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1.
J Neurochem ; 2020 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-33025573

RESUMO

Molecular abnormalities within the Glucocorticoid Receptor (GR) stress signaling pathway involved in dysfunction of mitochondria and confer vulnerability to stress-related psychiatric disorders. Bcl-2 associated athanogene (Bag-1) is a target for the actions of mood stabilizers. Bag-1 interacts with GR, thereby regulating glucocorticoid function. In this study, we investigate the potential role of Bag-1 in regulating GR translocation into mitochondria. Corticosterone (CORT) treatment significantly enhanced Bag-1/GR complex formation and GR mitochondrial translocation in cultured rat cortical neurons after treatment for 30 min and 24 hr. By contrast, after stimulation with CORT for 3 days, localization of the Bag-1/GR complex and mitochondrial GR were reduced. Similar results were obtained in mice, in which administrated CORT in drinking water for 21 days significantly impaired the GR levels in the mitochondria, while Bag-1 over-expression rescued this reduction. Furthermore, chronic CORT exposure led to anhedonia-like and depression-like behaviors in the sucrose-consumption test and forced swimming test, and these behaviors were rescued by Bag-1 over-expression. These results suggest that Bag-1 mediates GR trafficking to mitochondria and regulates affective resilience in response to a CORT increase and provide potential insight into the mechanisms by which Bag-1 and GR could contribute to the physiology and pathogenesis of psychiatric disorders in response to the change of stress hormone.

2.
Horm Behav ; 126: 104822, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32730760

RESUMO

Oxytocin is important for postnatal developmental experiences for mothers, infants, and transactions between them. Oxytocin is also implicated in adult affiliative behaviors, including social buffering of stress. There is evidence for connections between early life experience and adult oxytocin system functioning, but effects of early experience on behavioral, endocrine, and neurophysiological outcomes related to adult social buffering are not well explored. We use a limited bedding and nesting (LBN) material paradigm as an environmental disruption of early experiences and assessed central oxytocin systems in brain regions related to hypothalamic-pituitary-adrenal (HPA) axis regulation (paraventricular nucleus of the hypothalamus, amygdala, hippocampus). We also assessed developmentally-appropriate social behaviors and HPA reactivity during social buffering testing in adulthood. LBN litters had larger huddles and more pups visible compared to control litters during the first two weeks of life. LBN also altered the developmental trajectory of oxytocin-expressing cells and oxytocin receptor cells, with increases in oxytocin receptor cells at P15 in LBN pups. By adulthood, LBN females had more and LBN males had fewer oxytocin and oxytocin receptor cells in these areas compared to sex-matched controls. Adult LBN females, but not LBN males, had behavioral changes during social interaction and social buffering testing. The sex-specific effects of early experience on central oxytocin systems and social behavior may contribute to female resilience to early life adversity.

3.
Integr Comp Biol ; 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32483621

RESUMO

Stress is a common, if often unpredictable life event. It can be defined from an evolutionary perspective as a force an organism perceives it must adapt to. Thus stress is a useful tool to study adaptation and the adaptive capacity of organisms. The deep genome, long neglected as a pile of "junk" has emerged as a source of regulatory DNA and RNA as well as a potential stockpile of adaptive capacity at the organismal and species levels. Recent work on the regulation of transposable elements (TEs), the principle constituents of the deep genome, by stress has shown that these elements are responsive to host stress and other environmental cues. Further, we have shown that some are likely directly regulated by the glucocorticoid receptor (GR), one of the two major vertebrate stress steroid receptors in a fashion that appears adaptive. On the basis of this and other emerging evidence I argue that the deep genome may represent an adaptive toolkit for organisms to respond to their environments at both individual and evolutionary scales. This argues that genomes may be adapted for what Waddington called "trait adaptability" rather than being purely passive objects of natural selection and single nucleotide level mutation.

