Study Finds Neuronal Basis of Age-Related Cognitive Decline in Prefrontal Cortical Networks

A recent paper in Nature reveals the cellular basis of age-related cognitive decline.

Dr. Amy Arnsten, member of the Yale Kavli Institute for Neuroscience (KIN), and her colleagues in the Yale Department of Neurobiology, performed the first recordings of prefrontal cortical (PFC) neurons from aged monkeys performing a spatial working memory task. They found a marked, age-related reduction in the persistent network firing that is essential for working memory, the building block of higher cognition. In contrast, PFC neurons that responded to visual events in the environment had normal firing rates, showing that age-related changes are most evident in the networks that must generate and sustain firing through their own recurrent connections.

Although the reduction in persistent network firing likely arises from a number of factors that change in the aging brain, e.g. loss of dendritic spines, the age-related dysregulation of cAMP signaling likely plays a large role, as persistent firing was normalized in aged PFC neurons when cAMP signaling was inhibited or when specific, cAMP-sensitive potassium channels were blocked.

Understanding the unique influences of cAMP signaling on higher cortical circuits arose from an earlier, KIN-supported venture showing that the strength of higher cortical network connections in the young adult PFC is dynamically modulated by cAMP regulation of potassium channel open state. Thus, increases in cAMP-PKA signaling can open potassium channels near network synapses, transiently weakening that network connection. This form of rapid neuroplasticity, termed Dynamic Network Connectivity, helps to shape the subset of cortical networks that are connected at any one time, thus sculpting the contents of working memory, our “mental sketch pad”. This mechanism provides great flexibility in our mental abilities, but also confers vulnerability when the process is dysregulated, e.g. due to genetic insults (causing mental illness), or as we age, as shown in the current Nature paper. Indeed, a computational model in the Nature paper by KIN member Xiao-Jing Wang shows that a mere 15% reduction in network strength is sufficient to reduce persistent firing to the degree observed in the aged monkeys. The unique dysregulation of cognitive networks with age may also explain why these higher cortical circuits are so vulnerable to neurodegeneration in Fronto-Temporal Dementia and Alzheimer’s Disease.

Other authors on the Nature paper include Yale Kavli Institute member Dr. Daeyeol Lee, first author Dr. Min Wang, and Drs. J. Mazer, Y. Yang and M. Laubach, Ms. N. Gamo and Ms. L. Jin.

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