Functional effects of polymorphisms on glucocorticoid receptor modulation of human anxiogenic substance-P gene promoter activity in primary amygdala neurones

Hay, Colin W.; Shanley, Lynne; Davidson, Scott; Cowie, Philip; Lear, Marissa; McGuffin, Peter; Riedel, Gernot; McEwan, Iain J.; MacKenzie, Alasdair

doi:10.1016/j.psyneuen.2014.04.017

Cited by 14 publications

(12 citation statements)

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“…Apart from motor skill acquisition, other behavioral or situational factors could have influenced Tac1 expression within M1. It is known that Sub P plays a specific role in the behavioral response to stress, such as stress-related addiction or anxiety [ 59 , 60 ]. Activation of the glucocorticoid receptor—a classic component of the stress response—induces an up-regulation of Tac1 in primary amygdala neurons [ 59 ].…”

Section: Discussionmentioning

confidence: 99%

“…It is known that Sub P plays a specific role in the behavioral response to stress, such as stress-related addiction or anxiety [ 59 , 60 ]. Activation of the glucocorticoid receptor—a classic component of the stress response—induces an up-regulation of Tac1 in primary amygdala neurons [ 59 ]. Stressful stimuli increase levels of SP and Tac1 mRNA within the amygdala [ 61 ] of restrained rats and alters NK1-receptor trafficking in gerbils [ 62 ].…”

Section: Discussionmentioning

confidence: 99%

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Substance P signalling in primary motor cortex facilitates motor learning in rats

et al. 2017

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Among the genes that are up-regulated in response to a reaching training in rats, Tachykinin 1 (Tac1)—a gene that encodes the neuropeptide Substance P (Sub P)—shows an especially strong expression. Using Real-Time RT-PCR, a detailed time-course of Tac1 expression could be defined: a significant peak occurs 7 hours after training ended at the first and second training session, whereas no up-regulation could be detected at a later time-point (sixth training session). To assess the physiological role of Sub P during movement acquisition, microinjections into the primary motor cortex (M1) contralateral to the trained paw were performed. When Sub P was injected before the first three sessions of a reaching training, effectiveness of motor learning became significantly increased. Injections at a time-point when rats already knew the task (i.e. training session ten and eleven) had no effect on reaching performance. Sub P injections did not influence the improvement of performance within a single training session, but retention of performance between sessions became strengthened at a very early stage (i.e. between baseline-training and first training session). Thus, Sub P facilitates motor learning in the very early phase of skill acquisition by supporting memory consolidation. In line with these findings, learning related expression of the precursor Tac1 occurs at early but not at later time-points during reaching training.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Substance P signalling in primary motor cortex facilitates motor learning in rats

et al. 2017

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“…This was then replaced with supplemented Neurobasal A (Invitrogen) followed by mechanical dissociation. The cells were then resuspended in culture media, including Neurobasal A, B27, 1×GlutaMAX and 100 U/ml Pen/Strep (from Invitrogen), and then, the cells were incubated at 37 °C, 5% CO 2 [ 28 ]. The isolated amygdala neurons were used for the analysis of DNA methylation, epigenetic changes by chromatin immunosuppression (ChIP) assay on the ERβ promoter, and in vitro fatty acid lipid uptake.…”

Section: Methodsmentioning

confidence: 99%

Prenatal levonorgestrel exposure induces autism-like behavior in offspring through ERβ suppression in the amygdala

