Assessment of gene expression is a good place to start a quest for mechanisms of neural plasticity (McClung and Nestler, 2008). Of course, these mRNA and subsequent protein-level changes must eventually lead to synaptic alterations in order to have a role in neural adaptation. Nonetheless, the efficiency of large-scale transcription studies makes it a powerful initial approach. Although this strategy has been used extensively within the field of drug addiction (Robison and Nestler, 2011), few studies have systematically evaluated brain transcriptional adaptation in response to metabolic challenge.

We recently completed a microarray analysis to identify changes in gene expression in response to a brief (5 days) and moderate (<10% weight loss) reduction in food intake (Guarnieri et al, 2012). Analysis was conducted on RNA from four brain regions: ventral tegmental area, prefrontal cortex, hypothalamus and nucleus accumbens. Stress responsive genes were prominent in the list of genes that change after restriction, and corticosterone was shown to be necessary and sufficient for many of these changes. There were some surprises in these results that deserve emphasis: (1) the gene changes occurred rapidly (within the first 24 h of restriction) before any weight loss was apparent and (2) the expression changes detected were not restricted to one region, and usually were seen in 2–4 of the regions surveyed. This fast and universal response was not something that was anticipated, but is reasonable if a systemic factor such as corticosterone is the key signal. Finally, the changes seen were implicated in increased food motivation that occurred after restriction.

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