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1.
Mol Psychiatry ; 25(2): 283-296, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31745239

RESUMO

Adverse posttraumatic neuropsychiatric sequelae (APNS) are common among civilian trauma survivors and military veterans. These APNS, as traditionally classified, include posttraumatic stress, postconcussion syndrome, depression, and regional or widespread pain. Traditional classifications have come to hamper scientific progress because they artificially fragment APNS into siloed, syndromic diagnoses unmoored to discrete components of brain functioning and studied in isolation. These limitations in classification and ontology slow the discovery of pathophysiologic mechanisms, biobehavioral markers, risk prediction tools, and preventive/treatment interventions. Progress in overcoming these limitations has been challenging because such progress would require studies that both evaluate a broad spectrum of posttraumatic sequelae (to overcome fragmentation) and also perform in-depth biobehavioral evaluation (to index sequelae to domains of brain function). This article summarizes the methods of the Advancing Understanding of RecOvery afteR traumA (AURORA) Study. AURORA conducts a large-scale (n = 5000 target sample) in-depth assessment of APNS development using a state-of-the-art battery of self-report, neurocognitive, physiologic, digital phenotyping, psychophysical, neuroimaging, and genomic assessments, beginning in the early aftermath of trauma and continuing for 1 year. The goals of AURORA are to achieve improved phenotypes, prediction tools, and understanding of molecular mechanisms to inform the future development and testing of preventive and treatment interventions.

2.
Behav Ther ; 50(5): 952-966, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31422850

RESUMO

The addition of the dissociative subtype of posttraumatic stress disorder (PTSD) to the DSM-5 has spurred investigation of its genetic, neurobiological, and treatment response correlates. In order to reliably assess the subtype, we developed the Dissociative Subtype of PTSD Scale (DSPS; Wolf et al., 2017), a 15-item index of dissociative features. Our initial investigation of the dichotomous DSPS lifetime items in a veteran epidemiological sample demonstrated its ability to identify the subtype, supported a three-factor measurement structure, distinguished the three subscales from the normal-range trait of absorption, and demonstrated the greater contribution of derealization and depersonalization symptoms relative to other dissociative symptomatology. In this study, we replicated and extended these findings by administering self-report and interview versions of the DSPS, and assessing personality and PTSD in a sample of 209 trauma-exposed veterans (83.73% male, 57.9% with probable current PTSD). Results replicated the three-factor structure using confirmatory factor analysis of current symptom severity interview items, and the identification of the dissociative subtype (via latent profile analysis). Associations with personality supported the discriminant validity of the DSPS and suggested the subtype was marked by tendencies towards odd and unusual cognitive experiences and low positive affect. Receiver operating characteristic curves identified diagnostic cut-points on the DSPS to inform subtype classification, which differed across the interview and self-report versions. Overall, the DSPS performed well in psychometric analyses, and results support the utility of the measure in identifying this important component of posttraumatic psychopathology.


Assuntos
Transtornos Dissociativos/diagnóstico , Transtornos de Estresse Pós-Traumáticos/diagnóstico , Inquéritos e Questionários/normas , Veteranos/psicologia , Adulto , Despersonalização , Manual Diagnóstico e Estatístico de Transtornos Mentais , Transtornos Dissociativos/psicologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Personalidade , Psicometria , Autorrelato , Transtornos de Estresse Pós-Traumáticos/psicologia
3.
J Neurosci Res ; 97(11): 1469-1482, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31379045

