Age-Related Changes in the Prefrontal Cortex Associate with Loss of Memory
Researchers here investigate age-related changes correlating with loss of working memory. They work with mice, but produce results that line up with observations made in other species. How neural circuits function is one distinct way of looking at the brain. Like all such approaches, it is challenging to connect it to other distinct views of the aging brain, such as proteomic or transcriptomic or cell behavior or signaling changes, or the accumulation of specific forms of age-related molecular damage. Measuring one aspect of a complex system is one thing, figuring out how many different aspects fit together into a web of interacting causes and consequences is quite another.
Cognitive aging is the natural and gradual decline in cognitive function that occurs as people age and emerges as a major challenge for maintaining quality of life and employment. It is hence crucial to understand the neurobiology underlying cognitive aging in detail. Working memory (WM) decline is a fundamental aspect of cognitive aging and has the earliest onset among age-related cognitive deficits. Executive function is susceptible to aging. How aging impacts the circuit-level computations underlying executive function remains unclear. Using calcium imaging and optogenetic manipulation during memory-guided behavior, we show that working-memory coding and the relevant recurrent connectivity in the mouse medial prefrontal cortex (mPFC) are altered as early as middle age.
Population activity in the young adult mPFC exhibits dissociable yet overlapping patterns between tactile and auditory modalities, enabling crossmodal memory coding concurrent with modality-dependent coding. In middle age, however, crossmodal coding remarkably diminishes while modality-dependent coding persists, and both types of coding decay in advanced age. Resting-state functional connectivity, especially among memory-coding neurons, decreases already in middle age, suggesting deteriorated recurrent circuits for memory maintenance. Optogenetic inactivation reveals that the middle-aged mPFC exhibits heightened vulnerability to perturbations. These findings elucidate functional alterations of the prefrontal circuit that unfold in middle age and deteriorate further as a hallmark of cognitive aging.