Project 1- Aged animals and humans exhibit working memory deficits and increased vulnerability to distraction. Working memory operations rely on reverberating networks of prefrontal cortical (PFC) neurons, whose recurrent excitation maintains information in the absence of sensory stimulation. Aim 1 will record from ensembles of PFC neurons in young vs. aged monkeys performing working memory tasks, to assess PFC circuit strength with advancing age. Circuit connectivity will be assessed at multiple time scales, using noise correlation, cross-correlation and wavelet cross-spectrum analysis. It is hypothesized that neurons from aged monkeys will show reduced measures of functional connectivity. Aim 2 will probe the ability of PFC networks to maintain information in the presence of cognitive challenges, ie whether cells can maintain delay-related firing despite increasing delays or distractors. Behavioral data in aged monkeys and humans suggest that PFC neurons in aged animals will be less able to maintain delay-related firing in the presence of distractors or over an extended delay. Aim 3 will examine the neurochemical mechanisms contributing to circuit weakness with advancing age, by determining whether PFC neurons in aged monkeys are especially vulnerable to increased cAMP activity, and whether youthful patterns of functional connectivity can be restored by inhibition of cAMP or blockade of HCN (Hyperpolarization-activated Cyclic Nucleotide-gated) channels. HCN channels are on dendritic spines, where they are positioned to gate synaptic inputs when opened by cAMP. Recent physiological data from young monkeys have shown that delay-related firing is dramatically weakened by treatments that increase cAMP activity and open HCN channels. Conversely, blockade of HCN channels with ZD7288, or inhibition of cAMP production via a2A-adrenoceptor stimulation strengthens delay-related firing. These data have direct relevance to age-related PFC deficits, as aged animals have (1) increased cAMP signaling, as evidenced by immunocytochemical and pharmacological methods, and (2) reduced a2-adrenoceptor binding. This research will provide the first electrophysiological examination of the PFC in aged monkeys performing cognitive tasks. These studies will allow us to observe the cellular basis for weakened PFC cognitive functioning in advancing age. LAY SUMMARY: Project 1 will determine whether brain networks weaken with age, and if drugs can restore connectivity.