Abstract Epigenetica

ABSTRACT:Small non-coding RNAs (sncRNAs) are potential vectors at the interface between genes and environment. We found that traumatic stress in early life altered mouse microRNA (miRNA) expression, and behavioral and metabolic responses in the progeny. Injection of sperm RNAs from traumatized males into fertilized wild-type oocytes reproduced the behavioral and metabolic alterations in the resulting offspring.
Isabelle M Mansuy Nature Neuroscience 17,667–669,(2014)doi:10.1038/nn.3695

Vogel-Ciernia A, Wood MA Neuropharmacology. 2014 May;80:18-27. doi: 10.1016/j.neuropharm.2013.10.002. Epub 2013 Oct 15.
Long-term memory formation requires the coordinated regulation of gene expression. Until recently nucleosome remodeling, one of the major epigenetic mechanisms for controlling gene expression, had been largely unexplored in the field of neuroscience. Nucleosome remodeling is carried out by chromatin remodeling complexes (CRCs) that interact with DNA and histones to physically alter chromatin structure and ultimately regulate gene expression. Human exome sequencing and gene wide association studies have linked mutations in CRC subunits to intellectual disability disorders, autism spectrum disorder and schizophrenia. However, how mutations in CRC subunits were related to human cognitive disorders was unknown. There appears to be both developmental and adult specific roles for the neuron specific CRC nBAF (neuronal Brg1/hBrm Associated Factor). nBAF regulates gene expression required for dendritic arborization during development, and in the adult, contributes to long-term potentiation, a form of synaptic plasticity, and long-term memory. We propose that the nBAF complex is a novel epigenetic mechanism for regulating transcription required for long-lasting forms of synaptic plasticity and memory processes and that impaired nBAF function may result in human cognitive disorders.

Highlights

• Neurons contain aspecificchromatin remodeling complex (nBAF).
• nBAFis required for dendritic arborization and spine formation.
• BAF53bis a critical neuron-specific subunit of nBAF.
• BAF53bis required for long-term memory, long-term potentiation and gene expression in the adult.
• Mutations in nBAF subunits are linked tointellectual disability,autism, and schizophrenia.

Intact social memory forms the basis of meaningful interactions between individuals. Many factors can modulate the quality of social memory,

and these have been studied in detail in rodents. Social memory, however, cannot be considered a single entity.
The term social memory reflects different processes, such as social recognition of a novel conspecific individual and social learning (or ‘learning from others’).
This review summarizes the findings obtained with behavioral paradigms that were developed for the study of memory formation by social recognition and social learning.
In particular, we focus on studies that include tests for social habituation/discrimination paradigms, tests for memory of a previously established social hierarchy and the social transmission of the food preference test. The role of individual differences and the main neurobiological mechanisms (i.e., the brain regions and neurochemical systems involved) that have been implicated in each of these types of social-related memories are reviewed.
In addition, we address the key modulatory influence of stress on the formation of these types of memories; discussing the contribution of central
(corticotropin-releasing factor, CRF) and peripheral (glucocorticoids) stress systems and their interactions with the social neuropeptide systems.
Overall, we present here a general overview of the current state of a thriving research area within the field of social neuroscience.

Highlights

► There are important individual differences in social memory abilities.
► Social recognition memory and learning from others in rodents engage different neural systems, the former relying in the olfactory bulb, the medial amygdala and the lateral septum, while the latter in the hippocampus and neocortex.
► Stress is a potent modulator of social memory formation.
► Glucocorticoids can potentiate memory for social hierarchy.

Epigenetic regulation has been long considered to be a critical mechanism in the control of key aspects of cellular functions such as cell division,
growth, and cell fate determination. Exciting recent developments have demonstrated that epigenetic mechanisms can also play necessary roles
in the nervous system by regulating, for example, neuronal gene expression, DNA damage, and genome stability.
Despite the fact that postmitotic neurons are developmentally less active then dividing cells, epigenetic regulation appears to provide means
of both long-lasting and very dynamic regulation of neuronal function. Growing evidence indicates that epigenetic mechanisms
in the central nervous system (CNS) are important for regulating not only specific aspects of individual neuronal metabolism
but also for maintaining function of neuronal circuits and regulating their behavioral outputs.
Multiple reports demonstrated that higher-level cognitive behaviors, such as learning and memory, are subject to a sophisticated epigenetic control,
which includes interplay between multiple mechanisms of neuronal chromatin modification.

Experiments with animal models have demonstrated that various epigenetic manipulations can affect cognition in different ways,
from severe dysfunction to substantial improvement. In humans, epigenetic dysregulation has been known to underlie a number of disorders
that are accompanied by mental impairment. Here, we review some of the epigenetic mechanisms that regulate cognition and how their disruption
may contribute to cognitive dysfunctions. Due to the fact that histone acetylation and DNA methylation are some of the best-studied
and critically important epigenomic modifications our research team has particularly strong expertise in, in this review, we are going to concentrate
on histone acetylation, as well as DNA methylation/hydroxymethylation, in the mammalian CNS.
Additional epigenetic modifications, not surveyed here, are being discussed in depth in the other review articles in this issue of Neuropharmacology **.

