Bruno G Berardino
Laboratorio de Neuroepigenética y Adversidades Tempranas, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires - IQUIBICEN (CONICET)
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Symposia
The epigenetic basis of behavior
Chairs
Epigenetics has been proposed as a link between environmental exposures and phenotypic outcomes regulating gene expression. Particularly, early life adversities can leave epigenetic marks in the genome that could explain the higher vulnerability to develop long term disorders and cases of resilience. In 2017 and 2019 SAN meetings, symposia covering epigenetics were held, and many Argentinian researchers showed their results. During this symposium, well-known experts and pioneers in the field of behavioral epigenetics from USA and Canada will show us their recent results about the epigenetic mechanisms involved in cognition, mood disorders and drug addiction both in animal models and human studies. Behavioral epigenetics is a relatively new area of research and the proposed symposium will allow the discussion and interaction with outstanding researchers to encourage the growth of this field in Argentina.
Speakers
NRSF in novel epigenetic programs that contribute to hippocampal memory deficits and neuronal stunting after early-life adversity
Tallie Z. Baram
Departments of Pediatrics, Anatomy / Neurobiology, Neurology, Developmental and Cell Biology; University of California-Irvine, US
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Early-life adversity (ELA) is linked with lifelong risk of cognitive and memory problems dementia, yet the responsible mechanisms remain unclear. We imposed ELA by rearing rat pups in simulated poverty, assessed hippocampus-dependent memory in adulthood and probed related changes in gene expression, the underlying transcriptional processes, and the consequent disrupted hippocampal development. Adult ELA rats had poor hippocampus-dependent spatial memory and stunted hippocampal dendritic trees. RNA-seq identified ~140 differentially expressed genes. Bioinformatics uncovered glucocorticoid receptor and, unexpectedly, the transcription factor neuron-restrictive silencer factor (NRSF/REST) as putative upstream regulators. To examine the role of NRSF in the mechanisms of ELA-induced memory problems, we transiently blocked the binding of NRSF to the chromatin. Blocking NRSF function immediately after the ELA period rescued both spatial memory and the impoverished dendritic structure of hippocampal neurons in ELA rats. Blocking NRSF function in vitro augmented dendritic complexity of developing hippocampal neurons, suggesting that NRSF represses genes involved in neuronal maturation. These findings establish a novel, surprising contribution of NRSF to ELA-induced transcriptional programming which disrupts neuronal maturation. The repression of neuron-specific genes might be adaptive, promoting cell survival by reducing high energetic cost of neuronal differentiation and activity.
Molecular adaptations to early-life adversity: Insight from human postmortem brain studies
Gustavo Turecki
Department of Psychiatry, McGill University, Montreal, Canada
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Suicide is a complex behaviour that frequently associates with a history of early-life adversity. Dr. Turecki’s talk will discuss how adversity during childhood may differentially regulate molecular processes in the brain and increase lifetime risk of suicide. He will present data from his laboratory suggesting that specific biological pathways are regulated by the early-life environment through diverse epigenetic processes, which may contribute to suicide risk by differentially adjusting behavioural trait and emotional development, as well as influencing cognitive function. A conceptual framework to understand suicide risk among individuals exposed to early-life adversity will be presented.
Epigenetics Effects of Stress
Frances A Champagne
Department of Psychology, University of Texas at Austin
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Exposure to stress during development can shape a broad range of phenotypic outcomes. In addition to programming response to stressors, these early experiences shape later cognitive and social behaviors. Endocrine, neurobiological and molecular studies suggest that the quality of the early environment – particularly qualities indicative of stress or threat – can have lasting effects on multiple biological systems. Epigenetic changes induced by these environmental exposures may mediate the link between stress and phenotypic outcomes. We have examined the epigenetic, neurobiological and behavioral consequences of early life stressors in rodents with correlational studies also conducted in humans. Prenatal stress is associated with increased stress responsivity, altered neurodevelopmental trajectories and impairments in social/reproductive behaviors. These phenotypic outcomes are predicted by epigenetic variation in the placenta and associated with region-specific changes in gene expression and DNA methylation in the brain. Postnatal exposure to low vs. high stress environments is predictive of reduced maternal behaviour and impaired cognition in later life. Altered DNA methylation of hormone sensitive genes may account for these effects. Future work on the phenotypic outcomes and the molecular mechanisms that shape these outcomes may provide further insights into the within and across-generation emergence of stress-induced behavioral strategies.
Role of TET methylated DNA cytosine dioxygenase in addiction
Jian Feng
Department of Biological Science, Program in Neuroscience, Florida State University, Tallahassee, FL 32306, USA
The role of DNA methylation in drug addiction has been increasingly appreciated. Recently, additional forms of DNA epigenetic modifications have been identified through the oxidation of methylated DNA cytosine via TET dioxygenases (TET1, TET2, TET3). However the functional role of TETs in addiction remains largely unknown. We have found that TET1 in the nucleus accumbens (NAc), a key brain reward region, is implicated in cocaine action. In the NAc, there are two major types of medium spiny neurons (MSN), which are classified based on their distinct projections and gene expressions, including enrichment of dopamine D1 and D2 receptors. Though D1- and D2-MSNs are intermingled with similar morphology, they demonstrate different (and often opposite) roles in drug addiction. To identify TET1’s cell type specific functions, we generated the D1- and D2-MSN specific Tet1 knockout mice and characterized their addiction behaviors by using cocaine conditioned place preference and intravenous self-administration. We found that TET1 not only plays opposite roles in D1- and D2-MSNs in cocaine addiction, its effect is also sex-specific. We have been performing whole genome bisulfite sequencing to illustrate TET1 mediated DNA methylation changes in D1- and D2-MSNs. To gain more insight of the DNA epigenetic basis of addiction, we are continuing to explore the role of TET dioxygenases in other aspects of addiction, such as susceptibility difference.