RESUMO

Recent years have led to increased effort to describe and understand the peripheral nervous system and its influence on central mechanisms and behavior in gastropod molluscs. This study revealed that an antibody raised against keyhole limpet hemocyanin (KLH) cross-reacts with an antigen(s) found extensively in both the central and the peripheral nervous systems of Biomphalaria alexandrina. The results revealed KLH-like immunoreactive (LIR) neurons in the cerebral, pedal, buccal, left pleural, right parietal, and visceral ganglion within the CNS with fibers projecting throughout all the peripheral nerves. Numerous KLH-LIR peripheral sensory neurons located in the foot, lips, tentacles, mantle, esophagus, and penis exhibited a bipolar morphology with long tortuous dendrites. KLH-LIR cells were also present in the eye and statocyst, thus suggesting the labeling of multiple sensory modalities/cell types. KLH-LIR cells did not co-localize with tyrosine hydroxylase (TH)-LIR cells, which have previously been described in this and other gastropods. The results thus provide descriptions of thousands of peripheral sensory neurons, not previously described in detail. Future research should seek to pair sensory modalities with peripheral cell type and attempt to further elucidate the nature of KLH-like reactivity. These findings also emphasize the need for caution when analyzing results obtained through use of antibodies raised against haptens conjugated to carrier proteins, suggesting the need for stringent controls to help limit potential confounds caused by cross-reactivity. In addition, this study is the first to describe neuronal cross-reactivity with KLH in Biomphalaria, which could provide a substrate for host-parasite interactions with a parasitic trematode, Schistosoma.

4.
J Affect Disord ; 259: 201-209, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31446381

RESUMO

BACKGROUND: Evidence suggests that single nucleotide polymorphisms (SNPs) in genes involved in serotonergic signaling and stress response pathways moderate associations between PTSD and cortical thickness. This study examined a genetic regulator of these pathways, the PPM1F gene, which has also been implicated in mechanisms of stress responding and is differentially expressed in individuals with comorbid PTSD and depression compared to controls. METHODS: Drawing from a sample of 240 white non-Hispanic trauma-exposed veterans, we tested 18 SNPs spanning the PPM1F gene for association with PTSD and cortical thickness. RESULTS: Analyses revealed six PPM1F SNPs that moderated associations between PTSD symptom severity and cortical thickness of bilateral superior frontal and orbitofrontal regions as well as the right pars triangularis (all corrected p's < 0.05) such that greater PTSD severity was related to reduced cortical thickness as a function of genotype. A whole-cortex vertex-wise analysis using the most associated SNP (rs9610608) revealed this effect to be localized to a cluster in the right superior frontal gyrus (cluster-corrected p < 0.02). LIMITATIONS: Limitations of this study include the small sample size and that the sample was all-white, non-Hispanic predominately male veterans. CONCLUSIONS: These results extend prior work linking PPM1F to PTSD and suggest that variants in this gene may have bearing on the neural integrity of the prefrontal cortex (PFC).

5.
Aging (Albany NY) ; 11(11): 3487-3504, 2019 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-31173577

RESUMO

Epigenetic age estimations based on DNA methylation (DNAm) can predict human chronological age with a high level of accuracy. These DNAm age algorithms can also be used to index advanced cellular age, when estimated DNAm age exceeds chronological age. Advanced DNAm age has been associated with several diseases and metabolic and inflammatory pathology, but the causal direction of this association is unclear. The goal of this study was to examine potential bidirectional associations between advanced epigenetic age and metabolic and inflammatory markers over time in a longitudinal cohort of 179 veterans with a high prevalence of posttraumatic stress disorder (PTSD) who were assessed over the course of two years. Analyses focused on two commonly investigated metrics of advanced DNAm age derived from the Horvath (developed across multiple tissue types) and Hannum (developed in whole blood) DNAm age algorithms. Results of cross-lagged panel models revealed that advanced Hannum DNAm age at Time 1 (T1) was associated with increased (i.e., accounting for T1 levels) metabolic syndrome (MetS) severity at Time 2 (T2; p = < 0.001). This association was specific to worsening lipid panels and indicators of abdominal obesity (p = 0.001). In contrast, no baseline measures of inflammation or metabolic pathology were associated with changes in advanced epigenetic age over time. No associations emerged between advanced Horvath DNAm age and any of the examined biological parameters. Results suggest that advanced epigenetic age, when measured using an algorithm developed in whole blood, may be a prognostic marker of pathological metabolic processes. This carries implications for understanding pathways linking advanced epigenetic age to morbidity and mortality.

