Conversely, multiple studies have shown a decrease in Homer1 expression, with aging suggesting that Homer1, and possibly other candidate sleep-pressure signaling Benzoylaconine systems, may serve as a lynch pin for discrepancies between young and aged sleep behavior and molecular profiles. Interestingly, with the exception of Homer 1 and Synaptogyrin 1, analysis focused on synapse-related gene expression points to aging’s similarity to SD’s influence. Future studies examining the influence of stress, stress hormone, and their Pimozide interaction with sleep and Homer1 expression with age may help to further clarify these issues. Overlapping genes were categorized by direction of change in aging and SD, as well as by putative function. Processes that changed with aging and were apparently recapitulated with SD included cell differentiation/apoptosis, energy, antioxidant and transcription factor activity. Among genes that disagreed between aging and SD, two that influence sensitivity to glucocorticoid, Chrbp and Fkbp4, were upregulated in SD and downregulated with age in the present analysis. Changes in the expression of these candidate molecules may dampen glucocorticoid’s influence on immune/inflammatory and glial activity 
with age. Intriguing parallels to work on other steroid hormones, suggest that, with age, the brain may shift its response to glucocorticoids. Whether such mechanisms may involve nuclear or non-nuclear receptor pathways remains to be determined. Two sleep-related genes, Per2 and Homer1, were suppressed with age but upregulated with SD. Per2 is a circadian clock gene upregulated in prior SD studies as well as in our NES treatment group, suggesting it may not be a purely SD-related finding. Homer1 was among the few genes that showed a linear increase with extended SD and was not influenced by NES. Further, multiple SD studies have also reported Homer1 upregulation with SD. Homer1 may play an important role in sleep pressure signaling. Because the brain exhibits less deep-sleep with age in both humans and animal models, we speculate that Homer1’s consistent downregulation with aging could constitute a broken molecular switch leading to a loss of deep sleep with age. Results point to a focused effect on mRNA associated with synaptic function. We constructed an idealized hippocampal glutamatergic synapse, and superimposed SD profile results. Gene products were identified using literature and ontology database searches: 46 were significantly altered by sleep deprivation- the majority downregulated. Results suggest SD-induced synaptic efficacy and macromolecular synthesis changes, consistent with previous work. In keeping with the proposed mechanisms of action for current SD countermeasures, there appears to be a deficit in glutamatergic signaling with SD. Interestingly, Chga upregulation has been reported to suppress presynaptic vesicular release components and may, at least in part, play an upstream role in mRNA expression changes associated with the pre-synapse. This may help to explain how SD-countering drugs can exert their effects and highlights the potential clinical importance of astrocytic, orexinergic and adrenergic systems. Results also suggest that drugs facilitating Ca2+-dependent vesicular release, neurotransmitter re-uptake block may counter SD’s effects. Among newer agents, the ampakine CX717 is proposed to exert its wake-promoting effects via enhanced glutamatergic signaling. Conversely, drugs that constrain neuronal activity via: reduced sustained high frequency repetitive discharge; enhanced inhibitory surround; or disrupted vesicular release facilitate sleep.