4.
Dev Psychobiol ; 62(1): 116-122, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31342518

RESUMO

Neonatal abstinence syndrome (NAS) after in-utero opioid exposure remains a poorly understood condition with multiple factors contributing to severity. Exposure to maternal stress may be one contributing factor. Hair cortisol measurement represents a novel technique for assessing prenatal stress. In this pilot study, the association between maternal hair cortisol levels and NAS severity was examined in 70 postpartum women with opioid use disorder within 72 hr of delivery. Infants were monitored for NAS and treated according to institutional protocol. Forty-four (63%) of the infants were pharmacologically treated for NAS, with a mean length of hospital stay (LOS) for all infants of 14.2 (SD 9.0) days. The mean cortisol level in the mothers was 131.8 pg/mg (SD 124.7). In bivariate analysis, higher maternal hair cortisol levels were associated with shorter infant LOS (R = -.26, p = .03) and fewer infant opioid treatment days (R = -.28, p = .02). Results were no longer statistically significant in regression models after adjusting for maternal opioid and smoking. In conclusion, we demonstrated the feasibility of hair cortisol assaying within the first few days after delivery in mothers with opioid use disorder as a novel marker for NAS. The findings suggest that maternal stress may impact the severity of infant opioid withdrawal.


Assuntos
Cabelo/metabolismo , Hidrocortisona/metabolismo , Mães , Síndrome de Abstinência Neonatal/diagnóstico , Síndrome de Abstinência Neonatal/terapia , Transtornos Relacionados ao Uso de Opioides/complicações , Efeitos Tardios da Exposição Pré-Natal , Estresse Psicológico/metabolismo , Adulto , Estudos de Viabilidade , Feminino , Humanos , Recém-Nascido , Projetos Piloto , Gravidez , Índice de Gravidade de Doença , Adulto Jovem
5.
Front Neuroendocrinol ; 56: 100802, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31738947

RESUMO

The ability to adapt to stressful circumstances, known as emotional resilience, is a key factor in the maintenance of mental health. Several individual biomarkers of the stress response (e.g., corticosterone) that influence an animal's position along the continuum that ranges from adaptive allostasis to maladaptive allostatic load have been identified. Extending beyond specific biomarkers of stress responses, however, it is also important to consider stress-related responses relative to other relevant responses for a thorough understanding of the underpinnings of adaptive allostasis. In this review, behavioral, neurobiological, developmental and genomic variables are considered in the context of emotional resilience [e.g., explore/exploit behavioral tendencies; DHEA/CORT ratios and relative proportions of protein-coding/nonprotein-coding (transposable) genomic elements]. As complex and multifaceted relationships between pertinent allostasis biomediators are identified, translational applications for optimal resilience are more likely to emerge as effective therapeutic strategies.

6.
Trends Endocrinol Metab ; 30(11): 807-818, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31699238

RESUMO

The glucocorticoid receptor (GR) has been shown to be important for mediating cellular responses to stress and circulating glucocorticoids. Ligand-dependent transcriptional changes induced by GR are observed across numerous tissues. However, the mechanisms by which GR achieves cell and tissue-specific effects are less clear. Epigenetic mechanisms have been proposed to explain some of these differences as well as some of the lasting, even transgenerational, effects of stress and glucocorticoid action. GR functions in tandem with epigenetic cellular machinery to coordinate transcription and shape chromatin structure. Here, we describe GR interactions with these effectors and how GR acts to reshape the epigenetic landscape in response to the environment.


Assuntos
Epigênese Genética/genética , Receptores de Glucocorticoides/metabolismo , Animais , Metilação de DNA/fisiologia , Glucocorticoides/metabolismo , Humanos , RNA não Traduzido/genética , RNA não Traduzido/metabolismo
7.
Brain Sci ; 9(8)2019 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-31349644

