Molecular and Epigenetic Mechanisms for the Complex Effects of Stress on Synaptic Physiology and Cognitive Functions

Yuen, Eunice Y.; Wei, Jing; Zhang, Yan

doi:10.1093/ijnp/pyx052

Cited by 21 publications

(16 citation statements)

References 106 publications

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“…Reciprocal connections between mPFC and DR have been implicated in determining responses to stressors and emotional behaviors (Geddes et al., ; Volle et al., ). Layer 5 pyramidal neurons in PFC are particularly vulnerable to glucocorticoid‐induced hypofunction or cell death (Duman et al., ; Yuen, Wei, & Yan, ); therefore, our sEPSC findings could result from an anatomical bias toward fine reciprocity between DR and mPFC, resulting in greater reductions of glutamatergic input to DR‐mPFC neurons than DR‐LGN neurons after chronic CORT exposure. While systematic investigations of specific input‐output relationships in the serotonergic nuclei have not yet been conducted, advances in viral tracing and genetic markers useable for serotonergic intersectional genetics (Okaty et al., ), suggest that such studies will likely be forthcoming (Ogawa & Watabe‐Uchida, ).…”

Section: Discussionmentioning

confidence: 89%

Selective vulnerability of dorsal raphe‐medial prefrontal cortex projection neurons to corticosterone‐induced hypofunction

Prouty

Chandler

Gao

et al. 2019

Eur J of Neuroscience

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Glucocorticoid hormones and serotonin (5‐HT) are strongly associated with the development and treatment of depression, respectively. Glucocorticoids regulate the function of serotonergic neurons in the dorsal raphe nucleus (DR), which are the major source of 5‐HT to the forebrain. DR 5‐HT neurons are electrophysiologically heterogeneous, though whether this phenotypic variation aligns with specific brain functions or neuropsychiatric disease states is largely unknown. The goal of this work was to determine if chronic exogenous glucocorticoid administration differentially affects the electrophysiological profile of DR neurons implicated in the regulation of emotion versus visual sensation by comparing properties of cells projecting to medial prefrontal cortex (mPFC) versus lateral geniculate nucleus (LGN). Following retrograde tracer injection into mPFC or LGN, male Sprague‐Dawley rats received daily injections of corticosterone (CORT) for 21 days, after which whole‐cell patch clamp recordings were made from retrogradely labeled DR neurons. CORT‐treatment significantly increased the action potential half‐width of LGN‐projecting DR neurons, but did not significantly affect the firing frequency or excitatory postsynaptic currents of these cells. CORT‐treatment significantly reduced the input resistance, evoked firing frequency, and spontaneous excitatory postsynaptic current frequency of mPFC‐projecting DR neurons, indicating a concurrent reduction of both intrinsic excitability and excitatory drive. Our results suggest that the serotonergic regulation of cognitive and emotional networks in the mPFC may be more sensitive to the effects of glucocorticoid excess than visual sensory circuits in the LGN and that reduced 5‐HT transmission in the mPFC may underlie the association between glucocorticoid excess and depression.

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Section: Discussionmentioning

confidence: 89%

Selective vulnerability of dorsal raphe‐medial prefrontal cortex projection neurons to corticosterone‐induced hypofunction

Prouty

Chandler

Gao

et al. 2019

Eur J of Neuroscience

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“…The neurobiology of chronic stress is key to the understanding of a myriad of human mood disorders 26 . Social defeat is a source of chronic stress affecting normal brain physiology and behaviour.…”

Section: Csds Induces Depression Accompanied With An Increase In Nrg1mentioning

confidence: 99%

Nedd4l downregulation of NRG1 in the mPFC induces depression-like behaviour in CSDS mice

