A scoping review of recommendations in the English language on conducting research with trauma-exposed populations since publication of the Belmont report; thematic review of existing recommendations on research with trauma-exposed populations.

OBJECTIVE: To identify recommendations for conducting public health research with trauma-exposed populations. METHODS: Researchers searched Embase, PubMed, Scopus, Web of Science, Open Grey, and Google Scholar for recommendations. Trauma that causes psychological impact was our exposure of interest and we excluded clinical articles on treating physical trauma. We reviewed titles and abstracts of 8,070 articles and full text of 300 articles. We analyzed recommendations with thematic analysis, generated questions from the existing pool of recommendations, and then summarized select gaps. RESULTS: We abstracted recommendations from 145 articles in five categories: community benefit, participant benefit, safety, researcher well-being, and recommendations for conduct of trauma research. CONCLUSIONS: Gold standards to guide the conduct of trauma-informed public health research do not yet exist. The literature suggests participation in trauma research is not inherently harmful, and current recommendations concern using research to benefit communities and participants, protecting participants and researchers from harm, and improving professional practice. As public health researchers increasingly analyze trauma as a determinant of health, gold standards for the conduct of trauma-informed public health research would be appropriate and timely.

Combined neurodevelopmental exposure to deltamethrin and corticosterone is associated with Nr3c1 hypermethylation in the midbrain of male mice.

Attention-Deficit Hyperactivity Disorder (ADHD) is one of the most common neurodevelopmental disorders and manifests inattention, hyperactivity, and impulsivity symptoms in childhood that can last throughout life. Genetic and environmental studies implicate the dopamine system in ADHD pathogenesis. Work from our group and that of others indicates that deltamethrin insecticide and stress exposure during neurodevelopment leads to alterations in dopamine function, and we hypothesized that exposure to both of these factors together would lead to synergistic effects on DNA methylation of key genes within the midbrain, a highly dopaminergic region, that could contribute to these findings. Through targeted next-generation sequencing of a panel of cortisol and dopamine pathway genes, we observed hypermethylation of the glucocorticoid receptor gene, Nr3c1, in the midbrain of C57/BL6N males in response to dual deltamethrin and corticosterone exposures during development. This is the first description of DNA methylation studies of Nr3c1 and key dopaminergic genes within the midbrain in response to a pyrethroid insecticide, corticosterone, and these two exposures together. Our results provide possible connections between environmental exposures that impact the dopamine system and the hypothalamic-pituitary-adrenal axis via changes in DNA methylation and provides new information about the presence of epigenetic effects in adulthood after exposure during neurodevelopment.

A Neurodevelopmental Model of Combined Pyrethroid and Chronic Stress Exposure.

Attention-deficit hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders of childhood and previous studies indicate the dopamine system plays a major role in ADHD pathogenesis. Two environmental exposures independently associated with dopaminergic dysfunction and ADHD risk include exposure to deltamethrin, a pyrethroid insecticide, and chronic stress. We hypothesized that combined neurodevelopmental exposure to both deltamethrin and corticosterone (CORT), the major stress hormone in rodents, would result in additive changes within the dopamine system. To study this, we developed a novel dual exposure paradigm and exposed pregnant C57BL/6 dams to 3 mg/kg deltamethrin through gestation and weaning, and their offspring to 25 µg/mL CORT dissolved in the drinking water through adulthood. Midbrain RNA expression as well as striatal and cortical protein expression of key dopaminergic components were investigated, in addition to ADHD-like behavioral tasks and electrochemical dopamine dynamics via fast-scan cyclic voltammetry. Given the well-described sexual dimorphism of ADHD, males and females were assessed separately. Males exposed to deltamethrin had significantly decreased midbrain Pitx3 expression, decreased cortical tyrosine hydroxylase (TH) expression, increased activity in the Y maze, and increased dopamine uptake rate in the dorsal striatum. These effects did not occur in males exposed to CORT only, or in males exposed to both deltamethrin and CORT, suggesting that CORT may attenuate these effects. Additionally, deltamethrin- and CORT-exposed females did not display these dopaminergic features, which indicates these changes are sex-specific. Our results show dopaminergic changes from the RNA through the functional level. Moreover, these data illustrate the importance of testing multiple environmental exposures together to better understand how combined exposures that occur in certain vulnerable populations could affect similar neurodevelopmental systems, as well as the importance of studying sex differences of these alterations.

HIV and symptoms of depression are independently associated with impaired glucocorticoid signaling.