Highlights

• Epigenetic regulation is critical for learning and memory.
• DNA methylation and histone acetylation are critically important modifications.
• Mouse models have been instrumental in neuroepigenetic research.
• Disruption of DNA methylation and histone acetylation can lead to cognitive abnormalities.
• Epigenetic therapies should contribute to treating cognitive impairments.

Genetic variants linked to autism spectrum disorders (ASD) may have been positively selected during human evolution because they also contribute to enhanced cognition a new Yale study suggests.

 A genome-wide association study of ASD of more than 5,000 cases and an analysis of evolutionary gene selection showed that inherited variants linked to ASD were found under positive selection in larger numbers than would have been expected by chance.

 Variants that have a large negative impact on reproductive success are generally eliminated from the population quickly. However, common variants that occur with high frequency but small effect can cumulatively have big impacts on complex inherited traits — both positive and negative. If variants provide a better chance of survival, they are positively selected, or tend to stay in the genome through generations.

 “In this case, we found a strong positive signal that, along with autism spectrum disorder, these variants are also associated with intellectual achievement,” said Renato Polimanti, associate research scientist at Yale School of Medicine and VA Connecticut Health Center in West Haven, and first author of the paper.

For instance, many of the positively selected variants associated with ASD identified by the researchers were enriched for molecular functions related to creation of new neurons.

 “It might be difficult to imagine why the large number of gene variants that together give rise to traits like ASD are retained in human populations — why aren’t they just eliminated by evolution?” said Joel Gelernter, the Foundations Fund Professor of Psychiatry, professor of genetics and of neuroscience, and co-author. “The idea is that during evolution these variants that have positive effects on cognitive function were selected, but at a cost — in this case an increased risk of autism spectrum disorders.”

 The final version of the paper was published Feb. 27 in the journal PLOS Genetics.

 Widespread signatures of positive selection in common risk alleles associated to autism spectrum disorder by Renato Polimanti and Joel Gelernter in PLOS Genetics. Published online February 10 2017 doi:10.1371/journal.pgen.1006618

In the current paper, we describe the first voxel-level pair-wise whole brain comparison of resting state functional connectivity differences between subjects with autism and controls.
For this we needed a large number of autistic people and controls, and were able to use for this analysis data in a large resting state functional MRI data set, the autism brain imaging data exchange (ABIDE; http://fcon_1000.projects.nitrc.org/indi/abide/), which has already proved useful (Di Martino et al., 2014).The pair-wise voxel-level analysis presented here goes beyond previous studies because it assesses, across the whole brain, which pairs of voxels have different functional connectivity between subjects with autism and controls.

In conclusion, we have described the first pair-wise voxel-level analysis of functional connectivity in autism, made possible by the great efforts put into acquiring the data in the ABIDE database, which we fully acknowledge and appreciate.

We have identified a key system in the MTG/STS sulcus region that has reduced functional connectivity with other cortical areas (and increased connectivity with the medial thalamus), which is implicated in face expression and motion processing involved in social behaviour, and which has onward connections to the orbitofrontal cortex/ventromedial prefrontal cortex. The same system is implicated in theory of mind processing, and in audio-visual integration for e.g. speech, and possibly in further aspects of communication using language.
We have identified a second main system with reduced cortical connectivity in autism, the ventromedial prefrontal cortex (ORBsupmed), which itself is implicated in emotion and social communication by virtue of its reward and punishment, including face expression, processing (Rolls, 2014). Its reduced connectivity includes its connectivity with both the MTG regions implicated in face expression and theory of mind processing, and the precuneus/cuneus region involved in the sense of self.We have identified a third key system in the precuneus/superior parietal lobule (including paracentral lobule) region with reduced functional connectivity which is implicated in spatial functions including of oneself, and of the spatial environment, and have suggested that this provides an important contribution to theory of mind processing, which is impaired in autism.

The hypothesis that we have in mind is that these types of functionality, face expression-related, and of one’s self and the environment, are important components of the computations involved in theory of mind, whether of oneself or of others, and that reduced functional connectivity within and between the components of this circuitry may make a major contribution to the symptoms of autism.The reduced functional connectivity could reflect reduced connection strengths within and between areas, or impaired functioning of one of more of the areas that leads to reduced functional connectivity.

To verify whether listening to classical music has any effect on human transcriptome, we performed genome-wide transcriptional profiling from the peripheral blood of participants after listening to classical music (n=48), and after a control study without music exposure (n= 15).
As musical experience is known to influence the responses to music, we compared the transcriptional responses of musically experienced and inexperienced participants separately with those of the controls.

In musically experiencd participants, we observed the differential expression of 45 genes (27 up- and 18 down-regulated) and 97 genes (75 up- and 22 down-regulated) respectively based on subphenotype comparisons …One of the most up-regulated genes,alpha-synuclein (SNCA), is located in the best linkage region of musical aptitude on chromosome 4q22.1 and is regulated by GATA2, which is known to be associated with musical aptitude.
Several genes reported to regulate song perception and production in songbirds displayed altered activities, suggesting a possible evolutionary conservation of sound perception between species.
We observed no significant findings in musically inexperienced participants.