampo/diagnóstico por imagem , Adulto , Animais , Ansiedade/enzimologia , Ansiedade/genética , Estudos Transversais , Citocromo P-450 CYP2C19/genética , Depressão/enzimologia , Depressão/genética , Ativação Enzimática/fisiologia , Feminino , Hipocampo/enzimologia , Humanos , Masculino , Tamanho do Órgão/fisiologia
11.
Am J Physiol Cell Physiol ; 318(5): C870-C878, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32186931

RESUMO

Pituitary adenylate cyclase activating polypeptide (PACAP; ADCYAP1) is a pleiotropic neuropeptide widely distributed in both the peripheral and central nervous systems. PACAP and its specific cognate PAC1 receptor (ADCYAP1R1) play critical roles in the homeostatic maintenance of multiple physiological and behavioral systems. Notably, maladaptations in the PACAPergic system have been associated with several psychopathologies related to fear and anxiety. PAC1 receptor transcripts are highly expressed in granule cells of the dentate gyrus (DG). Here, we examined the direct effects of PACAP on DG granule cells in brain slices using whole cell patch recordings in current clamp mode. PACAP significantly increased the intrinsic excitability of DG granule cells via PAC1 receptor activation. This increased excitability was not mediated by adenylyl cyclase/cAMP or phospholipase C/PKC activation, but instead via activation of an extracellular signal-regulated kinase (ERK) signaling pathway initiated through PAC1 receptor endocytosis/endosomal signaling. PACAP failed to increase excitability in DG granule cells pretreated with the persistent sodium current blocker riluzole, suggesting that the observed PACAP effects required this component of the inward sodium current.


Assuntos
Ansiedade/genética , Encéfalo/metabolismo , Giro Denteado/metabolismo , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/genética , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/genética , Animais , Ansiedade/patologia , Encéfalo/patologia , Proliferação de Células/efeitos dos fármacos , Giro Denteado/patologia , Endocitose/genética , Endossomos/genética , Medo/psicologia , Regulação da Expressão Gênica/genética , Humanos , Sistema de Sinalização das MAP Quinases/genética , Neurônios/metabolismo , Neurônios/patologia , Técnicas de Patch-Clamp , Ratos , Riluzol/farmacologia
12.
Gynecol Oncol ; 157(1): 280-286, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32057464

RESUMO

BACKGROUND: Timely genetic testing at ovarian cancer diagnosis is essential as results impact front line treatment decisions. Our objective was to determine rates of genetic counseling and testing with an expedited genetics referral pathway wherein women with newly-diagnosed ovarian cancer are contacted by a genetics navigator to facilitate genetic counseling. METHODS: Patients were referred for genetic counseling by their gynecologic oncologist, contacted by a genetics navigator and offered appointments for genetic counseling. Patients completed quality of life (QoL) surveys immediately pre- and post-genetic assessment and 6 months later. The primary outcome was feasibility of this pathway defined by presentation for genetic counseling. RESULTS: From 2015 to 2018, 100 patients were enrolled. Seventy-eight had genetic counseling and 73 testing. Median time from diagnosis to genetic counseling was 34 days (range 10-189). Among patients who underwent testing, 12 (16%) had pathogenic germline mutations (BRCA1-7, BRCA2-4, MSH2-1). Sixty-five patients completed QoL assessments demonstrating stress and anxiety at time of testing, however, scores improved at 6 months. Despite the pathway leveling financial and logistical barriers, patients receiving care at a public hospital were less likely to present for genetic counseling compared to private hospital patients (56% versus 84%, P = 0.021). CONCLUSIONS: Facilitated referral to genetic counselors at time of ovarian cancer diagnosis is effective, resulting in high uptake of genetic counseling and testing, and does not demonstrate a long term psychologic toll. Concern about causing additional emotional distress should not deter clinicians from early genetics referral as genetic testing can yield important prognostic and therapeutic information.