Chronic inflammation caused by HIV infection may lead to deficient glucocorticoid (GC) signaling predisposing people living with HIV to depression and other psychiatric disorders linked to GC resistance. We hypothesized that comorbid HIV and depressive symptoms in women would synergistically associate with deficits in GC signaling. This cross-sectional study used samples obtained from the Women's Interagency HIV Study (WIHS). The Centers for Epidemiological Studies (CES-D) was used to define depression in four groups of women from the Women's Interagency HIV Study (WIHS): 1) HIV-negative, non-depressed (n = 37); 2) HIV-negative, depressed (n = 34); 3) HIV-positive, non-depressed (n = 38); and 4) HIV-positive, depressed (n = 38). To assess changes in GC signaling from peripheral blood mononuclear cells (PBMCs), we examined baseline and dexamethasone (Dex)-stimulated changes in the expression of the GC receptor (GR, gene: Nr3c1) and its negative regulator Fkbp5 via quantitative RT-PCR. GR sensitivity was evaluated in vitro by assessing the Dex inhibition of lipopolysaccharide (LPS)-stimulated IL-6 and TNF-α levels. Depressive symptoms and HIV serostatus were independently associated with elevated baseline expression of Fkbp5 and Nr3c1. Depressive symptoms, but not HIV status, was independently associated with reduced LPS-induced release of IL-6. Counter to predictions, there was no interactive association of depressive symptoms and HIV on any outcome. Comorbid depressive symptoms with HIV infection were associated with a gene expression and cytokine profile similar to that of healthy control women, a finding that may indicate further disruptions in disease adaptation.

A genome-wide assessment of conserved SNP alleles reveals a panel of regulatory SNPs relevant to the peripheral nerve.

BACKGROUND: Identifying functional non-coding variation is critical for defining the genetic contributions to human disease. While single-nucleotide polymorphisms (SNPs) within cis-acting transcriptional regulatory elements have been implicated in disease pathogenesis, not all cell types have been assessed and functional validations have been limited. In particular, the cells of the peripheral nervous system have been excluded from genome-wide efforts to link non-coding SNPs to altered gene function. Addressing this gap is essential for defining the genetic architecture of diseases that affect the peripheral nerve. We developed a computational pipeline to identify SNPs that affect regulatory function (rSNPs) and evaluated our predictions on a set of 144 regions in Schwann cells, motor neurons, and muscle cells. RESULTS: We identified 28 regions that display regulatory activity in at least one cell type and 13 SNPs that affect regulatory function. We then tailored our pipeline to one peripheral nerve cell type by incorporating SOX10 ChIP-Seq data; SOX10 is essential for Schwann cells. We prioritized 22 putative SOX10 response elements harboring a SNP and rapidly validated two rSNPs. We then selected one of these elements for further characterization to assess the biological relevance of our approach. Deletion of the element from the genome of cultured Schwann cells-followed by differential gene expression studies-revealed Tubb2b as a candidate target gene. Studying the enhancer in developing mouse embryos revealed activity in SOX10-positive cells including the dorsal root ganglia and melanoblasts. CONCLUSIONS: Our efforts provide insight into the utility of employing strict conservation for rSNP discovery. This strategy, combined with functional analyses, can yield candidate target genes. In support of this, our efforts suggest that investigating the role of Tubb2b in SOX10-positive cells may reveal novel biology within these cell populations.

GNB3 overexpression causes obesity and metabolic syndrome.

The G-protein beta subunit 3 (GNB3) gene has been implicated in obesity risk; however, the molecular mechanism of GNB3-related disease is unknown. GNB3 duplication is responsible for a syndromic form of childhood obesity, and an activating DNA sequence variant (C825T) in GNB3 is also associated with obesity. To test the hypothesis that GNB3 overexpression causes obesity, we created bacterial artificial chromosome (BAC) transgenic mice that carry an extra copy of the human GNB3 risk allele. Here we show that GNB3-T/+ mice have increased adiposity, but not greater food intake or a defect in satiety. GNB3-T/+ mice have elevated fasting plasma glucose, insulin, and C-peptide, as well as glucose intolerance, indicating type 2 diabetes. Fasting plasma leptin, triglycerides, cholesterol and phospholipids are elevated, suggesting metabolic syndrome. Based on a battery of behavioral tests, GNB3-T/+ mice did not exhibit anxiety- or depressive-like phenotypes. GNB3-T/+ and wild-type animals have similar activity levels and heat production; however, GNB3-T/+ mice exhibit dysregulation of acute thermogenesis. Finally, Ucp1 expression is significantly lower in white adipose tissue (WAT) in GNB3-T/+ mice, suggestive of WAT remodeling that could lead to impaired cellular thermogenesis. Taken together, our study provides the first functional link between GNB3 and obesity, and presents insight into novel pathways that could be applied to combat obesity and type 2 diabetes.