6.
J Neurotrauma ; 36(23): 3264-3273, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31232163

RESUMO

Evidence suggests that blast exposure has profound negative consequences for the health of the human brain, and that it may confer risk for the development of neurodegenerative diseases such as chronic traumatic encephalopathy and Alzheimer's disease (AD). Although the molecular mechanisms linking blast exposure to subsequent neurodegeneration is an active focus of research, recent studies suggest that genetic risk for AD may elevate the risk of neurodegeneration following traumatic brain injury (TBI). However, it is currently unknown if blast exposure also interacts with AD risk to promote neurodegeneration. In this study we examined whether apolipoprotein (APOE) ɛ4, a well-known genetic risk factor for AD, influenced the relationship between blast exposure and white matter integrity in a cohort of 200 Iraq and Afghanistan war veterans. Analyses revealed a significant interaction between close-range blast exposure (CBE) (close range being within 10 m) and APOE ɛ4 carrier status in predicting white matter abnormalities, measured by a voxelwise cluster-based method that captures spatial heterogeneity in white matter disruptions. This interaction remained significant after controlling for TBI, pointing to the specificity of CBE and APOE in white matter disruptions. Further, among veteran ɛ4 carriers exposed to close-range blast, we observed a positive association between the number of CBEs and the number of white matter abnormalities. These results raise the possibility that CBE interacts with AD genetic influences on neuropathological processes such as the degradation of white matter integrity.

7.
Epigenomics ; 11(9): 1089-1105, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31240951

RESUMO

Aim: We compared the performance of multiple testing corrections for candidate gene methylation studies, namely Sidak (accurate Bonferroni), false-discovery rate and three adjustments that incorporate the correlation between CpGs: extreme tail theory (ETT), Gao et al. (GEA), and Li and Ji methods. Materials & methods: The experiment-wide type 1 error rate was examined in simulations based on Illumina EPIC and 450K data. Results: For high-correlation genes, Sidak and false-discovery rate corrections were conservative while the Li and Ji method was liberal. The GEA method tended to be conservative unless a threshold parameter was adjusted. The ETT yielded an appropriate type 1 error rate. Conclusion: For genes with substantial correlation across measured CpGs, GEA and ETT can appropriately correct for multiple testing in candidate gene methylation studies.

8.
N Biotechnol ; 52: 84-93, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31125689

RESUMO

In high-rate activated sludge (HRAS) systems, extracellular adsorption and intracellular storage have been referred to as the dominant mechanisms for capturing organic carbon from wastewater. However, the quantification of storage products under short sludge retention time (SRT) of HRAS systems has rarely been studied. Since the measurement of storage products is complex and dependent on several variables, alternative solutions for substrate removal through storage are required to understand the high-rate system's carbon capture efficiency. To overcome the complexity of storage quantification experimentally, this study proposes a fundamental approach of determining the intracellular storage products from soluble organic carbon removal of domestic wastewater. A substrate partitioning approach was used which represents influent total chemical oxygen demand (COD) removal through storage, extracellular polymeric substance, biomass growth and energy production. The substrate partitioning approach based on stoichiometric analysis showed that storage accounted for 7-11% of influent soluble COD removal in A-stage systems operated at SRT range of 0.3-2 d. The stoichiometric analysis also showed that soluble COD removal through storage is dependent on dissolved oxygen (DO) level and removal through storage increased from 8% to 30% (influent soluble COD) when the DO level decreased from 2 to 0.01 mg/L at SRT of 1.5 d.


