The homunculus (argument) is a pesky problem in cognitive science – a little guy who might suddenly appear when you propose a mechanism for decision making, spontaneous action or forethought etc. – and would take credit for the origination of the neural impulse. While there are many mechanistic models of decision making that have slain the little bugger – by invoking competition between past experience and memory as the source of new thoughts and ideas – one must always tread lightly, I suppose, to be wary that cognitive mechanisms are based completely in neural properties devoid of a homuncular source.
Still, the human mind must begin somewhere. After all, its just a ball of cells initially, and then a tube and then some more folds, layers, neurogenesis and neural migration etc. before maturing – miraculously – into a child that one day looks at you and says, “momma” or “dada”. How do these neural networks come into being? Who or what guides their development toward that unforgettable, “momma (dada)” moment? A somewhat homuncluar “genetic program” – whose instructions we can attribute to millions of years of natural selection? Did early hominid babies say “momma (dada)? Hmmm. Seems like we might be placing a lot of faith in the so-called “instructions” provided by the genome, but who am I to quibble.
On the other hand, you might find that the recent paper by Akhtar et al., “Histone Deacetylases 1 and 2 Form a Developmental Switch That Controls Excitatory Synapse Maturation and Function” [doi:10.1523/jneurosci.0097-09.2009] may change the way you think about cognitive development. The team explores the function of two very important epigenetic regulators of gene expression – histone deacetylases 1,2 (HDAC1, HDAC2) on the functionality of synapses in early developing mice and mature animals. By epigenetic, I refer to the role of these genes in regulating chromatin structure and not via direct, site-specific DNA binding. The way the HDAC genes work is by de-acetylating – removing acetyl groups – thus removing a electrostatic repulsion of acetyl groups (negative charge) on histone proteins with the phosphate backbone of DNA (also a negative charge). When the histone proteins carry such an acetyl group, they do NOT bind well to DNA (negative-negative charge repulsion) and the DNA molecule is more open and exposed to binding of transcription factors that activate gene expression. Thus if one (as Akhtar do) turns off a de-acetylating HDAC gene, then the resulting animal has a genome that is more open and exposed to transcription factor binding and gene expression. Less HDAC = more gene expression!
What were the effects on synaptic function? To summarize, the team found that in early development (neonatal mouse hippocampal cells) cells where the HDAC1 or 2 genes were turned off (either through pharmacologic blockers or via partial deletion of the gene(s) via lentivirus introduction of Cre recombinase) had more synapses and more synaptic electrical activity than did hippocampal cells from control animals. Keep in mind that the HDACs are located in the nucleus of the neuron and the synapses are far, far away. Amazingly – they are under the control of an epigenetic regulator of gene expression; hence, ahem, “epigenetic puppetmasters”. In adult cells, the knockdown of HDACs did not show the same effects on synaptic formation and activity. Rather the cells where HDAC2 was shut down showed less synaptic formation and activity (HDAC1 had no effect). Again, it is amazing to see effects on synaptic function regulated at vast distances. Neat!
The authors suggest that the epigenetic regulatory system of HDAC1 & 2 can serve to regulate the overall levels of synaptic formation during early cognitive development. If I understand their comments in the discussion, this may be because, you don’t necessarily want to have too many active synapses during the formation of a neural network. Might such networks might be prone to excitotoxic damage or perhaps to being locked-in to inefficient circuits? The authors note that HDACs interact with MecP2, a gene associated with Rett Syndrome – a developmental disorder (in many ways similar to autism) where neural networks underlying cognitive development in children fail to progress to support higher, more flexible forms of cognition. Surely the results of Akhtar et al., must be a key to understanding and treating these disorders.
Interestingly, here, the controller of these developmental phenotypes is not a “genetic program” but rather an epigenetic one, whose effects are wide-spread across the genome and heavily influenced by the environment. So no need for an homunculus here.