Assuntos
Ansiedade/genética , Carcinoma Epitelial do Ovário/genética , Depressão/genética , Aconselhamento Genético/organização & administração , Testes Genéticos , Neoplasias Ovarianas/genética , Estresse Psicológico/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Ansiedade/etiologia , Carcinoma Epitelial do Ovário/psicologia , Depressão/etiologia , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/psicologia , Estudos Prospectivos , Encaminhamento e Consulta/organização & administração , Estresse Psicológico/etiologia , Adulto Jovem
13.
Exp Neurol ; 327: 113216, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32014439

RESUMO

Neuropeptide Y (NPY) is a 36-amino acid neuropeptide that is widely expressed in the central nervous system, including the cerebral cortex, nucleus accumbens (NAc) and hypothalamus. We previously analyzed the behavior of transgenic mice exclusively expressing an unedited RNA isoform of the 5-HT2C receptor. These mice showed decreased NPY gene expression in the NAc and exhibited behavioral despair, suggesting that NAc NPY neurons may be involved in mood disorder; however, their role in this behavior remained unknown. Therefore, in the present study, we investigated the functional role of NAc NPY neurons in anxiety-like behavior by examining the impact of specific ablation or activation of NAc NPY neurons using NPY-Cre mice and Cre-dependent adeno-associated virus. Diphtheria toxin-mediated ablation of NAc NPY neurons significantly increased anxiety-like behavior in the open field and elevated plus maze tests, compared with before toxin treatment. Moreover, chemogenetic activation of NAc NPY neurons reduced anxiety-like behavior in both behavioral tests compared with control mice. These results suggest that NPY neurons in the NAc are involved in the modulation of anxiety in mice.


Assuntos
Ansiedade/metabolismo , Comportamento Animal/fisiologia , Neurônios/metabolismo , Neuropeptídeo Y/metabolismo , Núcleo Accumbens/metabolismo , Animais , Ansiedade/genética , Camundongos , Camundongos Transgênicos , Atividade Motora/fisiologia , Neuropeptídeo Y/genética , Receptores de Neuropeptídeo Y/metabolismo
14.
J Abnorm Psychol ; 129(3): 237-247, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32077707

RESUMO

The valine66methionine (Val66Met) polymorphism (rs6265) of the brain-derived neurotrophic factor (BDNF) gene has been shown to influence autonomic arousal pathways, which in turn predict elevated syndromal anxiety in healthy humans. We examined whether the BDNF variant is associated with an increased risk of generalized anxiety disorder (GAD), one of the most prevalent anxiety disorders, through altering parasympathetic stress/relaxation reactivity. A total of 2,250 Han Chinese adults (750 GAD patients and 1,500 healthy controls) were included in the genotyping. High-frequency heart rate variability, an index of vagal (parasympathetic) activity, was measured during the supine-standing-supine test (5 min in each position); vagal withdrawal and vagal activation were calculated as baseline supine minus standing and recovery supine minus standing, respectively. Analysis of healthy participants indicated that Val/Val homozygotes displayed significantly blunted vagal withdrawal and vagal activation compared with Met allele carriers. After analyzing the entire sample, these effects remained significant. Furthermore, both attenuated vagal response patterns were found to be significantly associated with a higher incidence of GAD. Lastly, the path analysis identified a significant indirect effect of BDNF on the risk of GAD via diminishing vagal response to either orthostatic stress or supine relaxation. Even when further testing the subsample comprising only comorbidity- and medication-free GAD patients and healthy controls to minimize the confounding bias, the results still remained. Our findings demonstrate that individuals carrying the BDNF Val/Val genotype, compared to Met-carriers, may be at higher risk of GAD due to blunted vagal reactivity in response to both stress and relaxation. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


Assuntos
Transtornos de Ansiedade/genética , Ansiedade/genética , Fator Neurotrófico Derivado do Encéfalo/genética , Genótipo , Sistema Nervoso Parassimpático/fisiopatologia , Polimorfismo de Nucleotídeo Único , Adulto , Alelos , Ansiedade/fisiopatologia , Transtornos de Ansiedade/fisiopatologia , Nível de Alerta/fisiologia , Feminino , Frequência Cardíaca/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Nervo Vago/fisiopatologia
15.
Am J Psychiatry ; 177(3): 223-232, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31906708