Assuntos
Esgotos/química , Eliminação de Resíduos Líquidos , Análise da Demanda Biológica de Oxigênio , Reatores Biológicos , Dióxido de Carbono/análise , Oxigênio/análise , Solubilidade
9.
Biol Bull ; 236(2): 144-156, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30933636

RESUMO

The neurotransmitter gamma-aminobutyric acid (GABA) is widely distributed in the mammalian central nervous system, where it acts as a major mediator of synaptic inhibition. GABA also serves as a neurotransmitter in a range of invertebrate phyla, including arthropods, echinoderms, annelids, nematodes, and platyhelminthes. This article reviews evidence supporting the neurotransmitter role of GABA in gastropod molluscs, with an emphasis on its presence in identified neurons and well-characterized neural circuits. The collective findings indicate that GABAergic signaling participates in the selection and specification of motor programs, as well as the bilateral coordination of motor circuits. While relatively few in number, GABAergic neurons can influence neural circuits via inhibitory, excitatory, and modulatory synaptic actions. GABA's colocalization with peptidergic and classical neurotransmitters can broaden its integrative capacity. The functional properties of GABAergic neurons in simpler gastropod systems may provide insight into the role of this neurotransmitter phenotype in more complex brains.


Assuntos
Gastrópodes/fisiologia , Ácido gama-Aminobutírico/metabolismo , Animais , Gastrópodes/química , Neurônios Motores/química , Neurônios Motores/fisiologia , Neurônios/química , Neurônios/fisiologia , Neurotransmissores , Ácido gama-Aminobutírico/fisiologia
10.
Gen Comp Endocrinol ; 280: 1-8, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-30923005

RESUMO

Peptide hormones and neurotransmitters involved in reproduction and growth have been studied extensively in certain gastropod molluscs, such as Lymnaea stagnalis and Aplysia californica. The present study employs antisera that have been used to study peptidergic neurons in those species to probe the central nervous system of another gastropod, Biomphalaria alexandrina, an intermediate host of the parasitic trematode that causes schistosomiasis in humans. Whole mount preparations of central ganglia were stained immunohistochemically, and several populations of neurons appeared to be homologous to those forming the neuroendocrine axis that has been previously described in L. stagnalis. These cells include the caudodorsal cells and the light green and canopy cells, which produce hormones that regulate ovulation and growth, respectively. Other populations of cells containing APGWamide, FMRFamide and/or related peptides are consistent with ones that innervate the penis in L. stagnalis and other gastropods. Identification of neurons that might be responsible for the control of reproduction and growth in Biomphalaria provides an important initial step toward the development of novel methods of disease control and pest management directed toward reducing snail populations.


Assuntos
Biomphalaria/crescimento & desenvolvimento , Biomphalaria/fisiologia , Imuno-Histoquímica/métodos , Neurônios/metabolismo , Neuropeptídeos/metabolismo , Animais , Sistema Nervoso Central/metabolismo , Insulina/metabolismo , Sistemas Neurossecretores , Neurotransmissores/metabolismo , Reprodução/fisiologia
11.
Brain Behav Immun ; 80: 193-203, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30872092

RESUMO

BACKGROUND: Longevity gene klotho (KL) is associated with age-related phenotypes but has not been evaluated against a direct human biomarker of cellular aging. We examined KL and psychiatric stress, including posttraumatic stress disorder (PTSD), which is thought to potentiate accelerated aging, in association with biomarkers of cellular aging. METHODS: The sample comprised 309 white, non-Hispanic genotyped veterans with measures of epigenetic age (DNA methylation age), telomere length (n = 252), inflammation (C-reactive protein), psychiatric symptoms, metabolic function, and white matter neural integrity (diffusion tensor imaging; n = 185). Genotyping and DNA methylation were obtained on epi/genome-wide beadchips. RESULTS: In gene by environment analyses, two KL variants (rs9315202 and rs9563121) interacted with PTSD severity (peak corrected p = 0.044) and sleep disturbance (peak corrected p = 0.034) to predict advanced epigenetic age. KL variant, rs398655, interacted with self-reported pain in association with slowed epigenetic age (corrected p = 0.048). A well-studied protective variant, rs9527025, was associated with slowed epigenetic age (p = 0.046). The peak PTSD interaction term (with rs9315202) also predicted C-reactive protein (p = 0.049), and white matter microstructural integrity in two tracts (corrected ps = 0.005 - 0.035). This SNP evidenced a main effect with an index of metabolic syndrome severity (p = 0.015). Effects were generally accentuated in older subjects. CONCLUSIONS: Rs9315202 predicted multiple biomarkers of cellular aging such that psychiatric stress was more strongly associated with cellular aging in those with the minor allele. KL genotype may contribute to a synchronized pathological aging response to stress and could be a therapeutic target to alter the pace of cellular aging.

