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HPA-axis genes as potential risk variants for neurocognitive decline in trauma-exposed, HIV-positive females.

ABSTRACT: Purpose:Previous studies have independently provided evidence for the effects of HIV infection, hypothalamic-pituitary-adrenal (HPA) axis dysfunction and early life trauma on neurocognitive impairment (NCI). This study examined the interaction between single-nucleotide polymorphisms (SNPs) of two HPA axis genes, corticotrophin-releasing hormone receptor 1 (CRHR1; rs110402, rs242924, rs7209436, and rs4792888) and corticotrophin-releasing hormone-binding protein (CRHBP; rs32897, rs10062367, and rs1053989), childhood trauma, and HIV-associated NCI. Patients and methods:The sample comprised 128 HIV-positive Xhosa females of whom 88 (69%) had a history of childhood trauma. NCI was assessed using a battery of 17 measures sensitive to the effects of HIV, and the history of childhood trauma was assessed using the validated retrospective Childhood Trauma Questionnaire-Short Form. Generalized linear regression models were used to compare allelic distribution by trauma status and global NCI. The association between genotype, childhood trauma, and cognitive scores was also evaluated using generalized linear regression models, assuming additive models for the SNPs, and ANOVA. Results:Of the seven polymorphisms assessed, only the rs10062367 variant of CRHBP was significantly associated with global NCI (P=0.034), independent of childhood trauma. This polymorphism was not significantly associated with z-scores on any specific cognitive domain. The interaction of childhood trauma and variants of CRHR1 was associated with poorer learning (rs110402) and/or recall (rs110402 and rs4792888). Conclusion:These findings suggest that CRHBP rs10062367 A allele is a possible risk variant for NCI in HIV, independent of childhood trauma. Furthermore, results show that the interaction of childhood trauma with variants of CRHR1, rs110402 and rs4792888, confer added vulnerability to NCI in HIV-infected individuals in cognitive domains that are known to be impacted by HIV. While these findings need independent replication in larger samples, it adds CRHBP and CRHR1 to the list of known genes linked to HIV- and childhood trauma-associated neurocognitive phenotypes.

SUBMITTER: Jacobs S

PROVIDER: S-EPMC6167976 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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HPA-axis genes as potential risk variants for neurocognitive decline in trauma-exposed, HIV-positive females.

Jacobs Sean S Moxley Karis K Womersley Jacqueline S JS Spies Georgina G Hemmings Sian Mj SM Seedat Soraya S

Neuropsychiatric disease and treatment 20180928

<h4>Purpose</h4>Previous studies have independently provided evidence for the effects of HIV infection, hypothalamic-pituitary-adrenal (HPA) axis dysfunction and early life trauma on neurocognitive impairment (NCI). This study examined the interaction between single-nucleotide polymorphisms (SNPs) of two HPA axis genes, corticotrophin-releasing hormone receptor 1 (<i>CRHR1</i>; rs110402, rs242924, rs7209436, and rs4792888) and corticotrophin-releasing hormone-binding protein (<i>CRHBP</i>; rs328 ...[more]

PMID: 30319260

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Project description:Childhood trauma is among the most potent contributing risk factors for depression and is associated with poor treatment response. Hypothalamic-pituitary-adrenal (HPA) axis abnormalities have been linked to both childhood trauma and depression, but the underlying mechanisms are poorly understood. The present study aimed to investigate the link between childhood trauma, HPA axis activity and antidepressant response in patients with depression. As part of the Wellcome Trust NIMA consortium, 163 depressed patients and 55 healthy volunteers were included in this study. Adult patients meeting Structured Clinical Interview for Diagnostic and Statistical Manual Version-5 criteria for major depression were categorised into subgroups of treatment responder (n = 42), treatment non-responder (n = 80) and untreated depressed (n = 41) based on current depressive symptom severity measured by the 17-item Hamilton Rating Scale for Depression and exposure to antidepressant medications established by Antidepressant Treatment Response Questionnaire. Childhood Trauma Questionnaire was obtained. Baseline serum C-reactive protein was measured using turbidimetric detection. Salivary cortisol was analyzed at multiple time points during the day using the ELISA technique. Glucocorticoid resistance was defined as the coexistence of hypercortisolemia and inflammation. Our results show that treatment non-responder patients had higher exposure to childhood trauma than responders. No specific HPA axis abnormalities were found in treatment non-responder depressed patients. Untreated depressed showed increased diurnal cortisol levels compared with patients on antidepressant medication, and higher prevalence of glucocorticoid resistance than medicated patients and controls. The severity of childhood trauma was associated with increased diurnal cortisol levels only in individuals with glucocorticoid resistance. Therefore, our findings suggest that the severity of childhood trauma experience contributes to a lack of response to antidepressant treatment. The effects of childhood trauma on increased cortisol levels are specifically evident in patients with glucocorticoid resistance and suggest glucocorticoid resistance as a target for the development of personalized treatment for a subgroup of depressed patients with a history of childhood trauma rather than for all patients with resistance to antidepressant treatment.