RESUMO

One source of information we glean from everyday experience, which guides social interaction, is assessing the emotional state of others. Emotional state can be expressed through several modalities: body posture or movements, body odor, touch, facial expression, or the intonation in a voice. Much research has examined emotional processing within one sensory modality or the transfer of emotional processing from one modality to another. Yet, less is known regarding interactions across different modalities when perceiving emotions, despite our common experience of seeing emotion in a face while hearing the corresponding emotion in a voice. Our study examined if visual and auditory emotions of matched valence (congruent) conferred stronger perceptual and physiological effects compared to visual and auditory emotions of unmatched valence (incongruent). We quantified how exposure to emotional faces and/or voices altered perception using psychophysics and how it altered a physiological proxy for stress or arousal using salivary cortisol. While we found no significant advantage of congruent over incongruent emotions, we found that changes in cortisol were associated with perceptual changes. Following exposure to negative emotional content, larger decreases in cortisol, indicative of less stress, correlated with more positive perceptual after-effects, indicative of stronger biases to see neutral faces as happier.

8.
Methods Mol Biol ; 2011: 633-645, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31273725

RESUMO

Neuropsychiatric disorders are highly prevalent (e.g., affecting children 2-8 years old at a rate of 14%). Many of these disorders are highly heritable such as major depressive disorder and schizophrenia. Despite this, genome-wide association has failed to identify gene(s) significantly associated with diagnostic status suggesting a strong role for environmental factors and the epigenome. From a molecular standpoint, the study of DNA-protein interactions yields fruitful information regarding the regulation of cellular processes above the level of the nucleotide sequence. Understanding chromatin dynamics may continue to explain individual variation to environmental perturbation and subsequent behavioral response. Chromatin immunoprecipitation (ChIP) techniques have allowed for probing of epigenetic effectors at specific regions of the genome. The following article reviews the current techniques and considerations when incorporation ChIP into neuropsychiatric models.


Assuntos
Imunoprecipitação da Cromatina , Testes Neuropsicológicos , Neuropsicologia , Pesquisa , Cromatina/genética , Cromatina/metabolismo , Imunoprecipitação da Cromatina/métodos , Suscetibilidade a Doenças , Epigênese Genética , Humanos , Transtornos Mentais/etiologia , Transtornos Mentais/metabolismo , Neuropsicologia/métodos
9.
Neurobiol Stress ; 11: 100174, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31193573

RESUMO

Transposable elements make up a much larger portion of the genome than protein-coding genes, yet we know relatively little about their function in the human genome. However, we are beginning to more fully understand their role in brain development, neuroinflammation, and adaptation to environmental insults such as stress. For instance, glucocorticoid receptor activation regulates transposable elements in the brain following acute stress. Early life is a period of substantial brain development during which transposable elements play a role. Environmental exposures and experiences during early life that promote abnormal regulation of transposable elements may lead to a cascade of events that ultimately increase susceptibility to disorders later in life. Recent attention to transposable elements in psychiatric illness has begun to clarify associations indicative of dysregulation of different classes of transposable elements in stress-related and neurodevelopmental illness. Though individual susceptibility or resiliency to psychiatric illness has not been explained by traditional genetic studies, the wide inter-individual variability in transposable element composition in the human genome make TEs attractive candidates to elucidate this differential susceptibility. In this review, we discuss evidence that regulation of transposable elements in the brain are stage-specific, sensitive to environmental factors, and may be impacted by early life perturbations. We further present evidence of associations with stress-related and neurodevelopmental psychiatric illness from a developmental perspective.