12.
Artigo em Inglês | MEDLINE | ID: mdl-30503303

RESUMO

There is increasing evidence that epigenetic factors play a critical role in posttraumatic stress disorder (PTSD), by mediating the impact of environmental exposures to trauma on the regulation of gene expression. DNA methylation is one epigenetic process that has been highly studied in PTSD. This review will begin by providing an overview of DNA methylation (DNAm) methods, and will then highlight two major biological systems that have been identified in the epigenetic regulation in PTSD: (a) the immune system and (b) the stress response system. In addition to candidate gene approaches, we will review novel strategies to study epigenome-wide PTSD-related effects, including epigenome-wide algorithms that distill information from many loci into a single summary score (e.g., measures of "epigenetic age" which have been associated with PTSD). This review will also cover recent epigenome wide association studies (EWAS) of PTSD, and biological pathway models used to identify gene sets enriched in PTSD. Finally, we address technical and methodological advances and challenges to the field, and highlight exciting directions for future research.


Assuntos
Metilação de DNA , Epigênese Genética , Transtornos de Estresse Pós-Traumáticos/genética , Transtornos de Estresse Pós-Traumáticos/metabolismo , Humanos
13.
Neurosci Lett ; 692: 204-209, 2019 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-30366016

RESUMO

The inflammatory system has been implicated in the pathophysiology of a variety of psychiatric conditions. Individuals with PTSD, depression, and other fear- and anxiety-related disorders exhibit alterations in peripheral circulating inflammatory markers, suggesting dysregulation of the inflammatory system. The relationship between inflammation and PTSD has been investigated almost exclusively in the periphery, and has not been extensively explored in human postmortem brain tissue. Interleukins (ILs) represent a subtype of cytokines and are key signaling proteins in the immune and inflammatory systems. Based on prior research implicating IL signaling in PTSD and depression, we performed a preliminary investigation of IL gene expression in a region of the cortex involved in emotion regulation and PTSD, the dorsolateral prefrontal cortex (dlPFC), using tissue from the newly established VA National PTSD Brain Bank. Gene expression analyses were conducted on post-mortem tissue from the dlPFC from 50 donors: 13 controls, 12 PTSD cases, and 25 depressed cases. RNA was extracted from frozen dlPFC tissue, reverse transcribed to cDNA, and quantitative polymerase chain reaction (qPCR) was performed to assess gene expression of IL1A, IL1B, IL6, IL8, IL10, IL13, and IL15. We found a multiple-testing corrected significant decrease in IL1A expression in the dlPFC for PTSD and depression cases compared to controls (p < 0.005) with age at death, sex, race and RNA integrity number (RIN) included as covariates. To our knowledge this finding is the first demonstration of altered IL expression in brain tissue from deceased individuals with histories of PTSD and/or depression.


Assuntos
Interleucina-1alfa/genética , Córtex Pré-Frontal/metabolismo , Transtornos de Estresse Pós-Traumáticos/genética , Adulto , Feminino , Expressão Gênica , Humanos , Inflamação/genética , Inflamação/metabolismo , Interleucina-1alfa/biossíntese , Masculino , Pessoa de Meia-Idade , Transtornos de Estresse Pós-Traumáticos/metabolismo , Transcriptoma
14.
Psychol Med ; 49(11): 1905-1913, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30207258