Guo

Liu

et al. 2020

Transl Psychiatry

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The occurrence of major depressive disorders has been closely related to the vulnerability of stress. The medial prefrontal cortex (mPFC) is involved in regulating pathological reactivity to stress, changes in affective behaviour and cognitive functions by distress. Increasing evidence indicates that neuregulin 1 (NRG1) plays an important role in psychiatric illnesses, including depression, schizophrenia and bipolar disorder. However, whether NRG1 in the mPFC is related to stress vulnerability remains unclear. We here assessed the regulation of NRG1 by the E3 ubiquitin ligase Nedd4l (neural precursor cell expressed developmentally downregulated 4-like) and investigated whether NRG1 changes in the mPFC might lead to vulnerability to depression-like behaviours. We've identified a deficiency of NRG1 in the mPFC as a key factor that contributes to the regulation of stress susceptibility in mice, as further suggested by the finding that overexpression of NRG1 attenuated depression-like behaviours in the animal model of chronic social defeat stress (CSDS). Interestingly, RNA sequencing in the mPFC brain region showed no differences in NRG1 mRNA levels between control animals and stress-susceptible (SS) or resilient mice (RES) following CSDS. However, mRNA and protein levels of Nedd4l were markedly increased in SS mice, but not in RES mice compared to controls. Furthermore, ubiquitination of NRG1 was increased in SS mice. Remarkably, overexpression of Nedd4l in mouse mPFC induced a decrease in NRG1 level and caused vulnerability to stress by subthreshold social defeat stress (SSDS), while downregulation of Nedd4l expression in the mPFC rescued the vulnerability to stress-induced social avoidance and anhedonia. Our data strongly indicate that the Nedd4l-mediated downregulation of NRG1 acts as a critical role in depression-like phenotypes of mice in CSDS.

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“…The higher the degree of methylation is, the more "silent" the gene is, and vice versa; in other words, the level of gene transcription is inversely related to its methylation level. Abnormal DNA methylation patterns can cause a variety of human diseases, including hereditary diseases, tumors, autoimmune diseases, and neuropsychiatric diseases [10,11]. In the research of congenital diseases, abnormal DNA methylation patterns can cause imprinting dysfunction, which will affect the growth and development of the fetus, leading to the occurrence of genetic diseases, such as Beckwith-Weidemann syndrome (BWS) and Prader-Willi/Angelman syndrome [12][13][14].…”

Section: Introductionmentioning

confidence: 99%

High methylation of lysine acetyltransferase 6B is associated with the Cobb angle in patients with congenital scoliosis

Zhang

Tang

et al. 2020

J Transl Med

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Background: The etiology of congenital scoliosis (CS) is complex and uncertain. Abnormal DNA methylation affects the growth and development of spinal development. In this study, we investigated the role of DNA methylation in CS. Methods: The target region DNA methylation level in the peripheral blood of patients with CS was analyzed. Through in-depth analysis, genes closely related to the growth and development of the vertebra were identified. EdU staining was performed to verify the role of differentially expressed genes in chondrocyte proliferation. Results: The hypermethylated KAT6B gene was observed in patients with CS, and was positively correlated with the Cobb angle. KAT6B was primarily expressed on chondrocytes. The promoter of KAT6B in CS patients was hypermethylated, and its expression was significantly reduced. Further mechanistic studies revealed that EZH2 mediated trimethylation of lysine 27 on histone H3 of the KAT6B promoter. Overexpression of KAT6B in CS-derived primary chondrocytes can significantly promote chondrocyte proliferation, which may be related to activation of the RUNX2/Wnt/β-catenin signaling pathway. Conclusion: Epigenetic modification of KAT6B may be a cause of CS. If similar epigenetic modification abnormalities can be detected through maternal liquid biopsy screening, they may provide useful biomarkers for early screening and diagnosis of CS.

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Molecular and Epigenetic Mechanisms for the Complex Effects of Stress on Synaptic Physiology and Cognitive Functions

Cited by 21 publications

References 106 publications

Selective vulnerability of dorsal raphe‐medial prefrontal cortex projection neurons to corticosterone‐induced hypofunction

Selective vulnerability of dorsal raphe‐medial prefrontal cortex projection neurons to corticosterone‐induced hypofunction

Nedd4l downregulation of NRG1 in the mPFC induces depression-like behaviour in CSDS mice

High methylation of lysine acetyltransferase 6B is associated with the Cobb angle in patients with congenital scoliosis

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