Epigenetic regulation of transcriptional plasticity associated with developmental song learning

Ethologists discovered over 100 years ago that some lifelong behavioural patterns were acquired exclusively during restricted developmental phases called critical periods (CPs). Developmental song learning in zebra finches is one of the most striking examples of a CP for complex learned behaviour. After post-hatch day 65, whether or not a juvenile male can memorize the song of a ‘tutor' depends on his experiences in the month prior. If he experienced a tutor, he can no longer learn, but if he has been isolated from hearing a tutor the learning period is extended. We aimed to identify how tutor experience alters the brain and controls the ability to learn. Epigenetic landscapes are modulated by experience and are able to regulate the transcription of sets of genes, thereby affecting cellular function. Thus, we hypothesized that tutor experiences determine the epigenetic landscape in the auditory forebrain, a region required for tutor song memorization. Using ChIPseq, RNAseq and molecular biology, we provide evidence that naturalistic experiences associated with the ability to learn can induce epigenetic changes, and propose transcriptional plasticity as a mediator of CP learning potential.

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Exercise Ameliorates Spinal Cord Injury by Changing DNA Methylation

Cells ◽

10.3390/cells10010143 ◽

2021 ◽

Vol 10 (1) ◽

pp. 143

Author(s):

Ganchimeg Davaa ◽

Jin Young Hong ◽

Tae Uk Kim ◽

Seong Jae Lee ◽

Seo Young Kim ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Motor Cortex ◽

Functional Recovery ◽

Treadmill Exercise ◽

Exercise Group ◽

Control Group ◽

Epigenetic Changes ◽

Cord Injury ◽

The Brain

Exercise training is a traditional method to maximize remaining function in patients with spinal cord injury (SCI), but the exact mechanism by which exercise promotes recovery after SCI has not been identified; whether exercise truly has a beneficial effect on SCI also remains unclear. Previously, we showed that epigenetic changes in the brain motor cortex occur after SCI and that a treatment leading to epigenetic modulation effectively promotes functional recovery after SCI. We aimed to determine how exercise induces functional improvement in rats subjected to SCI and whether epigenetic changes are engaged in the effects of exercise. A spinal cord contusion model was established in rats, which were then subjected to treadmill exercise for 12 weeks. We found that the size of the lesion cavity and the number of macrophages were decreased more in the exercise group than in the control group after 12 weeks of injury. Immunofluorescence and DNA dot blot analysis revealed that levels of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) in the brain motor cortex were increased after exercise. Accordingly, the expression of ten-eleven translocation (Tet) family members (Tet1, Tet2, and Tet3) in the brain motor cortex also elevated. However, no macrophage polarization was induced by exercise. Locomotor function, including Basso, Beattie, and Bresnahan (BBB) and ladder scores, also improved in the exercise group compared to the control group. We concluded that treadmill exercise facilitates functional recovery in rats with SCI, and mechanistically epigenetic changes in the brain motor cortex may contribute to exercise-induced improvements.

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Programming of the reproductive axis by hormonal and genetic manipulation in mice

Reproduction ◽

10.1530/rep-18-0054 ◽

2018 ◽

Cited By ~ 2

Author(s):

Susana B Rulli ◽

María Julia Cambiasso ◽

Laura D Ratner

Keyword(s):

Sex Chromosome ◽

Genetic Manipulation ◽

Sex Differentiation ◽

Reproductive Function ◽

Gonadal Steroids ◽

Critical Periods ◽

Female Reproduction ◽

Control Male ◽

Male And Female ◽

The Brain

In mammals, the reproductive function is controlled by the hypothalamic-pituitary-gonadal axis. During development, mechanisms mediated by gonadal steroids exert an imprinting at the hypothalamic-pituitary level, by establishing sexual differences in the circuits that control male and female reproduction. In rodents, the testicular production of androgens increases drastically during the fetal/neonatal stage. This process is essential for the masculinization of the reproductive tract, genitals and brain. The conversion of androgens to estrogens in the brain is crucial for the male sexual differentiation and behavior. Conversely, feminization of the brain occurs in the absence of high levels of gonadal steroids during the perinatal period in females. Potential genetic contribution to the differentiation of brain cells through direct effects of genes located on sex chromosomes is also relevant. In this review, we will focus on the phenotypic alterations that occur on the hypothalamic-pituitary-gonadal axis of transgenic mice with persistently elevated expression of the human chorionic gonadotropin hormone (hCG). Excess of endogenously synthesized gonadal steroids due to a constant hCG stimulation is able to disrupt the developmental programming of the hypothalamic-pituitary axis in both transgenic males and females. Locally produced estrogens by the hypothalamic aromatase might play a key role in the phenotype of these mice. The “four core genotypes” mouse model demonstrated a potential influence of sex chromosome genes in brain masculinization before critical periods of sex differentiation. Thus, hormonal and genetic factors interact to regulate the local production of the neurosteroids necessary for the programming of the male and female reproductive function.

