The ERK phosphorylation levels in the amygdala predict anxiety symptoms in humans and MEK/ERK inhibition dissociates innate and learned defensive behaviors in rats

Carvalho, Cristiane Ribeiro de; Lopes, Mark William; Constantino, Leandra C.; Hoeller, Alexandre Ademar; Melo, Hiago Murilo; Guarnieri, Ricardo; Linhares, Marcelo Neves; Bortolotto, Zuner A.; Prediger, Rui Daniel; Latini, Alexandra; Lin, Kátia; Licinio, Júlio; Leal, Rodrigo Bainy; Walz, Roger

doi:10.1038/s41380-021-01203-0

Cited by 17 publications

(13 citation statements)

References 49 publications

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“…To test the effect of MS on anxiety-like behaviors at different developmental stages, we conducted series behavioral experiments including open field test (OFT), EPMT, and novelty suppressed feeding test (NSFT) ( Calhoon and Tye, 2015 ; de Carvalho et al, 2021 ; Qin et al, 2021 ). SPT and Forced Swimming Test (FST) were performed to observe depressive-like behavior, which related to two core symptom domains in depression ( Berton et al, 2012 ; Ramaker and Dulawa, 2017 ; Figure 1A ).…”

Section: Resultsmentioning

confidence: 99%

Early Life Stress Induces Different Behaviors in Adolescence and Adulthood May Related With Abnormal Medial Prefrontal Cortex Excitation/Inhibition Balance

et al. 2022

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Early life stress is thought to be a risk factor for emotional disorders, particularly depression and anxiety. Although the excitation/inhibition (E/I) imbalance has been implicated in neuropsychiatric disorders, whether early life stress affects the E/I balance in the medial prefrontal cortex at various developmental stages is unclear. In this study, rats exposed to maternal separation (MS) that exhibited a well-established early life stress paradigm were used to evaluate the E/I balance in adolescence (postnatal day P43–60) and adulthood (P82–100) by behavior tests, whole-cell recordings, and microdialysis coupled with high performance liquid chromatography-mass spectrometry (HPLC-MS) analysis. First, the behavioral tests revealed that MS induced both anxiety- and depressive-like behaviors in adolescent rats but only depressive-like behavior in adult rats. Second, MS increased the action potential frequency and E/I balance of synaptic transmission onto L5 pyramidal neurons in the prelimbic (PrL) brain region of adolescent rats while decreasing the action potential frequency and E/I balance in adult rats. Finally, MS increases extracellular glutamate levels and decreased the paired-pulse ratio of evoked excitatory postsynaptic currents (EPSCs) of pyramidal neurons in the PrL of adolescent rats. In contrast, MS decreased extracellular glutamate levels and increased the paired-pulse ratio of evoked EPSCs of pyramidal neurons in the PrL of adult rats. The present results reveal a key role of E/I balance in different MS-induced disorders may related to the altered probability of presynaptic glutamate release at different developmental stages.

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Section: Resultsmentioning

confidence: 99%

Early Life Stress Induces Different Behaviors in Adolescence and Adulthood May Related With Abnormal Medial Prefrontal Cortex Excitation/Inhibition Balance

et al. 2022

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“…Abnormal phosphorylation was associated with repetitive behaviors (RBs) which are the signature of OCD, for example, the elevated phosphorylation of rpS6 (neural activity marker) promoted RB in mice [ 48 ] and abnormal phosphorylation of RAP1 can be found in patients with OCD [ 49 ]. It can affect anxiety-like behavior as well that the study reported the phosphorylation levels of ERK (extracellular signal-regulated kinase) in the amygdala were associated with anxiety symptoms in human beings [ 50 ]. Studies suggested the influences of acetylation and sumoylation in anxiety-like behaviors, for example, increased acetylation of Arc SARE attenuated anxiety-like behavior in adult rats, besides, sumoylation of Rac1 [ 51 ] and serotonin 1a receptor [ 52 ] regulated anxiety-like behavior.…”

Section: Discussionmentioning

confidence: 99%

Epigenome-wide DNA methylation analysis of whole blood cells derived from patients with GAD and OCD in the Chinese Han population

Guo

Wei³

et al. 2022

Transl Psychiatry

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Generalized anxiety disorder (GAD) and obsessive-compulsive disorder (OCD) had high comorbidity and affected more than 44 million people around the world leading to a huge burden on health and economy. Here, we conducted an epigenome-wide DNA methylation study employing 93 patients with GAD, 65 patients with OCD, and 302 health controls, to explore epigenetic alterations associated with the onset and differences of GAD and OCD. We identified multiple differentially methylated positions (DMPs) and regions (DMRs): three DMP genes included RIOK3 (cg21515243, p = 8.00 × 10−10), DNASE2 (cg09379601, p = 1.10 × 10−9), and PSMB4 (cg01334186, p = 3.70 × 10−7) and two DMR genes USP6NL (p = 4.50 × 10−4) and CPLX1 (p = 6.95 × 10−4) were associated with the onset of GAD and OCD; three DMPs genes included LDLRAP1 (cg21400344, p = 4.40 × 10−12), ACIN1 (cg23712970, p = 2.98×10−11), and SCRT1 (cg25472897, p = 5.60 × 10−11) and three DMR genes WDR19 (p = 3.39 × 10−3), SYCP1 (p = 6.41 × 10−3), and FAM172A (p = 5.74 × 10−3) were associated with the differences between GAD and OCD. Investigation of epigenetic age and chronological age revealed a different epigenetic development trajectory of GAD and OCD. Conclusively, our findings which yielded robust models may aid in distinguishing patients from healthy controls (AUC = 0.90–0.99) or classifying patients with GAD and OCD (AUC = 0.89–0.99), and may power the precision medicine for them.

