If you ever looked at the inside of a computer, you would find intricate wirings and connections. But the computer is essentially useless until you’ve downloaded all the necessary software and applications. In a way, this analogy could be applied to the workings of the brain. The brain is essentially a circuitry consisting of billions of neuronal connections (or synapses) that is infinitely more complex than the typical computer hardware.

Since the discovery of neuronal synapses by Santiago Ramon Y Cajal in the 1900s, ongoing research have shown that memory formation is the result of changes in synaptic size and number. But recently, scientists discovered that memory is encoded not only by the brain’s connectivity itself, but also by a complex “molecular software” within neurons and their connections.

This molecular software is composed of two basic components: 1) the epigenetic program and 2) the microRNA program. The epigenetic program is the basic molecular software required for neurons to undergo synaptic plasticity, which in a sense is very much like your computer’s basic operating system.

Recent studies by Dr. Guoping Fan at UCLA (published in Nature Neuroscience this month, Feng et al., 2010) revealed that memory formation requires epigenetic regulation of gene expression. Briefly, epigenetic regulation is essentially modification of DNA structure to regulate gene expression. DNA is normally tightly wound around proteins called histones, which compacts the DNA into individual chromatins in the nucleus.

In order to allow gene expression, the DNA structure needs to unwind to enable transcription factors to access the promoter region of the gene. The chromatin structure is regulated by addition of methyl groups on nucleic acids (known as DNA methylation), which in turn recruits chromatin-modeling proteins (such as histone deacetylase) to drive chromatin condensation and subsequent inhibition in gene expression. The “epigenetic program” in postmitotic neurons is defined as a distinct pattern of DNA methylation. Studies by Feng et al. (2010) revealed that transgenic mice carrying conditional knockout mutation of DNA methyltransferase (an enzyme that mediates DNA methylation) demonstrated not only marked reduction in synaptic plasticity, but also profound disability in memory tasks. The studies suggest that DNA methylation program is likely the basic operating system for memory formation in post-mitotic neurons.

The second critical component of the brain’s molecular software is the microRNA program or database, which functions as a platform to encode memory formation by fine-tuning protein expression in the synapses. Studies in 2006 by Dr. Gehrard Schratt in the University of Heidelberg revealed that small regulatory RNAs called microRNAs are enriched in synaptic structures in the mouse brain, and that perturbation of their expression could lead to profound reduction in synapse size and number (Schratt et al., 2006). This was soon followed by studies revealing that microRNAs appear to fine-tune the translation of proteins that influence synaptic structure and activity (Schratt review, 2009).

Importantly, microRNA expression is often regulated by neuronal activity, indicating that experiences or inputs in the form of nerve impulses are encoded as subtle microRNA changes at the level of the synapses. This in turn translates to subtle changes in protein translation at the synapse, where subsequent modification in synaptic structure and activity would reflect memory formation.

Overall, the human brain is not simply a complex network of neuronal connections. Like the computer, the brain cannot work without the necessary molecular software including the basic epigenetic operating system but also microRNA-encoding platform (or database). The discovery of this complex molecular software has now driven neuroscience research into a new level.

Neuroscientists are presently keen on understanding how this molecular software works, and in particular understand what goes wrong in neurological disorders.

References:

Feng J et al. Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons. Nat Neurosci. 13, 423-30 (2010).

Schratt, G. M. et al. A brain-specific microRNA regulates dendritic spine development. Nature 439,
283–289 (2006).

Schratt G. microRNAs at the synapse. Nat Rev Neurosci. 10(12), 842-9 (2009).