Project description:BackgroundMuch work has documented hypothalamic pituitary adrenal (HPA) axis abnormalities in major depressive disorder (MDD), but inconsistencies leave this system's role in the illness unclear. Comparisons across studies are complicated by variation in co-morbidity (Posttraumatic Stress Disorder-PTSD, anxiety disorders), exposure to trauma, and timing of trauma (child vs. adult). Here, we examined the impact of these factors on HPA axis profiles in depression.MethodsWe recruited 5 groups of participants: MDD (n = 14), comorbid MDD + PTSD following adulthood trauma (MDD + PTSD-Adult; n = 12), comorbid MDD + PTSD following childhood trauma (MDD + PTSD-Child; n = 18), comorbid MDD + social anxiety disorder (MDD + SAD; n = 12), and non-depressed control participants who were sex and age matched to patients (combined total n = 36). HPA axis function was assessed using three challenges: stress reactivity via the Trier Social Stress Test (TSST), feedback sensitivity via a dexamethasone suppression test (DST), and central drive via a metyrapone challenge (MET). We compared hormonal responses between patient groups and their respective non-depressed controls.ResultsMDD + PTSD-Child showed low cortisol levels at baseline, and reduced adrenocorticotropic hormone (ACTH) levels at baseline and throughout the TSST. MDD-only, MDD + PTSD-Adult, and MDD + SAD did not differ from non-depressed controls in HPA axis responses to the TSST. Controlling for childhood trauma severity, the reduced baseline levels in MDD + PTSD-Child were no longer significant and significantly reduced baseline cortisol levels emerged for MDD + PTSD-Adult. No diagnostic group effects were detected with DST and MET. Childhood maltreatment subtypes were associated with unique HPA axis responses to TSST and MET.ConclusionComorbidity and trauma exposure, as well as their timing and type, contribute to inconsistencies in the depression literature and must be included in efforts to clarify the role of the HPA axis in MDD.

Project description:BackgroundHyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis constitutes a pivotal response by surgical trauma, manifesting as a critical aspect of the acute stress reaction. This hyperactivity resulted in adverse surgical outcomes and is often associated with increased postoperative anxiety. Increased evidence suggests that Nesfatin-1 plays a crucial role in stress responses and stress-related psychiatric disorders. Electroacupuncture (EA) is widely used to alleviate stress responses and anxiety, although its mechanism of action remains unclear. This study aimed to assess the mechanisms by which hypothalamic Nesfatin-1 contribute to the alleviation of HPA axis hyperactivity and anxiety by EA.MethodsPartial hepatectomy (HT) was performed to simulate surgical trauma, and EA was applied at Zusanli (ST36) and Sanyinjiao (SP6). The levels of hypothalamic Nesfatin-1, c-Fos, and corticotropin-releasing hormone (CRH) were detected, and serum adrenocorticotropic hormone (ACTH) and corticosterone (CORT) were regarded as indicators of HPA axis activity. Anxiety levels were assessed through open field tests (OFT), elevated plus maze (EPM), and light-dark box tests (LDBT). To investigate the role of Nesfatin-1, its expression was modulated using stereotactic viral injections or plasmid transfections. Transcriptome sequencing was employed to explore the downstream signaling pathways of Nesfatin-1. Additionally, brain cannula implantation was performed to facilitate targeted drug administration.ResultsOur findings demonstrated that EA reduced the hypothalamic overexpression of CRH and Nesfatin-1, as well as serum levels of ACTH and CORT. Additionally, it alleviated anxiety-like behaviors resulting from surgical trauma. We observed that overexpression of Nesfatin-1 in the hypothalamic paraventricular nucleus (PVN) triggered hyperactivity of the HPA axis and anxiety. Conversely, knocking down Nesfatin-1 in the PVN reversed these effects caused by surgical trauma. Transcriptome sequencing identified the extracellular regulated protein kinases (ERK)/cAMP-response element binding protein (CREB) pathway as a key mediator in the impacts of surgical trauma and EA on the hypothalamus. Both in vivo and in vitro studies showed that overexpression of Nesfatin-1 activated the ERK/CREB pathway. Furthermore, administering ERK or CREB inhibitors into the PVN mitigated HPA axis hyperactivity and anxiety-like behaviors induced by surgical trauma. Finally, EA was observed to decrease the phosphorylation levels of ERK and CREB in the PVN.ConclusionEA alleviates HPA axis hyperactivity and anxiety-like behaviors caused by surgical trauma through inhibition of Nesfatin-1/ERK/CREB pathway in the hypothalamus.

Dataset Information

HPA-axis genes as potential risk variants for neurocognitive decline in trauma-exposed, HIV-positive females.

Publications

HPA-axis genes as potential risk variants for neurocognitive decline in trauma-exposed, HIV-positive females.

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