ALZHEIMERS RESEARCH PROJECT: Neurocognitive Aging: Experience-Dependent Dynamics, Plasticity and Network Contributions

National Institute On Aging

Investigators

Linked publications & trials

Abstract

Cumulative project results suggest that circuit selective vulnerabilities drive disrupted neural network dynamics, comprising the proximal basis of age-related cognitive impairment. Growing evidence also implicates network-level adaptive reorganization among processes that support reserve and resilience against cognitive aging and AD. Insights in this area include indications that a wide distribution of brain regions, including the cerebellum – long overlooked beyond its roles in motor function – is both vulnerable to aging and participates in a surprising array of cognitive capacities. Recent project efforts have begun to address this gap in translational studies across animal models and humans. For example, in a previous neuroimaging analysis we reported that the brain-wide pattern of regional volumetric correlations with recognition memory seen in young monkeys is substantially reorganized in aged animals, prominently involving the cerebellum in addition to areas more traditionally linked with memory function (i.e., medial temporal lobe and prefrontal cortex). These findings prompted a related investigation using longitudinal data from the Baltimore Longitudinal Study of Aging to test for predictive validity in human aging. The experiments differed in important ways, but in broad strokes yielded results consistent with the preclinical animal data demonstrating significant age-related change in cerebellar volumetric associations with memory. Taking a reverse translational approach encouraged by results from monkeys and humans, another project effort turned to an established rat model to explore a cellular account of cerebellum vulnerability in cognitive aging. The initial target was Purkinje cell (PC) integrity, i.e., neurons that originate the sole output of the cerebellar cortex, and that when damaged cause a variety of behavioral abnormalities. We found that while total PC number remains stable in the aged cerebellum, regardless of subjects’ memory status, the regional pattern of correlations observed in young animals between memory and PC number was lost in the aged cerebellum. Corresponding biochemical analysis revealed that levels of two PC-specific proteins, measured in whole cerebellum homogenates, were decreased selectively in aged rats with spatial memory impairment. PC protein marker levels were also correlated with individual differences in memory among the aged animals. The specific proteins examined in this analysis (calbindin-D28k and pcp-2) share related functions, pointing to a possible mechanism of age-related vulnerability in cerebellum involving altered intracellular calcium kinetics. Together the work underscores the translational relevance of cerebellum vulnerability, and the bidirectional potential of the comparative perspective underlying the project. Social engagement and connectedness powerfully influence disease risk and other health outcomes in aging. Basic research on neurobiology of social cognition has advanced tremendously over the last decade, revealing at least a rudimentary outline of neural systems and neurochemical circuitry involved. How aging and the social brain interact has received limited attention, however, and there is currently very little basic science in animal models probing the underlying neurobiology of social cognition in old age. As a starting point, recent project efforts leveraged our established rat model of age-related memory impairment as a foundation for exploring the social neuroscience in cognitive aging. Key findings demonstrate that while young and aged animals exhibit significant and equivalent preference for social interaction with a conspecific over a non-social stimulus, on average they fail to display the striking preference for social novelty seen in young animals. Indeed a substantial proportion of aged rats exhibit a phenotype never observed in young subjects, i.e., a robust preference for interacting with a familiar rat over a novel animal. These effects were also entirely uncoupled from individual differences in spatial memory, demonstrating that at least some features of social cognition are vulnerable to aging in rats independent of other prominent cognitive outcomes. Extending these findings, neuromodulation via transcranial magnetic stimulation selectively enhanced social novelty preference in aged rats that displayed a familiarity preference prior to intervention, suggesting an underlying phenotype-specific neural mechanism. Together, novel findings from this project establish a foundation for pursuing the social neurobiology of cognitive aging.