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“…As a hypothesis-driven fMRI study, the bilateral amygdala and hippocampus, which are known to be associated with cognition and emotion in well-replicated studies ( Montagne et al, 2019 ; de Carvalho et al, 2021 ; Dogra et al, 2021 ; Duan et al, 2021 ; Mateus-Pinheiro et al, 2021 ; Nguyen et al, 2021 ), were selected as seed regions for subsequent rsFC analyses. Our results indicated that migraineurs showed decreased rsFC mainly in the occipital lobe, such as the bilateral calcarine/cuneus and lingual gyrus, using the left amygdala and left hippocampus as seeds.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have shown that migraineurs exhibited alterations in the rsFC of amygdala and hippocampus ( Hadjikhani et al, 2013 ; Zhu et al, 2021 ), and the two brain regions were associated with cognition and emotion ( Montagne et al, 2019 ; de Carvalho et al, 2021 ; Dogra et al, 2021 ; Duan et al, 2021 ; Mateus-Pinheiro et al, 2021 ; Nguyen et al, 2021 ). Considering the differences in neuropsychological performance between migraine and TTH ( Waldie et al, 2002 ; Gil-Gouveia et al, 2015 , 2016 ; Huang et al, 2017 ; Puledda et al, 2017 ; Karsan and Goadsby, 2018 ; Vuralli et al, 2018 ), we chose the bilateral amygdala and hippocampus as seed regions for rsFC analyses, to explore the potential rsFC features that may distinguish the two types of headache.…”

Section: Methodsmentioning

confidence: 99%

“…The interaction between neuropsychological performance and neuroimaging features may be one of the potential characteristics to distinguish patients with migraine from patients with TTH. The amygdala and hippocampus are the key brain regions related to cognition and emotion ( Montagne et al, 2019 ; de Carvalho et al, 2021 ; Dogra et al, 2021 ; Duan et al, 2021 ; Mateus-Pinheiro et al, 2021 ; Nguyen et al, 2021 ). The alterations in rsFC of the two brain regions have been reported in migraineurs when compared to healthy controls (HCs) ( Hadjikhani et al, 2013 ; Zhu et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

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Functional Connectivity Features of Resting-State Functional Magnetic Resonance Imaging May Distinguish Migraine From Tension-Type Headache

Wang

et al. 2022

Front. Neurosci.

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BackgroundMigraineurs often exhibited abnormalities in cognition, emotion, and resting-state functional connectivity (rsFC), whereas patients with tension-type headache (TTH) rarely exhibited these abnormalities. The aim of this study is to explore whether rsFC alterations in brain regions related to cognition and emotion could be used to distinguish patients with migraine from patients with TTH.MethodsIn this study, Montreal Cognitive Assessment (MoCA), Self-Rating Anxiety Scale (SAS), Self-Rating Depression Scale (SDS), and rsFC analyses were used to assess the cognition, anxiety, and depression of 24 healthy controls (HCs), 24 migraineurs, and 24 patients with TTH. Due to their important roles in neuropsychological functions, the bilateral amygdala and hippocampus were chosen as seed regions for rsFC analyses. We further assessed the accuracy of the potential rsFC alterations for distinguishing migraineurs from non-migraineurs (including HCs and patients with TTH) by the receiver operating characteristic (ROC) analysis. Associations between headache characteristics and rsFC features were calculated using a multi-linear regression model. This clinical trial protocol has been registered in the Chinese Clinical Trial Registry (registry number: ChiCTR1900024307, Registered: 5 July 2019-Retrospectively registered, http://www.chictr.org.cn/showproj.aspx?proj=40817).ResultsMigraineurs showed lower MoCA scores (p = 0.010) and higher SAS scores (p = 0.017) than HCs. Migraineurs also showed decreased rsFC in the bilateral calcarine/cuneus, lingual gyrus (seed: left amygdala), and bilateral calcarine/cuneus (seed: left hippocampus) in comparison to HCs and patients with TTH. These rsFC features demonstrated significant distinguishing capabilities and got a sensitivity of 82.6% and specificity of 81.8% with an area under the curve (AUC) of 0.868. rsFC alterations showed a significant correlation with headache frequency in migraineurs (p = 0.001, Pc = 0.020).ConclusionThe rsFC of amygdala and hippocampus with occipital lobe can be used to distinguish patients with migraine from patients with TTH.Clinical Trial Registration[http://www.chictr.org.cn/showproj.aspx?proj=40817], identifier [ChiCTR1900024307].

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The ERK phosphorylation levels in the amygdala predict anxiety symptoms in humans and MEK/ERK inhibition dissociates innate and learned defensive behaviors in rats

Abstract: Please refer to any applicable terms of use of the publisher.

Cited by 17 publications

References 49 publications

Early Life Stress Induces Different Behaviors in Adolescence and Adulthood May Related With Abnormal Medial Prefrontal Cortex Excitation/Inhibition Balance

Early Life Stress Induces Different Behaviors in Adolescence and Adulthood May Related With Abnormal Medial Prefrontal Cortex Excitation/Inhibition Balance

Epigenome-wide DNA methylation analysis of whole blood cells derived from patients with GAD and OCD in the Chinese Han population

Functional Connectivity Features of Resting-State Functional Magnetic Resonance Imaging May Distinguish Migraine From Tension-Type Headache

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