10.
Neurotoxicol Teratol ; 71: 41-49, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-29475055

RESUMO

Histories of early life stress (ELS) or social discrimination can reach levels of severity characterized as toxic to mental and physical health. Such toxic social stress during development has been linked to altered acute hypothalamic-pituitary-adrenal (HPA) response to social stress in adulthood. However, there are important individual differences in the size and direction of these effects. We explored developmental, genetic, epigenetic, and contextual sources of individual differences in the relationship between ELS, discrimination, and adult responses to acute social stress in a standard laboratory test. Additional measures included perceived status, social support, background activity of HPA axis, and genetic variants in aspects of the stress response system. Participants (n = 90) answered questions about historical and ongoing stress, provided a DNA sample to examine genetic polymorphisms and epigenetic marks, and underwent the Trier Social Stress Test (TSST) during which three saliva samples were collected to assess HPA function. Individuals who reported high levels of childhood adversity had a blunted salivary cortisol response to the TSST. Childhood adversity, discrimination experiences, and FKBP5 genotype were found to predict pretest cortisol levels. Following up on recent observations that the glucocorticoid receptor directly interacts with the mitochondrial genome, particularly the NADH dehydrogenase 6 (MT-ND6) gene, individuals who reported high childhood adversity were also found to have higher percent methylation across six CpG sites upstream of MT-ND6. These findings suggest multiple contributions across psychological, genetic, epigenetic, and social domains to vulnerability and resilience in hypothalamic-pituitary-adrenal axis regulation. Further study to examine how these multiple contributors affect developmental endpoints through integrated or independent pathways will be of use.


Assuntos
Epigênese Genética , Hidrocortisona/sangue , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Estresse Psicológico/genética , Adulto , Feminino , Genótipo , Humanos , Sistema Hipotálamo-Hipofisário/fisiopatologia , Masculino , Sistema Hipófise-Suprarrenal/fisiopatologia , Saliva/química , Estresse Psicológico/sangue , Estresse Psicológico/fisiopatologia , Inquéritos e Questionários
11.
J Mol Endocrinol ; 62(2): R121-R128, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30082335

RESUMO

Glucocorticoids have long been recognized for their role in regulating the availability of energetic resources, particularly during stress. Furthermore, bidirectional connections between glucocorticoids and the physiology and function of mitochondria have been discovered over the years. However, the precise mechanisms by which glucocorticoids act on mitochondria have only recently been explored. Glucocorticoids appear to regulate mitochondrial transcription via activation of glucocorticoid receptors (GRs) with elevated circulating glucocorticoid levels following stress. While several mechanistic questions remain, GR and other nuclear transcription factors appear to have the capacity to substantially alter mitochondrial transcript abundance. The regulation of mitochondrial transcripts by stress and glucocorticoids will likely prove functionally relevant in many stress-sensitive tissues including the brain.


Assuntos
Regulação da Expressão Gênica , Mitocôndrias/genética , Receptores de Glucocorticoides/metabolismo , Estresse Fisiológico/genética , Animais , Humanos , Modelos Biológicos , Transcrição Genética
12.
Biol Psychiatry ; 83(10): 849-865, 2018 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-29559087

RESUMO

Posttraumatic stress disorder (PTSD) is a pathologic response to trauma that impacts ∼8% of the population and is highly comorbid with other disorders, such as traumatic brain injury. PTSD affects multiple biological systems throughout the body, including the hypothalamic-pituitary-adrenal axis, cortical function, and the immune system, and while the study of the biological underpinnings of PTSD and related disorders are numerous, the roles of noncoding RNAs (ncRNAs) are just emerging. Moreover, deep sequencing has revealed that ncRNAs represent most of the transcribed mammalian genome. Here, we present developing evidence that ncRNAs are involved in critical aspects of PTSD pathophysiology. In that regard, we summarize the roles of three classes of ncRNAs in PTSD and related disorders: microRNAs, long-noncoding RNAs, and retrotransposons. This review evaluates findings from both animal and human studies with a special focus on the role of ncRNAs in hypothalamic-pituitary-adrenal axis abnormalities and glucocorticoid dysfunction in PTSD and traumatic brain injury. We conclude that ncRNAs may prove to be useful biomarkers to facilitate personalized medicines for trauma-related brain disorders.