RESUMO

OBJECTIVE: Anxiety disorders are common and often disabling. The goal of this study was to examine the genetic architecture of anxiety disorders and anxiety symptoms, which are also frequently comorbid with other mental disorders, such as major depressive disorder. METHODS: Using one of the world's largest biobanks including genetic, environmental, and medical information, the Million Veteran Program, the authors performed a genome-wide association study (GWAS) of a continuous trait for anxiety (based on score on the Generalized Anxiety Disorder 2-item scale [GAD-2], N=199,611) as the primary analysis and self-report of physician diagnosis of anxiety disorder (N=224,330) as a secondary analysis. RESULTS: The authors identified five genome-wide significant signals for European Americans and one for African Americans on GAD-2 score. The strongest were on chromosome 3 (rs4603973) near SATB1, a global regulator of gene expression, and on chromosome 6 (rs6557168) near ESR1, which encodes an estrogen receptor. The locus identified on chromosome 7 (rs56226325, MAF=0.17) near MAD1L1 was previously identified in GWASs of bipolar disorder and schizophrenia. The authors replicated these findings in the summary statistics of two major published GWASs for anxiety, and also found evidence of significant genetic correlation between the GAD-2 score results and previous GWASs for anxiety (rg=0.75), depression (rg=0.81), and neuroticism (rg=0.75). CONCLUSIONS: This is the largest GWAS of anxiety traits to date. The authors identified novel genome-wide significant associations near genes involved with global regulation of gene expression (SATB1) and the estrogen receptor alpha (ESR1). Additionally, the authors identified a locus (MAD1L1) that may have implications for genetic vulnerability across several psychiatric disorders. This work provides new insights into genetic risk mechanisms underpinning anxiety and related psychiatric disorders.


Assuntos
Transtornos de Ansiedade/genética , Ansiedade/genética , Loci Gênicos , Predisposição Genética para Doença , Fenótipo , Polimorfismo de Nucleotídeo Único , Idoso , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Veteranos
16.
Depress Anxiety ; 37(6): 512-520, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31951317

RESUMO

BACKGROUND: Anxiety and depressive disorders can be classified under a bidimensional model, where depression and generalized anxiety disorder are represented by distress and the other anxiety disorders, by fear. The phenotypic structure of this model has been validated, but twin studies only show partial evidence for genetic and environmental distinctions between distress and fear. Moreover, the effects of genetic variants are mostly shared between anxiety and depression, but the genome-wide genetic distinction between distress and fear remains unexplored. This study aimed to examine the degree of common genetic variation overlap between distress and fear, and their associations with the psychosocial risk factors of loneliness and social isolation. METHODS: We used genome-wide data from 157,366 individuals in the UK Biobank who answered a mental health questionnaire. RESULTS: Genetic correlations indicated that depression and generalized anxiety had a substantial genetic overlap, and that they were genetically partially distinct from fear disorders. Associations with loneliness, but not social isolation, showed that loneliness was more strongly associated with both distress disorders than with fear. CONCLUSIONS: Our findings shed light on genetic and environmental mechanisms that are common and unique to distress and fear and contribute to current knowledge on individuals' susceptibility to anxiety and depression.


Assuntos
Bancos de Espécimes Biológicos , Depressão , Ansiedade/genética , Transtornos de Ansiedade/genética , Depressão/genética , Humanos , Reino Unido
17.
Proc Natl Acad Sci U S A ; 117(4): 2170-2179, 2020 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-31932427

