Abstract
The putative link between gene expression of brain regions and their neural connectivity patterns is a fundamental question in neuroscience. Here this question is addressed in the first large scale study of a prototypical mammalian rodent brain, using a combination of rat brain regional connectivity data with gene expression of the mouse brain. Remarkably, even though this study uses data from two different rodent species (due to the data limitations), we still find that the connectivity of the majority of brain regions is highly predictable from their gene expression levels–the outgoing (incoming) connectivity is successfully predicted for 73% (56%) of brain regions, with an overall fairly marked accuracy level of 0.79 (0.83). Many genes are found to play a part in predicting both the incoming and outgoing connectivity (241 out of the 500 top selected genes, p-value<1e-5). Reassuringly, the genes previously known from the literature to be involved in axon guidance do carry significant information about regional brain connectivity. Surveying the genes known to be associated with the pathogenesis of several brain disorders, we find that those associated with schizophrenia, autism and attention deficit disorder are the most highly enriched in the connectivity-related genes identified here. Finally, we find that the profile of functional annotation groups that are associated with regional connectivity in the rodent is significantly correlated with the annotation profile of genes previously found to determine neural connectivity in C. elegans (Pearson correlation of 0.24, p<1e-6 for the outgoing connections and 0.27, p<1e-5 for the incoming). Overall, the association between connectivity and gene expression in a specific extant rodent species' brain is likely to be even stronger than found here, given the limitations of current data.
Highlights
Genes play a major role in the formation of the nervous system and in its continuous function
This association has been explored in two model animals: the worm C. elegans at the level of single neurons; and the mouse, where specific subpopulations of neurons in the hippocampus were studied
Our results show a higher degree of association between connectivity and expression than shown before, and key genes are identified that are highly predictive of brain connectivity
Summary
Genes play a major role in the formation of the nervous system and in its continuous function. Inspired by Roger Sperry’s classical chemo-affinity hypothesis that states that neuronal wiring takes place by selective attachment guided by specific molecular identifiers, a large array of studies have described various gene families that are involved in axonal guidance and in determining their specific targets (see [3,4,5,6,7] for reviews) Another central paradigm has posited that a central driving force in determining synaptic connectivity are activitydependent mechanisms, by which synapses are formed between neurons whose firing tends to be correlated in a self-organizing Hebbian manner (see [8,9] for reviews). These paradigms are obviously not mutually exclusive and are likely to concur concomitantly, and quantifying the extent of association between gene expression and connectivity may provide global constraints on their relative contribution
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