Minimal traumatic brain injury causes persistent changes in DNA methylation at BDNF gene promoters in rat amygdala: A possible role in anxiety-like behaviors

Sagarkar, Sneha; Bhamburkar, Tanmayi; Shelkar, Gajanan P.; Choudhary, Amit; Kokare, Dadasaheb M.; Sakharkar, Amul J.

doi:10.1016/j.nbd.2017.06.016

Cited by 52 publications

(46 citation statements)

References 63 publications

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“…Epigenetic studies have shown that DNA methylation regulates BDNF expression levels and that higher methylation status is associated with low BDNF expression. 46 Accordingly, growing bodies of evidence suggest that BDNF hypermethylation is associated with anxiety in animal models 26,27,47 and humans. 29,30 Consistent with previous studies, the present findings demonstrated that BDNF hypermethylation was associated with anxiety in a stroke population.…”

Section: Discussionmentioning

confidence: 99%

“…25 Although few studies have investigated the associations of BDNF methylation with stroke and/or anxiety, one previous study found that increased BDNF methylation was associated with poor outcomes in stroke patients. 22 In terms of anxiety, several studies of animal models showed that anxiety-related behaviors were associated with BDNF hypermethylation [26][27][28] ; two studies that identified positive correlations between methylation and anxiety in humans were unable to establish the biological mechanisms underlying this association. 29,30 Therefore, the present longitudinal study investigated the associations of BDNF methylation and polymorphisms with anxiety at 2 weeks and 1 year after stroke using a stroke cohort.…”

Section: Introductionmentioning

confidence: 99%

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A longitudinal study of the associations of BDNF genotype and methylation with poststroke anxiety

Kang

Kim

et al. 2019

Int J Geriat Psychiatry

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Background Although the precise etiology of poststroke anxiety (PSA) has yet to be fully elucidated, it is known that brain‐derived neurotrophic factor (BDNF) is important for neural plasticity and long‐term potentiation, associated with the pathophysiology of anxiety. The expression of BDNF is regulated by epigenetic and genetic profiles. Thus, we investigated the association between BDNF methylation status and PSA at 2 weeks and 1 year after stroke while accounting for interactions with the BDNF Val66Met polymorphism. Methods The baseline sample comprised 286 patients who were assessed at 2 weeks after stroke; of these patients, 222 (78%) were followed up with at 1 year after stroke. The presence of PSA was determined using the anxiety subscale of the Hospital Anxiety and Depression Scale (HADS), and the effects of BDNF methylation status and polymorphisms on PSA status were assessed with multivariate logistic regression models. Results The prevalence of PSA was slightly lower (27 [9.4%]) at baseline, and 35 (15.8%) patients were identified as having PSA at the 1‐year follow‐up. Stroke patients with a higher average methylation status were more likely to have PSA at 1 year. The BDNF Val66Met polymorphism was not independently associated with PSA during either the acute or chronic phase after stroke, but there was a significant interactive effect between BDNF methylation and genotype on PSA at 2 weeks. Conclusions In this study, BDNF methylation in combination with the met/met BDNF polymorphism (Val66Met polymorphism) was associated with PSA. These findings may help identify patients at higher risk for PSA.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A longitudinal study of the associations of BDNF genotype and methylation with poststroke anxiety

Kang

Kim

et al. 2019

Int J Geriat Psychiatry

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“…Again, the above applied model were also calculated for rs1519480 (CC and CT vs. TT) and rs12273363 (CC and CT vs. TT). Given previous studies associating BDNF and the amygdala (Montag et al, ; Sagarkar et al, ) and its central role in emotion processing (Phelps & LeDoux, ), all calculations were restricted to the bilateral amygdala as defined by Tzourio‐Mazoyer et al () using an anatomical mask created with the Wake Forest University (WFU) Pick Atlas (Maldjian, Laurienti, Kraft, & Burdette, ). However, to cover for potential nonhypothesized effects on other brain regions, we also conducted additional explorative whole brain analyses.…”

Section: Methodsmentioning

confidence: 99%

“…The brain derived neurotrophic factor (BDNF) has been shown to play a crucial role in neural development, function and plasticity of the amygdala, mediating anxiety‐like behaviors (Sagarkar et al, ). A wide range of studies have linked BDNF expression to the etiology and pathophysiology of several psychiatric disorders associated with deficient amygdala function, including mood disorders, anxiety disorders (Gottschalk & Domschke, ; Ikegame et al, ), eating disorders, and personality disorders (Thaler et al, ).…”

Section: Introductionmentioning

confidence: 99%

“…Numerous studies have associated BDNF gene methylation with certain psychiatric disorders (anxiety disorder, major depression, bipolar disorder, borderline personality disorder, schizophrenia) (Zheleznyakova, Cao, & Schiöth, ) and personality traits like novelty seeking (Duclot & Kabbaj, ), highlighting the potential of BDNF methylation as a biomarker of psychiatric diseases. Focusing on amygdala functions, animal studies showed epigenetic modifications of BDNF to be associated with BDNF mRNA levels in the amygdala (Sagarkar et al, ). However, in humans, the associations of BDNF genotype, BDNF methylation, and amygdala reactivity have not been investigated yet.…”