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The ex-illiterate brain: The critical period, cognitive reserve and HAROLD model

Dementia & Neuropsychologia ◽

10.1590/s1980-57642009dn30300008 ◽

2009 ◽

Vol 3 (3) ◽

pp. 222-227 ◽

Cited By ~ 4

Author(s):

Maria Vania Silva Nunes ◽

Alexandre Castro-Caldas ◽

Dolores Del Rio ◽

Fernado Maestú ◽

Tomás Ortiz

Keyword(s):

Recognition Test ◽

Cognitive Skills ◽

Critical Period ◽

Cognitive Reserve ◽

Brain Activity ◽

High Educational Level ◽

Critical Periods ◽

Language Recognition ◽

Regular Time ◽

The Brain

Abstract The lifelong acquisition of cognitive skills shapes the biology of the brain. However, there are critical periods for the best use of the brain to process the acquired information. Objectives: To discuss the critical period of cognitive acquisition, the concept of cognitive reserve and the HAROLD (Hemispheric Asymmetry Reduction in Older adults) model. Methods: Seven women who learned how to read and to write after the age of 50 (ex-illiterates) and five women with 10 years of regular schooling (controls) were submitted to a language recognition test while brain activity was being recorded using magnetoencephalography. Spoken words were delivered binaurally via two plastic tubs terminating in ear inserts, and recordings were made with a whole head magnetometer consisting of 148 magnetometer coils. Results: Both groups performed similarly on the task of identifying target words. Analysis of the number of sources of activity in the left and right hemispheres revealed significant differences between the two groups, showing that ex-illiterate subjects exhibited less brain functional asymmetry during the language task. Conclusions: These results should be interpreted with caution because the groups were small. However, these findings reinforce the concept that poorly educated subjects tend to use the brain for information processing in a different way to subjects with a high educational level or who were schooled at the regular time. Finally, the recruiting of both hemispheres to tackle the language recognition test occurred to a greater degree in the ex-illiterate group where this can be interpreted as a sign of difficulty performing the task.

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Epigenetic Changes in the Brain: Measuring Global Histone Modifications

Methods in Molecular Biology - Alzheimer's Disease and Frontotemporal Dementia ◽

10.1007/978-1-60761-744-0_18 ◽

2010 ◽

pp. 263-274 ◽

Cited By ~ 20

Author(s):

Gavin Rumbaugh ◽

Courtney A. Miller

Keyword(s):

Histone Modifications ◽

Epigenetic Changes ◽

The Brain

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Acute social isolation alters neurogenomic state in songbird forebrain

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1820841116 ◽

2019 ◽

Vol 117 (38) ◽

pp. 23311-23316 ◽

Cited By ~ 2

Author(s):

Julia M. George ◽

Zachary W. Bell ◽

Daniel Condliffe ◽

Kirstin Dohrer ◽

Teresa Abaurrea ◽

...

Keyword(s):

Gene Expression ◽

Social Isolation ◽

Axonal Guidance ◽

Sequencing Analysis ◽

Negative Effects ◽

Auditory Forebrain ◽

Gene Sets ◽

Brain And Behavior ◽

And Behavior ◽

The Brain

Prolonged social isolation has negative effects on brain and behavior in humans and other social organisms, but neural mechanisms leading to these effects are not understood. Here we tested the hypothesis that even brief periods of social isolation can alter gene expression and DNA methylation in higher cognitive centers of the brain, focusing on the auditory/associative forebrain of the highly social zebra finch. Using RNA sequencing, we first identified genes that individually increase or decrease expression after isolation and observed general repression of gene sets annotated for neurotrophin pathways and axonal guidance functions. We then pursued 4 genes of large effect size: EGR1 and BDNF (decreased by isolation) and FKBP5 and UTS2B (increased). By in situ hybridization, each gene responded in different cell subsets, arguing against a single cellular mechanism. To test whether effects were specific to the social component of the isolation experience, we compared gene expression in birds isolated either alone or with a single familiar partner. Partner inclusion ameliorated the effect of solo isolation on EGR1 and BDNF, but not on FKBP5 and UTS2B nor on circulating corticosterone. By bisulfite sequencing analysis of auditory forebrain DNA, isolation caused changes in methylation of a subset of differentially expressed genes, including BDNF. Thus, social isolation has rapid consequences on gene activity in a higher integrative center of the brain, triggering epigenetic mechanisms that may influence processing of ongoing experience.

