A working model indicating that energy metabolism and neuronal activity are tightly coupled. NMDAR (NR1 and NR2B) (Dhar and Wong-Riley, 2009), COX subunits (Dhar et al., 2008) and Nos1 (present study) are all co-regulated by the same transcription factor, NRF-1. A downstream mediator of NOS1 pathway, guanylyl cyclase, also has a potential NRF-1 binding site. Thus, NRF-1 is intimately associated with the coordinated regulation of energy metabolism as well as key neurochemicals associated with a major glutamatergic synaptic pathway in neurons.