Section: Introductionmentioning

confidence: 99%

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The role of BDNF methylation and Val⁶⁶Met in amygdala reactivity during emotion processing

Redlich

Schneider

Kerkenberg

et al. 2019

Human Brain Mapping

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Epigenetic alterations of the brain-derived neurotrophic factor (BDNF) gene have been associated with psychiatric disorders in humans and with differences in amygdala BDNF mRNA levels in rodents. This human study aimed to investigate the relationship between the functional BDNF-Val 66 Met polymorphism, its surrounding DNA methylation in BDNF exon IX, amygdala reactivity to emotional faces, and personality traits. Healthy controls (HC, n = 189) underwent functional MRI during an emotional face-matching task. Harm avoidance, novelty seeking and reward dependence were measured using the Tridimensional Personality Questionnaire (TPQ). Individual BDNF methylation profiles were ascertained and associated with several BDNF single nucleotide polymorphisms surrounding the BDNF-Val 66 Met, amygdala reactivity, novelty seeking and harm avoidance. Higher BDNF methylation was associated with higher amygdala reactivity (x = 34, y = 0, z = −26, t (166) = 3.00, TFCE = 42.39, p (FWE) = .045), whereby the BDNF-Val 66 Met genotype per se did not show any significant association with brain function. Furthermore, novelty seeking was negatively associated with BDNF methylation (r = −.19, p = .015) and amygdala reactivity (r = −.17, p = .028), while harm avoidance showed a trend for a positive association with BDNF † These authors contributed equally as joint first authors. ‡ These authors contributed equally as joint senior authors.

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DNA methylation: A mechanism for sustained alteration of KIR4.1 expression following central nervous system insult

Boni

Kahanovitch

Nwaobi

et al. 2020

Glia

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Kir4.1, a glial-specific inwardly rectifying potassium channel, is implicated in astrocytic maintenance of K + homeostasis. Underscoring the role of Kir4.1 in central nervous system (CNS) functioning, genetic mutations in KCNJ10, the gene which encodes Kir4.1, causes seizures, ataxia and developmental disability in humans.Kir4.1 protein and mRNA loss are consistently observed in CNS injury and neurological diseases linked to hyperexcitability and neuronal dysfunction, leading to the notion that Kir4.1 represents an attractive therapeutic target. Despite this, little is understood regarding the mechanisms that underpin this downregulation. Previous work by our lab revealed that DNA hypomethylation of the Kcnj10 gene functions to regulate mRNA levels during astrocyte maturation whereas hypermethylation in vitro led to decreased promoter activity. In the present study, we utilized two vastly different injury models with known acute and chronic loss of Kir4.1 protein and mRNA to evaluate the methylation status of Kcnj10 as a candidate molecular mechanism for reduced transcription and subsequent protein loss. Examining whole hippocampal tissue and isolated astrocytes, in a lithium-pilocarpine model of epilepsy, we consistently identified hypermethylation of CpG island two, which resides in the large intronic region spanning the Kcnj10 gene. Strikingly similar results were observed using the second injury paradigm, a fifth cervical (C5) vertebral hemi-contusion model of spinal cord injury. Our previous work indicates the same gene region is significantly hypomethylated when transcription increases during astrocyte maturation.Our results suggest that DNA methylation can bidirectionally modulate Kcnj10 transcription and may represent a targetable molecular mechanism for the restoring astroglial Kir4.1 expression following CNS insult. K E Y W O R D S astrocyte, DNA methylation, Kcnj10, Kir4.1, Pilocarpine

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Minimal traumatic brain injury causes persistent changes in DNA methylation at BDNF gene promoters in rat amygdala: A possible role in anxiety-like behaviors

Cited by 52 publications

References 63 publications

A longitudinal study of the associations of BDNF genotype and methylation with poststroke anxiety

A longitudinal study of the associations of BDNF genotype and methylation with poststroke anxiety

The role of BDNF methylation and Val⁶⁶Met in amygdala reactivity during emotion processing

DNA methylation: A mechanism for sustained alteration of KIR4.1 expression following central nervous system insult

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Minimal traumatic brain injury causes persistent changes in DNA methylation at BDNF gene promoters in rat amygdala: A possible role in anxiety-like behaviors

Cited by 52 publications

References 63 publications

A longitudinal study of the associations of BDNF genotype and methylation with poststroke anxiety

A longitudinal study of the associations of BDNF genotype and methylation with poststroke anxiety

The role of BDNF methylation and Val66Met in amygdala reactivity during emotion processing

DNA methylation: A mechanism for sustained alteration of KIR4.1 expression following central nervous system insult

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The role of BDNF methylation and Val⁶⁶Met in amygdala reactivity during emotion processing