RESUMO

Tuberous Sclerosis Complex (TSC) is a rare genetic disease that manifests with early symptoms, including cortical malformations, childhood epilepsy, and TSC-associated neuropsychiatric disorders (TANDs). Cortical malformations arise during embryonic development and have been linked to childhood epilepsy before, but the underlying mechanisms of this relationship remain insufficiently understood. Zebrafish have emerged as a convenient model to study elementary neurodevelopment; however, without in-depth functional analysis, the Tsc2-deficient zebrafish line cannot be used for studies of TANDs or new drug screening. In this study, we found that the lack of Tsc2 in zebrafish resulted in heterotopias and hyperactivation of the mTorC1 pathway in pallial regions, which are homologous to the mammalian cortex. We observed commissural thinning that was responsible for brain dysconnectivity, recapitulating TSC pathology in human patients. The lack of Tsc2 also delayed axonal development and caused aberrant tract fasciculation, corresponding to the abnormal expression of genes involved in axon navigation. The mutants underwent epileptogenesis that resulted in nonmotor seizures and exhibited increased anxiety-like behavior. We further mapped discrete parameters of locomotor activity to epilepsy-like and anxiety-like behaviors, which were rescued by reducing tyrosine receptor kinase B (TrkB) signaling. Moreover, in contrast to treatment with vigabatrin and rapamycin, TrkB inhibition rescued brain dysconnectivity and anxiety-like behavior. These data reveal that commissural thinning results in the aberrant regulation of anxiety, providing a mechanistic link between brain anatomy and human TANDs. Our findings also implicate TrkB signaling in the complex pathology of TSC and reveal a therapeutic target.


Assuntos
Ansiedade/metabolismo , Epilepsia/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Receptor trkB/metabolismo , Esclerose Tuberosa/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Animais , Ansiedade/genética , Ansiedade/psicologia , Modelos Animais de Doenças , Epilepsia/genética , Epilepsia/psicologia , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Receptor trkB/genética , Convulsões/genética , Convulsões/metabolismo , Convulsões/psicologia , Esclerose Tuberosa/genética , Esclerose Tuberosa/psicologia , Peixe-Zebra , Proteínas de Peixe-Zebra/genética
18.
Neuron ; 105(3): 475-490.e6, 2020 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-31780330

RESUMO

Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders with symptoms including social deficits, anxiety, and communication difficulties. However, ASD pathogenic mechanisms are poorly understood. Mutations of CUL3, which encodes Cullin 3 (CUL3), a component of an E3 ligase complex, are thought of as risk factors for ASD and schizophrenia (SCZ). CUL3 is abundant in the brain, yet little is known of its function. Here, we show that CUL3 is critical for neurodevelopment. CUL3-deficient mice exhibited social deficits and anxiety-like behaviors with enhanced glutamatergic transmission and neuronal excitability. Proteomic analysis revealed eIF4G1, a protein for Cap-dependent translation, as a potential target of CUL3. ASD-associated cellular and behavioral deficits could be rescued by pharmacological inhibition of the eIF4G1 function and chemogenetic inhibition of neuronal activity. Thus, CUL3 is critical to neural development, neurotransmission, and excitation-inhibition (E-I) balance. Our study provides novel insight into the pathophysiological mechanisms of ASD and SCZ.


Assuntos
Ansiedade/metabolismo , Proteínas Culina/metabolismo , Potenciais Pós-Sinápticos Excitadores/fisiologia , Potenciais Pós-Sinápticos Inibidores/fisiologia , Biossíntese de Proteínas/fisiologia , Habilidades Sociais , Animais , Ansiedade/genética , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/metabolismo , Encéfalo/metabolismo , Células Cultivadas , Proteínas Culina/genética , Células HEK293 , Humanos , Locomoção/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
19.
Biochim Biophys Acta Mol Basis Dis ; 1866(3): 165622, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31770620