Assuntos
Glucocorticoides/metabolismo , RNA não Traduzido/metabolismo , Transtornos de Estresse Pós-Traumáticos , Estresse Psicológico/complicações , Humanos , Medicina de Precisão , Transtornos de Estresse Pós-Traumáticos/complicações , Transtornos de Estresse Pós-Traumáticos/genética , Transtornos de Estresse Pós-Traumáticos/metabolismo , Transtornos de Estresse Pós-Traumáticos/psicologia
13.
Front Neuroendocrinol ; 49: 170-174, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29551355

RESUMO

The brain is responsible for both recognition and adaptation to stressful stimuli. Many molecular mechanisms have been implicated in this response including those governing neuronal plasticity, neurogenesis and, changes gene expression. Far less is known regarding effects of stress on the deep genome. In the hippocampus, stress appears to regulate expression of non-coding elements of the genome as well as the chromatin permissive for their transcription. Specifically, hippocampal retrotransposon (RT) elements are regulated by acute stress via the accumulation of the repressive H3K9me3 mark at RT loci. Further, corticosteroids appear to induce changes in heterochromatin status as well as RT expression in both adrenalectomized animal and rat cell culture models. Dysregulation of RT expression is predicted to result in functional deficits in affected brain areas. More broadly, however, transposons may have a variety of adaptive functions. As techniques improve to probe the deep genome, this approach to understanding stress neurobiology has the potential to yield insights into environment and genome interactions that may contribute to the physiology underlying a number of stress-related mental health disorders.


Assuntos
Epigênese Genética/fisiologia , Genoma/fisiologia , Hipocampo/metabolismo , RNA não Traduzido/metabolismo , Retroelementos/fisiologia , Estresse Psicológico/metabolismo , Animais , Humanos
14.
Adv Exp Med Biol ; 978: 145-166, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28523545

RESUMO

Anxiety disorders are highly prevalent psychiatric disorders often comorbid with depression and substance abuse. Twin studies have shown that anxiety disorders are moderately heritable. Yet, genome-wide association studies (GWASs) have failed to identify gene(s) significantly associated with diagnosis suggesting a strong role for environmental factors and the epigenome. A number of anxiety disorder subtypes are considered "stress related." A large focus of research has been on the epigenetic and anxiety-like behavioral consequences of stress. Animal models of anxiety-related disorders have provided strong evidence for the role of stress on the epigenetic control of the hypothalamic-pituitary-adrenal (HPA) axis and of stress-responsive brain regions. Neuroepigenetics may continue to explain individual variation in susceptibility to environmental perturbations and consequently anxious behavior. Behavioral and pharmacological interventions aimed at targeting epigenetic marks associated with anxiety may prove fruitful in developing treatments.


Assuntos
Transtornos de Ansiedade/genética , Ansiedade/genética , Epigênese Genética/genética , Adolescente , Corticosteroides/fisiologia , Adulto , Animais , Ansiolíticos/uso terapêutico , Ansiedade/tratamento farmacológico , Ansiedade/etiologia , Ansiedade/psicologia , Transtornos de Ansiedade/tratamento farmacológico , Transtornos de Ansiedade/etiologia , Transtornos de Ansiedade/psicologia , Criança , Modelos Animais de Doenças , Suscetibilidade a Doenças , Doenças em Gêmeos/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Sistema Hipotálamo-Hipofisário/fisiopatologia , Padrões de Herança , Plasticidade Neuronal , Sistema Hipófise-Suprarrenal/fisiopatologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Estresse Psicológico , Estudos em Gêmeos como Assunto
15.
Front Behav Neurosci ; 10: 107, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27375447

RESUMO

Waddington coined the term "epigenetic" to attempt to explain the complex, dynamic interactions between the developmental environment and the genome that led to the production of phenotype. Waddington's thoughts on the importance of both adaptability and canalization of phenotypic development are worth recalling as well, as they emphasize the available range for epigenetic action and the importance of environmental feedback (or lack thereof) in the development of complex traits. We suggest that a dynamic systems view fits well with Waddington's conception of epigenetics in the developmental context, as well as shedding light on the study of the molecular epigenetic effects of the environment on brain and behavior. Further, the dynamic systems view emphasizes the importance of the multi-directional interchange between the organism, the genome and various aspects of the environment to the ultimate phenotype.

