Project 1- Aged animals and humans exhibit working memory deficits and increased vulnerability todistraction. 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 recordfrom ensembles of PFC neurons in young vs. aged monkeys performing working memory tasks, to assessPFC circuit strength with advancing age. Circuit connectivity will be assessed at multiple time scales, usingnoise correlation, cross-correlation and wavelet cross-spectrum analysis. It is hypothesized that neuronsfrom aged monkeys will show reduced measures of functional connectivity.
Aim 2 will probe the ability ofPFC networks to maintain information in the presence of cognitive challenges, ie whether cells can maintaindelay-related firing despite increasing delays or distractors. Behavioral data in aged monkeys and humanssuggest that PFC neurons in aged animals will be less able to maintain delay-related firing in the presence ofdistractors or over an extended delay.
Aim 3 will examine the neurochemical mechanisms contributing tocircuit weakness with advancing age, by determining whether PFC neurons in aged monkeys are especiallyvulnerable to increased cAMP activity, and whether youthful patterns of functional connectivity can berestored 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 whenopened by cAMP. Recent physiological data from young monkeys have shown that delay-related firing isdramatically 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 stimulationstrengthens delay-related firing. These data have direct relevance to age-related PFC deficits, as agedanimals have (1) increased cAMP signaling, as evidenced by immunocytochemical and pharmacologicalmethods, and (2) reduced a2-adrenoceptor binding. This research will provide the first electrophysiologicalexamination of the PFC in aged monkeys performing cognitive tasks. These studies will allow us to observethe cellular basis for weakened PFC cognitive functioning in advancing age. LAY SUMMARY: Project 1 willdetermine whether brain networks weaken with age, and if drugs can restore connectivity.
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