RESUMO

Isolated methylmalonic aciduria (MMAuria) is primarily caused by deficiency of methylmalonyl-CoA mutase (MMUT or MUT). Biochemically, MUT deficiency results in the accumulation of methylmalonic acid (MMA), propionyl-carnitine (C3) and other metabolites. Patients often exhibit lethargy, failure to thrive and metabolic decompensation leading to coma or even death, with kidney and neurological impairment frequently identified in the long-term. Here, we report a hemizygous mouse model which combines a knock-in (ki) missense allele of Mut with a knock-out (ko) allele (Mut-ko/ki mice) that was fed a 51%-protein diet from day 12 of life, constituting a bespoke model of MMAuria. Under this diet, mutant mice developed a pronounced metabolic phenotype characterized by drastically increased blood levels of MMA and C3 compared to their littermate controls (Mut-ki/wt). With this bespoke mouse model, we performed a standardized phenotypic screen to assess the whole-body impairments associated with this strong metabolic condition. We found that Mut-ko/ki mice show common clinical manifestations of MMAuria, including pronounced failure to thrive, indications of mild neurological and kidney dysfunction, and degenerative morphological changes in the liver, along with less well described symptoms such as cardiovascular and hematological abnormalities. The analyses also reveal so far unknown disease characteristics, including low bone mineral density, anxiety-related behaviour and ovarian atrophy. This first phenotypic screening of a MMAuria mouse model confirms its relevance to human disease, reveals new alterations associated with MUT deficiency, and suggests a series of quantifiable readouts that can be used to evaluate potential treatment strategies.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/genética , Erros Inatos do Metabolismo dos Aminoácidos/patologia , Metilmalonil-CoA Mutase/deficiência , Metilmalonil-CoA Mutase/genética , Animais , Ansiedade/genética , Ansiedade/patologia , Densidade Óssea/genética , Modelos Animais de Doenças , Feminino , Rim/patologia , Masculino , Ácido Metilmalônico/metabolismo , Camundongos , Fenótipo
20.
J Neurosci ; 40(1): 237-254, 2020 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-31704787

RESUMO

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disability that demonstrates impaired social interactions, communication deficits, and restrictive and repetitive behaviors. ASD has a strong genetic basis and many ASD-associated genes have been discovered thus far. Our previous work has shown that loss of expression of the X-linked gene NEXMIF/KIDLIA is implicated in patients with autistic features and intellectual disability (ID). To further determine the causal role of the gene in the disorder, and to understand the cellular and molecular mechanisms underlying the pathology, we have generated a NEXMIF knock-out (KO) mouse. We find that male NEXMIF KO mice demonstrate reduced sociability and communication, elevated repetitive grooming behavior, and deficits in learning and memory. Loss of NEXMIF/KIDLIA expression results in a significant decrease in synapse density and synaptic protein expression. Consistently, male KO animals show aberrant synaptic function as measured by excitatory miniatures and postsynaptic currents in the hippocampus. These findings indicate that NEXMIF KO mice recapitulate the phenotypes of the human disorder. The NEXMIF KO mouse model will be a valuable tool for studying the complex mechanisms involved in ASD and for the development of novel therapeutics for this disorder.SIGNIFICANCE STATEMENT Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder characterized by behavioral phenotypes. Based on our previous work, which indicated the loss of NEXMIF/KIDLIA was associated with ASD, we generated NEXMIF knock-out (KO) mice. The NEXMIF KO mice demonstrate autism-like behaviors including deficits in social interaction, increased repetitive self-grooming, and impairments in communication and in learning and memory. The KO neurons show reduced synapse density and a suppression in synaptic transmission, indicating a role for NEXMIF in regulating synapse development and function. The NEXMIF KO mouse faithfully recapitulates the human disorder, and thus serves as an animal model for future investigation of the NEXMIF-dependent neurodevelopmental disorders.


Assuntos
Transtorno do Espectro Autista/genética , Modelos Animais de Doenças , Proteínas do Tecido Nervoso/fisiologia , Animais , Ansiedade/genética , Transtorno do Espectro Autista/psicologia , Células Cultivadas , Comportamento Exploratório , Medo , Genes Ligados ao Cromossomo X , Asseio Animal/fisiologia , Hipocampo/citologia , Hipocampo/fisiologia , Relações Interpessoais , Masculino , Aprendizagem em Labirinto , Transtornos da Memória/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Proteínas do Tecido Nervoso/deficiência , Proteínas do Tecido Nervoso/genética , Neurônios/fisiologia , Interferência de RNA , RNA Interferente Pequeno/genética , Comportamento Estereotipado/fisiologia , Sinapses/fisiologia , Vocalização Animal
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