16.
Proc Natl Acad Sci U S A ; 113(32): 9099-104, 2016 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-27457949

RESUMO

Glucocorticoids (GCs) are involved in stress and circadian regulation, and produce many actions via the GC receptor (GR), which is classically understood to function as a nuclear transcription factor. However, the nuclear genome is not the only genome in eukaryotic cells. The mitochondria also contain a small circular genome, the mitochondrial DNA (mtDNA), that encodes 13 polypeptides. Recent work has established that, in the brain and other systems, the GR is translocated from the cytosol to the mitochondria and that stress and corticosteroids have a direct influence on mtDNA transcription and mitochondrial physiology. To determine if stress affects mitochondrially transcribed mRNA (mtRNA) expression, we exposed adult male rats to both acute and chronic immobilization stress and examined mtRNA expression using quantitative RT-PCR. We found that acute stress had a main effect on mtRNA expression and that expression of NADH dehydrogenase 1, 3, and 6 (ND-1, ND-3, ND-6) and ATP synthase 6 (ATP-6) genes was significantly down-regulated. Chronic stress induced a significant up-regulation of ND-6 expression. Adrenalectomy abolished acute stress-induced mtRNA regulation, demonstrating GC dependence. ChIP sequencing of GR showed that corticosterone treatment induced a dose-dependent association of the GR with the control region of the mitochondrial genome. These findings demonstrate GR and stress-dependent transcriptional regulation of the mitochondrial genome in vivo and are consistent with previous work linking stress and GCs with changes in the function of brain mitochondria.


Assuntos
Corticosterona/farmacologia , DNA Mitocondrial/genética , Regulação da Expressão Gênica , Hipocampo/metabolismo , Receptores de Glucocorticoides/fisiologia , Estresse Psicológico/metabolismo , Animais , Masculino , Mitocôndrias/fisiologia , NADH Desidrogenase/genética , RNA Mensageiro/análise , RNA Mitocondrial , Ratos , Ratos Sprague-Dawley
17.
Epigenomics ; 8(2): 237-49, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26791965

RESUMO

Classically thought as genomic clutter, the functional significance of transposable elements (TEs) has only recently become a focus of attention in neuroscience. Increasingly, studies have demonstrated that the brain seems to have more retrotransposition and TE transcription relative to other somatic tissues, suggesting a unique role for TEs in the central nervous system. TE expression and transposition also appear to vary by brain region and change in response to environmental stimuli such as stress. TEs appear to serve a number of adaptive roles in the nervous system. The regulation of TE expression by steroid, epigenetic and other mechanisms in interplay with the environment represents a significant and novel avenue to understanding both normal brain function and disease.


Assuntos
Genoma , Genômica , Adaptação Biológica , Animais , Sistema Nervoso Central/metabolismo , Elementos de DNA Transponíveis , Meio Ambiente , Epigênese Genética , Evolução Molecular , Regulação da Expressão Gênica , Interação Gene-Ambiente , Aptidão Genética , Genômica/métodos , Humanos , Sistema Nervoso/metabolismo , Retroelementos , Estresse Fisiológico/genética
18.
Nat Neurosci ; 18(10): 1353-63, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26404710

RESUMO

The brain is the central organ involved in perceiving and adapting to social and physical stressors via multiple interacting mediators, from the cell surface to the cytoskeleton to epigenetic regulation and nongenomic mechanisms. A key result of stress is structural remodeling of neural architecture, which may be a sign of successful adaptation, whereas persistence of these changes when stress ends indicates failed resilience. Excitatory amino acids and glucocorticoids have key roles in these processes, along with a growing list of extra- and intracellular mediators that includes endocannabinoids and brain-derived neurotrophic factor (BDNF). The result is a continually changing pattern of gene expression mediated by epigenetic mechanisms involving histone modifications and CpG methylation and hydroxymethylation as well as by the activity of retrotransposons that may alter genomic stability. Elucidation of the underlying mechanisms of plasticity and vulnerability of the brain provides a basis for understanding the efficacy of interventions for anxiety and depressive disorders as well as age-related cognitive decline.


