Until recently, the computational role of the brain was mostly seen as a series of rapid electrical and electrochemical events, such as spike coding, local field potentials and EEG rhythms. To this was added the discovery some 20 years ago, pioneered by Eric Kandel, of a complex web of second messenger systems that translate synaptic activation into the local modulation of synaptically relevant protein synthesis by transcription factors such as CREB (cAMP response element binding proteins). The past decade has witnessed an even greater development in our understanding of how a wide swathe of the brain's functions is controlled, in this case by a further battery of epigenetic factors. These include DNA and histone methylation and acetylation that switch genes on and off, a wide range of transcription factors exported beyond the synapse that produced them, the activity of a multitude of non-coding RNAs (including the microRNAs that block mRNAs) and carrier organelles for these epigenetic loads, such as exosomes.
Exosomes are small lipoprotein vesicles that are known to bud-off from all cells and carry payloads of selected molecules. During the 1980s, it was thought that their function was simply to remove unwanted molecules—the ‘garbage can’ hypothesis. Then, it was discovered that they actually carry a wide assortment of nucleic acids and proteins, in particular, transcription factors and a variety of RNAs, which suggested that their true function is intercellular communication. This observation triggered an ever-increasing flood of papers, as it has become apparent that exosomes are involved in a very wide variety of cellular functions leading to radical new methods of diagnosis and therapy, with particular relevance for cancer. In the nervous system, they afford the organism critically important functions in the context of neuronal specification, plasticity and information processing.
This Theme Issue presents a series of 18 selected reviews and original research from peer-acknowledged experts in their respective disciplines on some of the highlights in this nascent and rapidly developing field. Some of these contributions present an overarching survey or a large segment of it, while others provide for a deep dive into a particular aspect. In the former category, Smalheiser  describes the role of exosomes in synaptic function and their orchestration of synaptic plasticity. Qureshi & Mehler  provide an overview of the staggering complexity of the epigenetic mechanisms thus far discovered in the brain. Imamura et al.  discuss the role of epigenetic regulation in neural cell reprogramming, engineering and transplantation. Roberts et al.  offer us a broad perspective of the putative role of long non-coding RNAs in neurodevelopment and brain function, with an emphasis on the epigenetic regulation of gene expression. The role of DNA modifications in the context of epigenetics, and more specifically with regard to the mammalian brain, is presented by Shin et al. . An in-depth analysis of the role of microRNAs in synaptic plasticity and cognition, with a focus on neurological diseases, is given by Aksoy-Aksel et al. . Prochiantz et al.  describe the remarkable role played by the transcription factors Otx2 and Engrained in the neuroplasticity of midbrain dopamine cell function and GABAergic cells in the visual cortex.
Detailed reviews of particular themes are as follows:
— the role of exosomes as causative factors and diagnostic tools in traumatic brain injury ;
— the differential role of microvesicles, exosomes and tunnelling microtubules in interneuronal communication ;
— the role of miRNAs in cerebellar climbing fibre interactions with Purkinje cells ;
— the role of histone H3K4 methylation and epigenetic risk architectures in neurodevelopmental disorders such as autism and schizophrenia ;
— the function of extracellular vesicles and exosomes in cellular homeostasis with foci on the intercellular transfer of misfolded proteins, signals that control inflammation and their role in neuropathology and drug delivery ; and
— the presentation of specific hypotheses as to the mode of operation of exosomes and their payloads, and of Otx2 in synaptic plasticity and information processing in the brain .
In addition, we are fortunate to include the following five original research papers among our broad array of 18 contributions, thus affording our readers a virtual entrée into laboratories at the forefront of this rapidly advancing field:
— the clinical use of exosome cargo analysis in a diagnostic and biomarker capacity, and of exosomes themselves in therapy ;
— the modulation of mRNA stability during synaptic plasticity involving 3′-UTRs and specific miRNAs regulating networks of genes important for neural plasticity and development ;
— the action of exosomes derived from oligodendroglia on neurons involving redox mechanisms, the modulation of neuronal firing rates and the differential expression of genes and altered signal transduction pathways ;
— the role of maternal care on the epigenetic state and transcriptional activity of the glucocorticoid receptor in the fetal hippocampus and its molecular mechanism ; and
— a detailed analysis of the role of microRNAs in synaptogenesis specific to the neuromuscular junction in Drosophila via the coordinated regulation of pre- and post-synaptic cell adhesion molecules .
It is no exaggeration to state that the subjects discussed in this Theme Issue have revolutionized our view of how the brain works in both health and disease, especially where these insights have radically altered our understanding of the molecular components of life-threatening maladies and have suggested rewarding lines of diagnosis and treatment which are just beginning to be realized.
One contribution of 19 to a Theme Issue ‘Epigenetic information-processing mechanisms in the brain’.
- © 2014 The Author(s) Published by the Royal Society. All rights reserved.