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Timing of perineuronal net development in the zebra finch song control system correlates with developmental song learning

Proceedings of The Royal Society B Biological Sciences ◽

10.1098/rspb.2018.0849 ◽

2018 ◽

Vol 285 (1883) ◽

pp. 20180849 ◽

Cited By ~ 9

Author(s):

Gilles Cornez ◽

Elisabeth Jonckers ◽

Sita M. ter Haar ◽

Annemie Van der Linden ◽

Charlotte A. Cornil ◽

...

Keyword(s):

Control System ◽

Neural Plasticity ◽

Ocular Dominance ◽

Song Learning ◽

Dominance Model ◽

Perineuronal Net ◽

Acoustic Environment ◽

Auditory Forebrain ◽

Song Control System ◽

Song Control

The appearance of perineuronal nets (PNNs) represents one of the mechanisms that contribute to the closing of sensitive periods for neural plasticity. This relationship has mostly been studied in the ocular dominance model in rodents. Previous studies also indicated that PNN might control neural plasticity in the song control system of songbirds. To further elucidate this relationship, we quantified PNN expression and their localization around parvalbumin interneurons at key time-points during ontogeny in both male and female zebra finches, and correlated these data with the well-described development of song in this species. We also extended these analyses to the auditory system. The development of PNN during ontogeny correlated with song crystallization although the timing of PNN appearance in the four main telencephalic song control nuclei slightly varied between nuclei in agreement with the established role these nuclei play during song learning. Our data also indicate that very few PNN develop in the secondary auditory forebrain areas even in adult birds, which may allow constant adaptation to a changing acoustic environment by allowing synaptic reorganization during adulthood.

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Identification of a Novel BRCA1 Alteration in Recurrent Melanocytoma Resulting in Increased Proliferation

Journal of Neuropathology & Experimental Neurology ◽

10.1093/jnen/nlaa089 ◽

2020 ◽

Vol 79 (11) ◽

pp. 1233-1238

Author(s):

Teresa San-Miguel ◽

Lara Navarro ◽

Beatriz Sánchez-Sendra ◽

Javier Megías ◽

Lisandra Muñoz-Hidalgo ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Prognostic Value ◽

Proliferation Index ◽

Benign Neoplasms ◽

Epigenetic Changes ◽

Epigenetic Landscape ◽

Meningeal Melanocytoma ◽

The Central Nervous System ◽

The One

Abstract Primary meningeal melanocytomas are rare tumors of the central nervous system. Although they are considered benign neoplasms, some reports describe recurrent rates up to 45%. Little is known about their genetic and epigenetic landscape because of their infrequency. Even less has been described about markers with prognostic value. Here we describe a patient who developed a primary meningeal melanocytoma, suffered 3 recurrences in a period of 6 years and died of the tumor. The genetic and epigenetic changes explored confirmed GNAQ mutation as an initiating event. We found an epigenetic alteration of GSTP1, a feature that has recently been described in meningiomas, from the beginning of the disease. In addition, there was loss of heterozygosity in BRCA1 beginning in the second recurrence that was linked to an increase in the proliferation index; this suggested a progression pathway similar to the one described in uveal melanomas. These findings underscore the necessity of further research focused on these tumors.

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Progesterone Receptors and Neural Development: A Gap between Bench and Bedside?

Endocrinology ◽

10.1210/en.2008-0049 ◽

2008 ◽

Vol 149 (6) ◽

pp. 2743-2749 ◽

Cited By ~ 32

Author(s):

Christine K. Wagner

Keyword(s):

Neural Development ◽

Potential Role ◽

Progesterone Receptors ◽

Basic Research ◽

Future Research ◽

Clinical Use ◽

Critical Periods ◽

Cell Layers ◽

Brain And Behavior ◽

The Brain

Despite a recent increase in the clinical use of progesterone in pregnant women and premature neonates, very little is understood about the potential role of this hormone and its receptors in neural development. Findings from rodent models indicate that the brain is indeed sensitive to progesterone during critical periods of development and maturation. Dramatic sex differences in progesterone receptor (PR) expression, in which males express higher levels of PR than females in specific regions, suggest that PR may play an important role in the sexual differentiation of brain and behavior and that the expression of PR may be one mechanism by which testicular hormones masculinize the brain. PR is also transiently expressed during fetal and neonatal development in areas of the brain associated with cognitive behaviors. PR protein and mRNA are expressed in pyramidal cell layers of perinatal cortex in an anatomically and developmentally specific manner, generating the intriguing hypothesis that progesterone is essential for normal cortical development. Basic research elucidating a potential role for progesterone and PR in developing brain is reviewed in light of the clinical use of this hormone. The necessity for future research integrating findings from the bench and the bedside is evident.

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