RESUMO

BACKGROUND: Externalizing disorders are known to be partly heritable, but the biological pathways linking genetic risk to the manifestation of these costly behaviors remain under investigation. This study sought to identify neural phenotypes associated with genomic vulnerability for externalizing disorders. METHODS: One-hundred fifty-five White, non-Hispanic veterans were genotyped using a genome-wide array and underwent resting-state functional magnetic resonance imaging. Genetic susceptibility was assessed using an independently developed polygenic score (PS) for externalizing, and functional neural networks were identified using graph theory based network analysis. Tasks of inhibitory control and psychiatric diagnosis (alcohol/substance use disorders) were used to measure externalizing phenotypes. RESULTS: A polygenic externalizing disorder score (PS) predicted connectivity in a brain circuit (10 nodes, nine links) centered on left amygdala that included several cortical [bilateral inferior frontal gyrus (IFG) pars triangularis, left rostral anterior cingulate cortex (rACC)] and subcortical (bilateral amygdala, hippocampus, and striatum) regions. Directional analyses revealed that bilateral amygdala influenced left prefrontal cortex (IFG) in participants scoring higher on the externalizing PS, whereas the opposite direction of influence was observed for those scoring lower on the PS. Polygenic variation was also associated with higher Participation Coefficient for bilateral amygdala and left rACC, suggesting that genes related to externalizing modulated the extent to which these nodes functioned as communication hubs. CONCLUSIONS: Findings suggest that externalizing polygenic risk is associated with disrupted connectivity in a neural network implicated in emotion regulation, impulse control, and reinforcement learning. Results provide evidence that this network represents a genetically associated neurobiological vulnerability for externalizing disorders.

15.
Psychol Med ; 49(5): 791-800, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-29897034

RESUMO

BACKGROUND: Posttraumatic stress disorder (PTSD) and stress/trauma exposure are cross-sectionally associated with advanced DNA methylation age relative to chronological age. However, longitudinal inquiry and examination of associations between advanced DNA methylation age and a broader range of psychiatric disorders is lacking. The aim of this study was to examine if PTSD, depression, generalized anxiety, and alcohol-use disorders predicted acceleration of DNA methylation age over time (i.e. an increasing pace, or rate of advancement, of the epigenetic clock). METHODS: Genome-wide DNA methylation and a comprehensive set of psychiatric symptoms and diagnoses were assessed in 179 Iraq/Afghanistan war veterans who completed two assessments over the course of approximately 2 years. Two DNA methylation age indices (Horvath and Hannum), each a weighted index of an array of genome-wide DNA methylation probes, were quantified. The pace of the epigenetic clock was operationalized as change in DNA methylation age as a function of time between assessments. RESULTS: Analyses revealed that alcohol-use disorders (p = 0.001) and PTSD avoidance and numbing symptoms (p = 0.02) at Time 1 were associated with an increasing pace of the epigenetic clock over time, per the Horvath (but not the Hannum) index of cellular aging. CONCLUSIONS: This is the first study to suggest that posttraumatic psychopathology is longitudinally associated with a quickened pace of the epigenetic clock. Results raise the possibility that accelerated cellular aging is a common biological consequence of stress-related psychopathology, which carries implications for identifying mechanisms of stress-related cellular aging and developing interventions to slow its pace.

16.
PLoS One ; 13(12): e0208891, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30586424

RESUMO

Histological evidence points to the presence of dopamine (DA) in the cephalic sensory organs of multiple gastropod molluscs, suggesting a possible sensory role for the neurotransmitter. We investigated the sensory function of DA in the nudipleuran Pleurobranchaea californica, in which the central neural correlates of sensation and foraging behavior have been well characterized. Tyrosine hydroxylase-like immunoreactivity (THli), a signature of the dopamine synthetic pathway, was similar to that found in two other opisthobranchs and two pulmonates previously studied: 1) relatively few (<100) THli neuronal somata were observed in the central ganglia, with those observed found in locations similar to those documented in the other snails but varying in number, and 2) the vast majority of THli somata were located in the peripheral nervous system, were associated with ciliated, putative primary sensory cells, and were highly concentrated in chemotactile sensory organs, giving rise to afferent axons projecting to the central nervous system. We extended these findings by observing that applying a selective D2/D3 receptor antagonist to the chemo- and mechanosensory oral veil-tentacle complex of behaving animals significantly delayed feeding behavior in response to an appetitive stimulus. A D1 blocker had no effect. Recordings of the two major cephalic sensory nerves, the tentacle and large oral veil nerves, in a deganglionated head preparation revealed a decrease of stimulus-evoked activity in the former nerve following application of the same D2/D3 antagonist. Broadly, our results implicate DA in sensation and engender speculation regarding the foraging-based decisions the neurotransmitter may serve in the nervous system of Pleurobranchaea and, by extension, other gastropods.


