Cellular metabolism alters patterns of gene expression through a variety of 
mechanisms, including alterations in histone modifications and transcription 
factor activity. Nicotinamide adenine dinucleotide (NAD)-dependent proteins such 
as poly(ADP ribose) polymerases (PARPs) and sirtuin deacetylases play important 
roles in this regulation, thus NAD provides a crucial link between metabolism 
and these cellular signaling processes. Here, we found that lowering NAD levels 
in mouse primary cortical neurons led to decreased activity-dependent BDNF 
expression. The altered BDNF transcription occurred independently of Sirt or 
Parp activities; instead, low NAD levels promoted increased DNA methylation of 
the activity-dependent BDNF promoter. Increased methylation at this promoter 
triggered the dissociation of the insulator protein CTCF as well as the 
accompanying cohesin from the BDNF locus. The loss of these proteins resulted in 
histone acetylation and methylation changes at this locus consistent with 
chromatin compaction and gene silencing. Because BDNF is critical for neuronal 
function, these results suggest that age- or nutrition-associated declines in 
NAD levels as well as deficits in cohesin function associated with disease 
modulate BDNF expression and could contribute to cognitive impairment.