Impairment in the mesohippocampal dopamine circuit following exposure to the brominated flame retardant, HBCDD.

Many chemicals have been used to increase the safety of consumer products by reducing their flammability and risk for ignition. Recent focus on brominated flame retardants, such as polybrominated diphenyl ethers (PBDEs) has shown them to contribute to neurobehavioral deficits in children, including learning and memory. As the manufacture and use of PBDEs have been reduced, replacement chemicals, such as hexabromocyclododecane (HBCDD) have been substituted. Our current study evaluated the neurotoxicity of HBCDD, concentrating on dopaminergic innervation to the hippocampus. Using an in vivo model, we exposed male mice to HBCDD and then assessed alterations to the dopamine synapse 6 weeks later. These exposures elicited significant reductions in presynaptic dopaminergic proteins, including TH, COMT, MAO-B, DAT, VMAT2, and alpha-synuclein. In contrast, postsynaptic dopamine receptors were not impaired. These findings suggest that the mesohippocampal dopamine circuit is vulnerable to HBCDD and the dopamine terminal may be a selective target for alteration.

Posttraumatic stress disorder: A metabolic disorder in disguise?

Posttraumatic stress disorder (PTSD) is a heterogeneous psychiatric disorder that affects individuals exposed to trauma and is highly co-morbid with other adverse health outcomes, including cardiovascular disease and obesity. The unique pathophysiological feature of PTSD is the inability to inhibit fear responses, such that individuals suffering from PTSD re-experience traumatic memories and are unable to control psychophysiological responses to trauma-associated stimuli. However, underlying alterations in sympathetic nervous system activity, neuroendocrine systems, and metabolism associated with PTSD are similar to those present in traditional metabolic disorders, such as obesity and diabetes. The current review highlights existing clinical, translational, and preclinical data that support the notion that underneath the primary indication of impaired fear inhibition, PTSD is itself also a metabolic disorder and proposes altered function of inflammatory responses as a common underlying mechanism. The therapeutic implications of treating PTSD as a whole-body condition are significant, as targeting any underlying biological system whose activity is altered in both PTSD and metabolic disorders, (i.e. HPA axis, sympathetic nervous systems, inflammation) may elicit symptomatic relief in individuals suffering from these whole-body adverse outcomes.

The Synapse as a Central Target for Neurodevelopmental Susceptibility to Pesticides.

The developmental period of the nervous system is carefully orchestrated and highly vulnerable to alterations. One crucial factor of a properly-functioning nervous system is the synapse, as synaptic signaling is critical for the formation and maturation of neural circuits. Studies show that genetic and environmental impacts can affect diverse components of synaptic function. Importantly, synaptic dysfunction is known to be associated with neurologic and psychiatric disorders, as well as more subtle cognitive, psychomotor, and sensory defects. Given the importance of the synapse in numerous domains, we wanted to delineate the effects of pesticide exposure on synaptic function. In this review, we summarize current epidemiologic and molecular studies that demonstrate organochlorine, organophosphate, and pyrethroid pesticide exposures target the developing synapse. We postulate that the synapse plays a central role in synaptic vulnerability to pesticide exposure during neurodevelopment, and the synapse is a worthy candidate for investigating more subtle effects of chronic pesticide exposure in future studies.

A loss-of-function variant in the human histidyl-tRNA synthetase (HARS) gene is neurotoxic in vivo.

Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed enzymes responsible for ligating amino acids to cognate tRNA molecules. Mutations in four genes encoding an ARS have been implicated in inherited peripheral neuropathy with an axonal pathology, suggesting that all ARS genes are relevant candidates for disease in patients with related phenotypes. Here, we present results from a mutation screen of the histidyl-tRNA synthetase (HARS) gene in a large cohort of patients with peripheral neuropathy. These efforts revealed a rare missense variant (c.410G>A/p.Arg137Gln) that resides at a highly conserved amino acid, represents a loss-of-function allele when evaluated in yeast complementation assays, and is toxic to neurons when expressed in a worm model. In addition to the patient with peripheral neuropathy, p.Arg137Gln HARS was detected in three individuals by genome-wide exome sequencing. These findings suggest that HARS is the fifth ARS locus associated with axonal peripheral neuropathy. Implications for identifying ARS alleles in human populations and assessing them for a role in neurodegenerative phenotypes are discussed.