Assuntos
Dopamina/metabolismo , Sistema Nervoso Periférico/metabolismo , Pleurobranchaea/metabolismo , Células Receptoras Sensoriais/metabolismo , Animais , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Sistema Nervoso Periférico/efeitos dos fármacos , Pleurobranchaea/efeitos dos fármacos , Células Receptoras Sensoriais/efeitos dos fármacos , Tirosina 3-Mono-Oxigenase/metabolismo
17.
J Trauma Stress ; 31(5): 676-686, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30338579

RESUMO

Traumatic stress is thought to be associated with shortened telomere length (TL) in leukocytes, an age-related marker of increased risk for cellular senescence, although findings thus far have been mixed. We assessed associations between posttraumatic stress disorder (PTSD) symptom severity, temperament, and TL in a sample of 453 White, non-Hispanic, middle-aged, trauma-exposed male and female veterans and civilians. Given that prior research has suggested an association between PTSD and accelerated cellular age, we also examined associations between TL and an index of accelerated cellular age derived from DNA methylation data (DNAm age). Analyses revealed that, controlling for chronological age, PTSD was not directly associated with TL but rather this association was moderated by age, ß = -.14, p = .003, ΔR2 = .02. Specifically, PTSD severity evidenced a stronger negative association with TL among relatively older participants (≥ 55 years of age). In a subset of veterans with data pertaining to temperament (n = 150), positive emotionality, and, specifically, a drive toward achievement, ß = .26, p = .002, ΔR2 = .06, were positively associated with TL. There was no evidence of an association between age-adjusted TL and accelerated DNAm age. Collectively, these results indicate that older adults may be more vulnerable to the negative health effects of PTSD but that traits such as achievement, resilience, and psychological hardiness may be protective. These findings underscore the importance of identifying reliable biomarkers of cellular aging and senescence and of determining the biological mechanisms that contribute to stress-related disease and decline.


Assuntos
Transtornos de Estresse Pós-Traumáticos/genética , Encurtamento do Telômero/fisiologia , Temperamento/fisiologia , Adulto , Idoso , Estudos Transversais , Metilação de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Determinação da Personalidade , Polimorfismo de Nucleotídeo Único , Reação em Cadeia da Polimerase em Tempo Real , Índice de Gravidade de Doença , Transtornos de Estresse Pós-Traumáticos/psicologia , Veteranos
18.
Neurosci Lett ; : 133562, 2018 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-29689343

RESUMO

Progress in PTSD pharmacotherapy has lagged far behind that of other major mental illnesses. Unfortunately, due to the enormous costs and lengthy process involved in bringing drugs to market, delivering new treatments to patients with PTSD in the near future will remain a challenge. However, by capitalizing on recent advances in the pharmacogenetics of antidepressants, precision psychiatry approaches can be leveraged to optimize the delivery of currently-available medications in a fraction of the time and cost required to develop novel therapeutics. This paper provides a review of the pharmacogenetics of the four serotonin reuptake inhibitors (SRIs) that are currently endorsed for the treatment of PTSD (paroxetine, sertraline, fluoxetine and venlafaxine). It focuses on genes involved in SRI pharmacokinetics (including the liver enzyme genes CYP2D6 and CYP2C19 and blood-brain barrier-relevant gene ABCB1) as well as those implicated in both SRI pharmacodynamics and the pathophysiology of PTSD and related conditions (e.g., BDNF, FKBP5, HTR1A, HTR2A, TPH2). The review concludes with an overview of emerging commercial platforms for pharmacogenetic-guided prescription and a discussion of challenges and directions for future pharmacogenetic research on PTSD.