et al. 2017

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BackgroundAutism spectrum disorder (ASD) is characterized by impairments in social communication and restricted or repetitive behaviors or interests. ASD is now diagnosed in more than one out of 100 children and is biased towards males by a ratio of at least 4:1. Many possible explanations and potential causative factors have been reported, such as genetics, sex, and environmental factors, although the detailed mechanisms of ASD remain unclear.MethodsThe dams were exposed through oral contraceptives to either vehicle control (VEH) alone, levonorgestrel (LNG) alone, ethinyl estradiol (EE) alone, or a combination of LNG/EE for 21 days during their pregnancy. The subsequent 10-week-old offspring were used for autism-like behavior testing, and the limbic tissues were isolated for analysis. In another experimental group, 8-week-old male offspring were treated by infusion of ERβ overexpression/knockdown lentivirus in the amygdala, and the offspring were analyzed after 2 weeks.ResultsWe show that prenatal exposure of either LNG alone or a LNG/EE combination, but not EE alone, results in suppression of ERβ (estrogen receptor β) and its target genes in the amygdala with autism-like behavior in male offspring, while there is a much smaller effect on female offspring. However, we find that there is no effect on the hippocampus and hypothalamus. Further investigation shows that ERβ suppression is due to LNG-mediated altered methylation on the ERβ promoter and results in tissue damage with oxidative stress and the dysfunction of mitochondria and fatty acid metabolism, which subsequently triggers autism-like behavior. Overexpression of ERβ in the amygdala completely restores LNG-induced ERβ suppression and autism-like behaviors in offspring, while ERβ knockdown mimics this effect, indicating that ERβ expression in the amygdala plays an important role in autism-like behavior development.ConclusionsWe conclude that prenatal levonorgestrel exposure induces autism-like behavior in offspring through ERβ suppression in the amygdala. To our knowledge, this is the first time the potential effect of oral contraceptives on the contribution of autism-like behavior in offspring has been discovered.Electronic supplementary materialThe online version of this article (doi:10.1186/s13229-017-0159-3) contains supplementary material, which is available to authorized users.

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“…The amygdala neurons were isolated for in vitro primary cell culture analysis [ 9 , 35 ]. The DNA methylation on the rat ERβ promoter was evaluated by a real-time PCR-based methylation-specific PCR (MSP) analysis as described previously with some modifications [ 9 , 36 – 38 ].…”

Section: Methodsmentioning

confidence: 99%

Resveratrol ameliorates prenatal progestin exposure-induced autism-like behavior through ERβ activation

Xie

et al. 2018

Molecular Autism

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BackgroundRecent literatures indicate that maternal hormone exposure is a risk factor for autism spectrum disorder (ASD). We hypothesize that prenatal progestin exposure may counteract the neuroprotective effect of estrogen and contribute to ASD development, and we aim to develop a method to ameliorate prenatal progestin exposure-induced autism-like behavior.MethodsExperiment 1: Prenatal progestin exposure-induced offspring are treated with resveratrol (RSV) through either prenatal or postnatal exposure and then used for autism-like behavior testing and other biomedical analyses. Experiment 2: Prenatal norethindrone (NET) exposure-induced offspring are treated with ERβ knockdown lentivirus together with RSV for further testing. Experiment 3: Pregnant dams are treated with prenatal NET exposure together with RSV, and the offspring are used for further testing.ResultsEight kinds of clinically relevant progestins were used for prenatal exposure in pregnant dams, and the offspring showed decreased ERβ expression in the amygdala with autism-like behavior. Oral administration of either postnatal or prenatal RSV treatment significantly reversed this effect with ERβ activation and ameliorated autism-like behavior. Further investigation showed that RSV activates ERβ and its target genes by demethylation of DNA and histone on the ERβ promoter, and then minimizes progestin-induced oxidative stress as well as the dysfunction of mitochondria and lipid metabolism in the brain, subsequently ameliorating autism-like behavior.ConclusionsWe conclude that resveratrol ameliorates prenatal progestin exposure-induced autism-like behavior through ERβ activation. Our data suggest that prenatal progestin exposure is a strong risk factor for autism-like behavior. Many potential clinical progestin applications, including oral contraceptive pills, preterm birth drugs, and progestin-contaminated drinking water or seafood, may be risk factors for ASD. In addition, RSV may be a good candidate for clinically rescuing or preventing ASD symptoms in humans, while high doses of resveratrol used in the animals may be a potential limitation for human application.Electronic supplementary materialThe online version of this article (10.1186/s13229-018-0225-5) contains supplementary material, which is available to authorized users.

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Functional effects of polymorphisms on glucocorticoid receptor modulation of human anxiogenic substance-P gene promoter activity in primary amygdala neurones

Cited by 14 publications

References 40 publications

Substance P signalling in primary motor cortex facilitates motor learning in rats

Substance P signalling in primary motor cortex facilitates motor learning in rats

Prenatal levonorgestrel exposure induces autism-like behavior in offspring through ERβ suppression in the amygdala

Resveratrol ameliorates prenatal progestin exposure-induced autism-like behavior through ERβ activation

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