Assuntos
Encéfalo/fisiopatologia , Estresse Psicológico/psicologia , Animais , Epigênese Genética , Humanos , Plasticidade Neuronal/fisiologia , Estresse Psicológico/fisiopatologia
19.
Proc Natl Acad Sci U S A ; 112(22): 6828-33, 2015 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-25385609

RESUMO

Stress plays a substantial role in shaping behavior and brain function, often with lasting effects. How these lasting effects occur in the context of a fixed postmitotic neuronal genome has been an enduring question for the field. Synaptic plasticity and neurogenesis have provided some of the answers to this question, and more recently epigenetic mechanisms have come to the fore. The exploration of epigenetic mechanisms recently led us to discover that a single acute stress can regulate the expression of retrotransposons in the rat hippocampus via an epigenetic mechanism. We propose that this response may represent a genomic stress response aimed at maintaining genomic and transcriptional stability in vulnerable brain regions such as the hippocampus. This finding and those of other researchers have made clear that retrotransposons and the genomic plasticity they permit play a significant role in brain function during stress and disease. These observations also raise the possibility that the transposome might have adaptive functions at the level of both evolution and the individual organism.


Assuntos
Epigênese Genética/fisiologia , Regulação da Expressão Gênica/fisiologia , Hipocampo/metabolismo , Modelos Biológicos , Retroelementos/fisiologia , Esteroides/metabolismo , Estresse Fisiológico/fisiologia , Animais , Plasticidade Neuronal/fisiologia , Ratos
20.
Proc Natl Acad Sci U S A ; 111(45): 16130-5, 2014 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-25349423

RESUMO

Genetic evidence suggests cell-type-specific functions for certain nucleoporins, and gene expression profiling has revealed that nucleoporin p62 (NUP62) transcripts are decreased in the prefrontal cortex of major depressives. Chronic stress, which can precipitate depression, induces changes in the architecture and plasticity of apical dendrites that are particularly evident in the CA3 region of the hippocampus. Genetically targeted translating ribosome affinity purification revealed a selective reduction in translated Nup62 transcripts in CA3 of chronically stressed mice, and the Nup62 protein content of nuclei extracted from whole hippocampus was found to be decreased in chronically stressed rats. In cultured cells, phosphorylation of a FAK/proline-rich tyrosine kinase 2 (PYK2) consensus site in the alpha-helical domain of NUP62 (human Y422) is shown to be associated with shedding of NUP62 from the nuclear pore complex (NPC) and/or retention of NUP62 in the cytoplasm. Increased levels of phospho-Y425 Nup62 were observed in cytoplasmic fractions of hippocampi from chronically stressed rats, and immunofluorescence microscopy revealed redistribution of activated Pyk2 to the perinuclear region of stressed pyramidal neurons. Depletion of Nup62 from cultured embryonic day 18 rat hippocampal and cortical neurons resulted in simplification and retraction of dendritic arbors, without disruption of axon initial segment integrity. Thus, at least two types of mechanisms--one affecting expression and the other association with the NPC--could contribute to loss of NUP62 from CA3 pyramidal neurons during chronic stress. Their combined actions may account for the enhanced responsiveness of CA3 apical dendrites to chronic stress and may either be pathogenic or serve to protect CA3 neurons from permanent damage.


Assuntos
Região CA3 Hipocampal/metabolismo , Quinase 2 de Adesão Focal/metabolismo , Glicoproteínas de Membrana/metabolismo , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Células Piramidais/metabolismo , Estresse Psicológico/metabolismo , Animais , Axônios/metabolismo , Axônios/patologia , Região CA3 Hipocampal/patologia , Doença Crônica , Dendritos/metabolismo , Dendritos/patologia , Quinase 2 de Adesão Focal/genética , Humanos , Glicoproteínas de Membrana/genética , Camundongos , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Células Piramidais/patologia , Ratos , Ratos Sprague-Dawley , Estresse Psicológico/genética , Estresse Psicológico/patologia
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