19.
J Comp Neurol ; 526(11): 1790-1805, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29633264

RESUMO

The simpler nervous systems of certain invertebrates provide opportunities to examine colocalized classical neurotransmitters in the context of identified neurons and well defined neural circuits. This study examined the distribution of γ-aminobutyric acid-like immunoreactivity (GABAli) in the nervous system of the panpulmonates Biomphalaria glabrata and Biomphalaria alexandrina, major intermediate hosts for intestinal schistosomiasis. GABAli neurons were localized in the cerebral, pedal, and buccal ganglia of each species. With the exception of a projection to the base of the tentacle, GABAli fibers were confined to the CNS. As GABAli was previously reported to be colocalized with markers for dopamine (DA) in five neurons in the feeding network of the euopisthobranch gastropod Aplysia californica (Díaz-Ríos, Oyola, & Miller, 2002), double-labeling protocols were used to compare the distribution of GABAli with tyrosine hydroxylase immunoreactivity (THli). As in Aplysia, GABAli-THli colocalization was limited to five neurons, all of which were located in the buccal ganglion. Five GABAli-THli cells were also observed in the buccal ganglia of two other intensively studied panpulmonate species, Lymnaea stagnalis and Helisoma trivolvis. These findings indicate that colocalization of the classical neurotransmitters GABA and DA in feeding central pattern generator (CPG) interneurons preceded the divergence of euopisthobranch and panpulmonate taxa. These observations also support the hypothesis that heterogastropod feeding CPG networks exhibit a common universal design.


Assuntos
Biomphalaria/metabolismo , Músculos/inervação , Músculos/fisiologia , Tirosina 3-Mono-Oxigenase/metabolismo , Ácido gama-Aminobutírico/metabolismo , Animais , Geradores de Padrão Central/fisiologia , Extremidades/inervação , Extremidades/fisiologia , Comportamento Alimentar , Gânglios dos Invertebrados/citologia , Gânglios dos Invertebrados/fisiologia , Imuno-Histoquímica , Interneurônios/fisiologia , Lymnaea , Músculos/metabolismo , Fibras Nervosas/fisiologia , Neurônios/fisiologia , Especificidade da Espécie
20.
J Trauma Stress ; 31(2): 191-201, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29630742

RESUMO

Longitudinal studies have demonstrated transactional associations between psychopathology and stressful life events (SLEs), such that psychopathology predicts the occurrence of new SLEs, and SLEs in turn predict increasing symptom severity. The association between posttraumatic stress disorder (PTSD), specifically, and stress generation remains unclear. This study used temporally sequenced data from 116 veterans (87.9% male) to examine whether PTSD symptoms predicted new onset SLEs, and if these SLEs were associated with subsequent PTSD severity. The SLEs were objectively rated, using a clinician-administered interview and consensus-rating approach, to assess the severity, frequency, and personal dependence (i.e., if the event was due to factors that were independent of or dependent on the individual) of new-onset SLEs. A series of mediation models were tested, and results provided evidence for moderated mediation whereby baseline PTSD severity robustly predicted personally dependent SLEs, B = 0.03, p = .006, and dependent SLEs predicted increases in follow-up PTSD symptom severity, B = -0.04, p = .003, among participants with relatively lower baseline PTSD severity. After we controlled for baseline PTSD severity, personality traits marked by low constraint (i.e., high impulsivity) were also associated with an increased number of dependent SLEs. Our results provide evidence for a stress-generative role of PTSD and highlight the importance of developing interventions aimed at reducing the occurrence of personally dependent stressors.


Assuntos
Acontecimentos que Mudam a Vida , Transtornos de Estresse Pós-Traumáticos/psicologia , Estresse Psicológico/etiologia , Veteranos/psicologia , Idoso , Feminino , Humanos , Comportamento Impulsivo , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Modelos Psicológicos , Personalidade , Escalas de Graduação Psiquiátrica , Índice de Gravidade de Doença , Estados Unidos
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